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Glomerulonephristis, histology and classification

The document outlines various glomerular diseases, their classification, etiology, histological findings, and management options. It emphasizes specific conditions such as acute proliferative glomerulonephritis, minimal change disease, focal segmental glomerulosclerosis, and membranous nephropathy, detailing their clinical presentations, underlying pathophysiology, and treatment strategies. The potential for new therapeutic approaches aimed at enhancing podocyte protection and reducing proteinuria is also discussed.

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GLOMERULAR DISEASES Prof Olutayo Alebiosu Osun State University BSc, MBChB, FWACP
Objectives • Participants able to review the classification of glomerular diseases • Participants able to discuss the etiology of glomerular diseases. • Participants able to highlight the histological findings associated with glomerular diseases. • Participants able to outline the management considerations for the different diseases grouped under the term 'glomerulonephritis.' •
Introduction • Numerous inflammatory and non inflammatory diseases affect the glomerulus and lead to alterations in glomerular permeability, structure and function. • However, not all glomerular diseases is caused by GN and other causes need to be considered in its differential diagnosis including diabetic nephropathy, amyloidosis and hereditary nephropathies including Alports syndrome
Introduction – Pathogenesis • In GN, the dominant histologic lesions are in the glomeruli, at times described as focal or diffuse; may be segmental or global. • Lesions may also be hypercellular due to either an increase in endogenous endothelial or mesangial cells – proliferative, and / or to an infiltration of inflammatory leukocytes – exudative changes. • Severe acute inflammation may produce glomerular necrosis, which is often segmental. • Crescents may develop which are inflammatory collections of cells in Bowmans space, and consist of proliferating parietal and visceral epithelial cells, infiltrating fibroblasts, lymphoblasts and monocytes/macrophages, often with local fibrin deposition.
Introduction – Pathogenesis and Classification • Indirect immunofluorescence and immunoperoxidase staining are both used to identify immune reactants, looking for the deposition of immunoglobulins IgG, IgA, and IgM, for components of both the classical and alternative pathways of complements – usually C3, C4 and C1q, and for the presence of fibrin. • Granular deposits in glomerular are called immune complexes which are local formation of antigen/antibody complex in the glomerulus.
Acute Proliferative Glomerulonephritis
• This condition is characterized histologically by diffuse proliferation of glomerular cells, associated with influx of leucocytes, typically caused by immune complexes. The inciting antigen may be exogenous or endogenous. • The prototype exogenous antigen-induced disease pattern is post-infectious glomerulonephritis. • APGN has mainly two types- • Post-streptococcal Glomerulonephritis • Non-Streptococcal Glomerulonephritis
Poststreptoccocal Glomerulonephritis • Produces the nephritic syndrome (hematuria, red cell casts, moderate proteinuria and edema) in children two weeks following a respiratory or skin infection with a "nephritogenic strain" of group A, beta-hemolytic streptococci. • Clinically, this disease is manifested by a rather abrupt onset of gross hematuria, edema, proteinuria, hypertension and impaired renal function. • The serum levels of hemolytic complement activity and C3 protein are abnormally reduced.
Poststreptoccocal Glomerulonephritis • Latent period between infection and onset of nephritis is compatible with the time required for the production of antibodies and formation of immune complexes. • There is deposition of circulating immune complexes which fix complement and attract PMN's. • This chokes off their blood supply, making the glomeruli hypercellular and bloodless. • This explains the oliguria, edema, and hypertension; 2% to 5% patient die during acute episode.
Acute Proliferative GMN - LM
Acute Proliferative GMN - Immunofluorescence
Acute Proliferative Glomerulonephritis - EM
Acute Proliferative Glomerulonephritis
Minimal Change Disease
Introduction Minimal Change Disease is a glomerular disorder that leads to the sudden onset of nephrotic-range proteinuria with edema of the extremities and face, hypoalbuminemia. Others: hyperlipidemia, hypercoagulability.
Epidemiology • Race: Asians may be at increased risk. • Sex: twice as frequently in boys than in girls. Same in both sexes in adulthood. • Age: incidence peaks in children aged 2 years (approximately 80% are below 6 years at the time of diagnosis). • In adults, the mean age of onset is 40 years.
Types: Primary or Secondary Secondary: 10 to 15% Drugs: •NSAIDs and selective COX-2 Inhibitors •Antimicrobials (ampicillin, rifampicin, cephalosporins) •Lithium •D-penicillamine, sulfasalazine (any 5-ASA derivative) •Pamidronate (and presumably other bisphosphonates) •Gamma interferon •Immunizations Neoplasia: •Hodgkin Lymphoma (0.4%) •Non-Hodgkin Lymphoma and Leukemia •Cases of MCD are rarely associated with solid tumors •MCD diagnosis may precede signs and symptoms of the malignancy •Proteinuria typically resolves with treatment of the malignancy
Minimal change disease - secondary Infections: Rare associations with syphyllis, tuberculosis, mycoplasma, Hep C, echinococcus MCD has been described in HIV infection but collapsing FSGS much more commonly seen Allergy Associations: •History of allergy described in up to 30% of cases •Multiple allergens described (fungi, cat fur, poison ivy, pollen, bee stings, house dust) •Onset and relapses have been triggered by bee stings and allergic reactions •Limited evidence for involvement of food allergy
Association with Glomerular Diseases •Association with IgA Nephropathy, with mesangial IgA deposits and mild mesangial proliferation seen in concurrence with MCD on biopsy •There are reports of MCD also occur with the following conditions, but rare: – Systemic Lupus Erythematosus – Type 1 Diabetes – Polycystic Kidney Diseases Minimal change disease - secondary
Pathology The pathological/histological features distinguish the various forms of NS. •LM: not much different from normal glomeruli but in some cases there are some increase in cells or deposition of mesangium noted. •IM: no antibody deposits •EM: shows the characteristic foot process effacement
Minimal change disease • Accounts for 80% of all cases of the idiopathic nephrotic syndrome in children. • Majority of cases are seen in 3 - 4 year age groups. • Male predominance of 2.5:1 in children but no difference seen in adults. • 80-90% idiopathic. • Associated with infectious diseases, recent immunization, ingestion of heavy metals. • In adults, also related to use of NSAIDS.
Minimal change disease • The most common presentation is a full blown nephrotic syndrome with heavy proteinuria often of selective type. • On light microscopy, changes may be seen in the convoluted tubules where large amounts of lipid and protein droplets accumulate in the cell cytoplasm (lipoid nephrosis) • In contrast all the glomeruli appear normal.
MCD – Light Microscopy Glomerulus is normocellular, capillary loops are patent, & the BM is normal in thickness
MCD - Immunofluorescence No deposits of complement or immunoglobulins seen in IF. (nil deposit disease)
MCD – Electron microscope Portion of a glomerulus from a patient with MCD showing obliteration of foot processes. The epithelial cell cytoplasm is hyperactive and shows microvillus and cyst formation.
Work up • Laboratory Studies: - diagnosis - monitoring - complications - biopsy - steroid therapy • Imaging Studies • Biopsy and histology
Treatment • Currently available therapies • New approaches with available drugs • Selected novel pathways that have been found to mediate podocyte injury will be highlighted: these pathways may offer the potential to develop better targeted and more effective therapies for the future.
Currently available therapies Glucocorticoid therapy Treatment of choice initially - Prednisone 1 mg/kg daily (max 80 mg daily) Complete response and remission defined as reduction of proteinuria to 300 mg/day A partial response is a reduction of ≥50 percent, and to less than 3.5 g/day. Relapse defined as return to 3.5g/day or more after previous remission Frequent relapse is defined as 3 or more relapses per year - Remission occurs in 85-90% with steroids but may take several months to remit in adults (25% take longer than 3-6 months) - Response to initial steroid therapy most important prognostic indicator
• Steroid dependence is considered relapse on therapy or patients who must stay on steroids to maintain remission • Steroid resistance: little or no reduction in proteinuria after 16 weeks of adequate prednisone therapy • Relapses may be triggered by infection or allergy. Most relapses occur within one year of stopping therapy but have been known to occur up to 25 years later • Steroid taper should not be started for minimum of 8 weeks or 1-2 weeks after complete remission - Very slow tapering is recommended to prevent relapse
Second line therapy Though most patients achieve complete remission after an initial course but most case series indicate that ≥50% of adult MCD patients eventually relapse In relapse patients, repeat steroid course Relapsing while on steroids or frequent relapsers may need additional treatment  Alkylating agents such as cyclophosphamide can be used but must be monitored closely  Antimetabolites (azathioprine, mycophenolate mofetil) are often helpful  CNIs such as cyclosporine or tacrolimus effective but may cause renal injury  Direct antiproteinuric effect on the podocyte  Continuous low-dose prednisone often considered but watch out for long-term side effects  Alternative agents are also useful where side effects preclude the further use of steroids.
New approaches with available drugs Rituximab: is a humanized monoclonal antibody Some case reports described the use of rituximab in MCD. Failed therapy with: 1. cyclosporine and mycophenolate mofetil, a 23-year old had a prolonged remission (>28 months) after 4 weekly doses of 375 mg/m2 2. 15-year-old girl with MCD, with NS dependent on high-dose steroids, had remission with a course of rituximab, allowing significant reduction of steroid dose. 3. Rituximab, induced partial remission in a 20-year-old woman, who previously had been nephrotic despite prednisone, tacrolimus, and MMF. A retrospective review of 37 children with SDNS found that 375 mg/m weekly for 1–4 courses 26 children (70%) for 12 months. Of 29 children followed >2 years, 12 (41%) remained in remission. Kemper et al Nephrol Dial Transplant (20112011) 0: 1–6
• Galactose – shown to bind the FSGS permeability factor with high affinity and is able to alter glomerular permeability. Currently being tested in Novel Therapies in resistant Focal Segmental Glomerulosclerosis (FONT2) clinical trial • Adalimumab – is a monoclonal anti-tumor necrosis factor (TNF) antibody hence it binds TNF and prevents it from activating TNF receptors in FSGS. Also being tested in (FONT2) • Thiazolidinediones: improved CKD resulting from metabolic syndrome. It reduced proteinuria, microalbuminuria, podocyte injury, vascular injury, inflammation and fibrosis in both diabetic nephropathy and nondiabetic glomerulosclerosis in animal models and in humans. protected
Potential future treatments • Protein kinases: p38 MAPK, MK2 and PKCα signaling • Notch signaling • IL-13 • Suppressing the unfolded protein response • Maintaining redox homeostasis
Other treatments • Renoprotection + treatment of hypertension: ACEI and ARBs • Loop diuretics • Lipid lowering drugs: also renoprotective • Anticoagulation - Warfarin • Calcium and vitamin D therapy should be used to decrease the risk of osteoporosis. • Trimethoprim-sulfamethoxazole for prophylaxis against Pneumocystis carinii in patients on >15 mg/day of prednisone; dapsone and atovaquone are alternatives
Prognosis • Excellent even in adults • Spontaneous remission: - approx 20% in untreated MCD cases at 6mths - nearly 65% at 2 years • With corticosteroid therapy remission in 80%-90%
Focal Segmental Glomerulosclerosis
Focal Segmental Glomerulosclerosis • Focal segmental glomerulosclerosis (FSGS) defines a characteristic pathologic pattern of glomerular injury. • The hallmark of kidney biopsy is an increased degree of scarring seen on light microscopy of some but not all of the glomeruli present (focal) that involves some but not all portions of the affected glomeruli (segmental). • Characterized by proteinuria commonly in nephrotic range.
Focal Segmental Glomerulosclerosis
Focal Segmental Glomerulosclerosis • Primary FSGS makes up approximately 10% - 15% of NS in children and 20% - 30% in adults. • It is the predominant cause of idiopathic nephrotic syndrome in adults. • Mainly sporadic type, Onset is insidious. • Involves children under 5 years of age and adults in 3rd & 4th decades. • About 40% to 60% of patients progress to ESRD disease within 10 to 20 years.
Focal Segmental Glomerulosclerosis - LM • Focal and segmental lesions may involve only a minority of the glomeruli and may be missed if the biopsy specimen contains an insufficient number of glomeruli. • The lesion initially tends to involve the juxtamedullary glomeruli and subsequently becomes generalized. In the sclerotic segments there is collapse of capillary loops, increase in matrix and segmental deposition of plasma proteins along the capillary wall (hyalinosis). • The hyalinosis may become so pronounced as to occlude the capillary lumen. Lipid and foam cells are often present. • Glomeruli that do not show segmental lesion usually appear normal. •
Focal Segmental Glomerulosclerosis - LM Biopsy from a patient with FSGS: One of the glomeruli shows segmental sclerosis while others appear unremarkable Tubular atrophy is also seen.
Focal Segmental Glomeruloscerosis narrowing of capillary lumens, proliferation and swelling of visceral epithelial cells, and prominent accumulation of intracellular protein absorption droplets in the visceral epithelial cells.
Focal Segmental Glomerulosclerosis – Variants Glomerular Tip Lesion Characterized by a consolidation of the glomerular segment adjacent to the origin of proximal tubule - characterized by a "tip" (from the glomerular tip). There are adhesions and sclerosis, hyaline deposits and endocapillary hypercellularity.
FSG - Immunofluorescence Immunofluores cence microscopy demonstrating segmental deposition of IgM in a biopsy from a patient
FSG – Electron Microscopy Early FSG. There is mild segmental prominence of the mesangium (upper third) & vacuolization of the epithelial cell cytoplasm. A lipid-laden intracapillary cell with foamy cyto plasm is also seen (arrows).
Membraneous nephropathy
Membraneous nephropathy • Common cause of nephrotic syndrome in adults. • Characterized by diffuse accumulation of electron dense, Ig- containing deposits along the sub-epithelial side of basement membrane. [Formation of membrane attack protein (C5b-C9) causes the capillary damage and hence leakage of proteins]. • In about 85% of patients, no associated condition can be uncovered and are considered idiopathic. In about 15% patients there is another systemic condition associated with it and is referred to as secondary membranous glomerulopathy.
Membranous Nephropathy • Secondary type is a form of chronic immune complex-mediated disease. • The inciting antigens can sometimes be identified in the immune complexes. For eg exogenous antigen (hepatitis B or Treponema), Endogenous nonrenal antigens (thyroglobin), Endogenous renal antigens (membrane protein antigen). • The most notable associations are seen with: a) Infections - Hepatitis B, Hepatitis C, Syphilis, malaria. b) Drugs - Penicillamine, Captopril, Gold NSAIDs c) Malignant tumors - Ca lung, Ca colon , Melanoma d) SLE - 10%-15% of glomerulonephritis in SLE is of membranous type e) Auto immune disorders - Thyroiditis.
Membranous Nephropathy • Uniform, diffuse thickening of the glomerular capillary wall. • Basement membrane material is laid down between these deposits, appearing as irregular spikes which protrude from the GBM. • These spikes are best seen by silver stains, which color the basement membrane black.
• The course of the disease is variable but generally indolent. • Although proteinuria persists in more than 60% of patients, only about 10% die or progress to renal failure within 10 years, • And no more than 40% eventually develop renal insufficiency. Membranous Nephropathy
Normal capillaries with thin walls Membranous capillaries with thick walls Membranous Nephropathy - LM Marked diffuse thickening of the capillary walls without an increase in the number of cells. There are prominent spikes projecting from basement membrane.
Membranous Nephropathy - Immunofluorescence Granular deposits contain both immunoglobulins & complement .
Membranous Nephropathy - EM Electron micrograph showing electron dense deposits along the epithelial side of the basement membrane. There is effacement of
Membranoploliferative GMN
Membranoploliferative GMN • Accounts for 10% to 20% of cases of nephrotic syndrome. • MPGN is characterized by alteration of glomerular cells and leukocyte infiltration. Persistent and slowly progressive. • Proliferation is predominantly in the mesengium and involves capillary loops and thus the synonym mesengiocapillary glomerulonephritis is used.
Membranoploliferative - Classification • Primary MPGN :- when the cause is idiopathic. • Secondary MPGN :- when associated with other systemic disorders. • On the basis of distinct ultra structural, immunofluorescence and pathological findings it is divided into:- • A) Type I MPGN • B) Type II MPGN (dense deposit disease) • C) Type III MPGN (very rare, it is characterized by a mixture of subepithelial deposits and the typical pathological findings of Type I disease)
Membrano-proliferative -Type 1 MPGN • Account for 5% of the cases of end stage renal disease. • Children and young adults are more frequently involved. • Approx one third of patients present with nephritic syndrome. Approx two thirds of the patients develop hypocomplementemia with predominant depletion in C3 levels. • Evidence of immune complexes in the glomerulus and activation of both classical and alternative complement pathways are usually present. • Antigens involved are unknown, but sometimes believed to be protein derived from infectious agents like hepatitis C and B viruses.(planted antigens)
Membranoploliferative -Type 2 MPGN (Dense Deposit Dx) • Rarer than type 1. • Shows unique morphological appearance of basement membrane best seen by electron microscopy. • Type II MPGN tends to present with nephritis while MPGN type I presents more often with nephrotic features. • There is activation of alternative complement pathway. Serum levels of C3 remains low for a longer period than type I disease. • More than 70% of patients have a circulating antibody termed C3 nephiritic factor ( C3NeF ).
Membranoploliferative – Secondary
Membranoploliferative - LM • Light microscopy of both types of MPGN are similar, but the cellular proliferation, and especially the circumferential mesengeal interposition is less prominent in type 2 MPGN. • Glomeruli are large and hypercellular. • Hypercellularity is produced both by proliferation of cells in the mesengium and endocapillary also.
Thickening of capillary walls (global & diffuse) with hypercellularity. Much of this hypercellularity is mesangial proliferation, and some of the capillary wall thickening is caused by mesangial interposition into the subendothelial zone of the capillary loops. Membranoploliferative - LM
• Glomeruli have lobular appearance due to proliferating mesengial cells and increased mesengeal matrix. • The GBM is thickened, often segmentally. • The glomerular capillary wall often show a double contour or tram-track appearance especially evident in silver or PAS stains. This is caused by splitting of GBM. Membranoploliferative - LM
Membranoploliferative – Type I C3, IgG and IgM deposits – frequently C3 . These deposits are granular in the capillary walls. Often they are elongated and smooth in their external edge because they are subendothelial and they are molded to the GBM.
Membranoploliferative – Type II Immunofluorescence The bright deposits scattered along capillary walls and in the mesangium with antibody to complement component C3 are typical for type II membranoproliferative glomerulonephritis.
IgA Nephropathy • It is the commonest form of glomerulonephritis resulting in ESRD throughout the world. Male predominance. • Also known as IgA nephritis, Berger's disease, Synpharyngitic glomerulonephritis • Frequent cause of gross and microscopic hematuria • Characterized by the presence of prominent IgA deposits in the mesengeal region. • Suspected by light microscopy, but diagnosis is made only by immunochemical method.
IgAN Pathogenesis • Abnormalities of immune regulation leads to increased IgA synthesis in response to respiratory or gastrointestinal exposure to environmental agents. • IgA1 (nephritogenic form) and IgA1-containing immune complexes are then trapped in the mesangium, where they activate the alternative complement pathway and initiate glomerular injury. • IgA nephropathy occurs with increased frequency in individuals with gluten enteropathy and in liver diseases (defective hepatobiliary clearance of IgA complexes)
IgAN Light Microscopy Glomeruli may be normal or may show mesangial widening and endocapillary proliferation. The mesangial widening is due to cell proliferation, accumulation of matrix and immune deposits.
IgAN Immunofluorescence The IF pattern parallels the distribution of deposits seen by EM. It shows deposits of IgA often with C3 and properdin and lesser amounts of IgG or IgM. Early complement components are usually absent.
IgAN Electron Microscopy Portion of a glomerulus from a patient with IgA nephropathy showing electron-dense mesangial deposits
Alport’s Syndrome
Alport’s Syndrome • Alports Syndrome is a primary basement membrane disorder manifested by progressive nephritis (hematuria and proteinuria), deafness and ocular abnormalities. • Approximately 80%-85% of patients have X linked form of syndrome resulting from mutation of COL4A5. • Gross or microscopic hematuria is the most common and earliest manifestation.
Nonspecific findings. There is focal and segmental glomerular hypercellularity of the mesangial and endothelial cells. Renal interstitial foam cells can be found and represent lipid-laden macrophages which can be seen in many renal diseases. Alport’s Syndrome - LM
Alports Syndrome Glomerular capillary loop showing diffuse, irregular thickening of GBM . The lamina densa is split into multiple interwoven lamellae
Summary • Overview of glomerular diseases was discussed • It was noted that numerous inflammatory and non inflammatory diseases affect the glomerulus and lead to alterations in glomerular permeability, structure and function. • However, not all glomerular diseases is caused by GN and other causes were noted in its differential diagnosis inclusive of diabetic nephropathy, amyloidosis, hereditary nephropathies and Alports syndrome •
References Becker D (2008). Minimal change disease. Nephrology Rounds, 6, 8; http://www.nephrologyrounds.org/crus/nephus_10_08.pdf . Coward RJ, Foster RR, Patton D et al. (2005). Nephrotic plasma alters slit diaphragm-dependent signaling and translocates nephrin, podocin, and CD2 associated protein in cultured human podocytes. J Am Soc Nephrol, 16: 629–637. Greenbaum LA, Benndorf R, Smoyer WE (2012). Childhood nephrotic syndrome—current and future therapies. Nat. Rev. Nephrol. 8, 445–458. Greka A, Mundel P (2012). Cell Biology and Pathology of Podocytes. Annu. Rev. Physiol., 74:299–323. Healy H (2002).Treatments conferring renoprotection in patients with nephrotic syndrome. Nephrology, 7: S16-S20. Herve C, Dantal J (2006). Possible new perspectives for our understanding of nephrotic syndrome recurrence. Nephrol Dial Transplant, 21: 10–13. Lahdenkari A-T, Kestila M, Holmberg et al (2004). Nephrin gene (NPHS1) in patients with minimal change nephrotic syndrome (MCNS). Kidney International, 65: 1856–1863. Tryggvason K, Patrakka J, Wartiovaara J et al (2006). Hereditary Proteinuria Syndromes and Mechanisms of Proteinuria. N Engl J Med, 354:1387-401. Kemper MJ, Gellermann J, Habbig S et al (2011). Long-term follow-up after rituximab for steroid-dependent idiopathic nephrotic syndrome. Nephrol Dial Transplant (20112011) 0: 1–6 doi: 10.1093/ndt/gfr548.

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Glomerulonephristis, histology and classification

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    GLOMERULAR DISEASES Prof OlutayoAlebiosu Osun State University BSc, MBChB, FWACP
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    Objectives • Participants ableto review the classification of glomerular diseases • Participants able to discuss the etiology of glomerular diseases. • Participants able to highlight the histological findings associated with glomerular diseases. • Participants able to outline the management considerations for the different diseases grouped under the term 'glomerulonephritis.' •
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    Introduction • Numerous inflammatoryand non inflammatory diseases affect the glomerulus and lead to alterations in glomerular permeability, structure and function. • However, not all glomerular diseases is caused by GN and other causes need to be considered in its differential diagnosis including diabetic nephropathy, amyloidosis and hereditary nephropathies including Alports syndrome
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    Introduction – Pathogenesis •In GN, the dominant histologic lesions are in the glomeruli, at times described as focal or diffuse; may be segmental or global. • Lesions may also be hypercellular due to either an increase in endogenous endothelial or mesangial cells – proliferative, and / or to an infiltration of inflammatory leukocytes – exudative changes. • Severe acute inflammation may produce glomerular necrosis, which is often segmental. • Crescents may develop which are inflammatory collections of cells in Bowmans space, and consist of proliferating parietal and visceral epithelial cells, infiltrating fibroblasts, lymphoblasts and monocytes/macrophages, often with local fibrin deposition.
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    Introduction – Pathogenesisand Classification • Indirect immunofluorescence and immunoperoxidase staining are both used to identify immune reactants, looking for the deposition of immunoglobulins IgG, IgA, and IgM, for components of both the classical and alternative pathways of complements – usually C3, C4 and C1q, and for the presence of fibrin. • Granular deposits in glomerular are called immune complexes which are local formation of antigen/antibody complex in the glomerulus.
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    • This conditionis characterized histologically by diffuse proliferation of glomerular cells, associated with influx of leucocytes, typically caused by immune complexes. The inciting antigen may be exogenous or endogenous. • The prototype exogenous antigen-induced disease pattern is post-infectious glomerulonephritis. • APGN has mainly two types- • Post-streptococcal Glomerulonephritis • Non-Streptococcal Glomerulonephritis
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    Poststreptoccocal Glomerulonephritis • Producesthe nephritic syndrome (hematuria, red cell casts, moderate proteinuria and edema) in children two weeks following a respiratory or skin infection with a "nephritogenic strain" of group A, beta-hemolytic streptococci. • Clinically, this disease is manifested by a rather abrupt onset of gross hematuria, edema, proteinuria, hypertension and impaired renal function. • The serum levels of hemolytic complement activity and C3 protein are abnormally reduced.
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    Poststreptoccocal Glomerulonephritis • Latentperiod between infection and onset of nephritis is compatible with the time required for the production of antibodies and formation of immune complexes. • There is deposition of circulating immune complexes which fix complement and attract PMN's. • This chokes off their blood supply, making the glomeruli hypercellular and bloodless. • This explains the oliguria, edema, and hypertension; 2% to 5% patient die during acute episode.
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    Acute Proliferative GMN- Immunofluorescence
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    Introduction Minimal Change Diseaseis a glomerular disorder that leads to the sudden onset of nephrotic-range proteinuria with edema of the extremities and face, hypoalbuminemia. Others: hyperlipidemia, hypercoagulability.
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    Epidemiology • Race: Asiansmay be at increased risk. • Sex: twice as frequently in boys than in girls. Same in both sexes in adulthood. • Age: incidence peaks in children aged 2 years (approximately 80% are below 6 years at the time of diagnosis). • In adults, the mean age of onset is 40 years.
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    Types: Primary orSecondary Secondary: 10 to 15% Drugs: •NSAIDs and selective COX-2 Inhibitors •Antimicrobials (ampicillin, rifampicin, cephalosporins) •Lithium •D-penicillamine, sulfasalazine (any 5-ASA derivative) •Pamidronate (and presumably other bisphosphonates) •Gamma interferon •Immunizations Neoplasia: •Hodgkin Lymphoma (0.4%) •Non-Hodgkin Lymphoma and Leukemia •Cases of MCD are rarely associated with solid tumors •MCD diagnosis may precede signs and symptoms of the malignancy •Proteinuria typically resolves with treatment of the malignancy
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    Minimal change disease- secondary Infections: Rare associations with syphyllis, tuberculosis, mycoplasma, Hep C, echinococcus MCD has been described in HIV infection but collapsing FSGS much more commonly seen Allergy Associations: •History of allergy described in up to 30% of cases •Multiple allergens described (fungi, cat fur, poison ivy, pollen, bee stings, house dust) •Onset and relapses have been triggered by bee stings and allergic reactions •Limited evidence for involvement of food allergy
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    Association with GlomerularDiseases •Association with IgA Nephropathy, with mesangial IgA deposits and mild mesangial proliferation seen in concurrence with MCD on biopsy •There are reports of MCD also occur with the following conditions, but rare: – Systemic Lupus Erythematosus – Type 1 Diabetes – Polycystic Kidney Diseases Minimal change disease - secondary
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    Pathology The pathological/histological featuresdistinguish the various forms of NS. •LM: not much different from normal glomeruli but in some cases there are some increase in cells or deposition of mesangium noted. •IM: no antibody deposits •EM: shows the characteristic foot process effacement
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    Minimal change disease •Accounts for 80% of all cases of the idiopathic nephrotic syndrome in children. • Majority of cases are seen in 3 - 4 year age groups. • Male predominance of 2.5:1 in children but no difference seen in adults. • 80-90% idiopathic. • Associated with infectious diseases, recent immunization, ingestion of heavy metals. • In adults, also related to use of NSAIDS.
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    Minimal change disease •The most common presentation is a full blown nephrotic syndrome with heavy proteinuria often of selective type. • On light microscopy, changes may be seen in the convoluted tubules where large amounts of lipid and protein droplets accumulate in the cell cytoplasm (lipoid nephrosis) • In contrast all the glomeruli appear normal.
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    MCD – LightMicroscopy Glomerulus is normocellular, capillary loops are patent, & the BM is normal in thickness
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    MCD - Immunofluorescence Nodeposits of complement or immunoglobulins seen in IF. (nil deposit disease)
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    MCD – Electronmicroscope Portion of a glomerulus from a patient with MCD showing obliteration of foot processes. The epithelial cell cytoplasm is hyperactive and shows microvillus and cyst formation.
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    Work up • LaboratoryStudies: - diagnosis - monitoring - complications - biopsy - steroid therapy • Imaging Studies • Biopsy and histology
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    Treatment • Currently availabletherapies • New approaches with available drugs • Selected novel pathways that have been found to mediate podocyte injury will be highlighted: these pathways may offer the potential to develop better targeted and more effective therapies for the future.
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    Currently available therapies Glucocorticoidtherapy Treatment of choice initially - Prednisone 1 mg/kg daily (max 80 mg daily) Complete response and remission defined as reduction of proteinuria to 300 mg/day A partial response is a reduction of ≥50 percent, and to less than 3.5 g/day. Relapse defined as return to 3.5g/day or more after previous remission Frequent relapse is defined as 3 or more relapses per year - Remission occurs in 85-90% with steroids but may take several months to remit in adults (25% take longer than 3-6 months) - Response to initial steroid therapy most important prognostic indicator
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    • Steroid dependenceis considered relapse on therapy or patients who must stay on steroids to maintain remission • Steroid resistance: little or no reduction in proteinuria after 16 weeks of adequate prednisone therapy • Relapses may be triggered by infection or allergy. Most relapses occur within one year of stopping therapy but have been known to occur up to 25 years later • Steroid taper should not be started for minimum of 8 weeks or 1-2 weeks after complete remission - Very slow tapering is recommended to prevent relapse
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    Second line therapy Thoughmost patients achieve complete remission after an initial course but most case series indicate that ≥50% of adult MCD patients eventually relapse In relapse patients, repeat steroid course Relapsing while on steroids or frequent relapsers may need additional treatment  Alkylating agents such as cyclophosphamide can be used but must be monitored closely  Antimetabolites (azathioprine, mycophenolate mofetil) are often helpful  CNIs such as cyclosporine or tacrolimus effective but may cause renal injury  Direct antiproteinuric effect on the podocyte  Continuous low-dose prednisone often considered but watch out for long-term side effects  Alternative agents are also useful where side effects preclude the further use of steroids.
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    New approaches withavailable drugs Rituximab: is a humanized monoclonal antibody Some case reports described the use of rituximab in MCD. Failed therapy with: 1. cyclosporine and mycophenolate mofetil, a 23-year old had a prolonged remission (>28 months) after 4 weekly doses of 375 mg/m2 2. 15-year-old girl with MCD, with NS dependent on high-dose steroids, had remission with a course of rituximab, allowing significant reduction of steroid dose. 3. Rituximab, induced partial remission in a 20-year-old woman, who previously had been nephrotic despite prednisone, tacrolimus, and MMF. A retrospective review of 37 children with SDNS found that 375 mg/m weekly for 1–4 courses 26 children (70%) for 12 months. Of 29 children followed >2 years, 12 (41%) remained in remission. Kemper et al Nephrol Dial Transplant (20112011) 0: 1–6
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    • Galactose –shown to bind the FSGS permeability factor with high affinity and is able to alter glomerular permeability. Currently being tested in Novel Therapies in resistant Focal Segmental Glomerulosclerosis (FONT2) clinical trial • Adalimumab – is a monoclonal anti-tumor necrosis factor (TNF) antibody hence it binds TNF and prevents it from activating TNF receptors in FSGS. Also being tested in (FONT2) • Thiazolidinediones: improved CKD resulting from metabolic syndrome. It reduced proteinuria, microalbuminuria, podocyte injury, vascular injury, inflammation and fibrosis in both diabetic nephropathy and nondiabetic glomerulosclerosis in animal models and in humans. protected
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    Potential future treatments •Protein kinases: p38 MAPK, MK2 and PKCα signaling • Notch signaling • IL-13 • Suppressing the unfolded protein response • Maintaining redox homeostasis
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    Other treatments • Renoprotection+ treatment of hypertension: ACEI and ARBs • Loop diuretics • Lipid lowering drugs: also renoprotective • Anticoagulation - Warfarin • Calcium and vitamin D therapy should be used to decrease the risk of osteoporosis. • Trimethoprim-sulfamethoxazole for prophylaxis against Pneumocystis carinii in patients on >15 mg/day of prednisone; dapsone and atovaquone are alternatives
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    Prognosis • Excellent evenin adults • Spontaneous remission: - approx 20% in untreated MCD cases at 6mths - nearly 65% at 2 years • With corticosteroid therapy remission in 80%-90%
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    Focal Segmental Glomerulosclerosis •Focal segmental glomerulosclerosis (FSGS) defines a characteristic pathologic pattern of glomerular injury. • The hallmark of kidney biopsy is an increased degree of scarring seen on light microscopy of some but not all of the glomeruli present (focal) that involves some but not all portions of the affected glomeruli (segmental). • Characterized by proteinuria commonly in nephrotic range.
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    Focal Segmental Glomerulosclerosis •Primary FSGS makes up approximately 10% - 15% of NS in children and 20% - 30% in adults. • It is the predominant cause of idiopathic nephrotic syndrome in adults. • Mainly sporadic type, Onset is insidious. • Involves children under 5 years of age and adults in 3rd & 4th decades. • About 40% to 60% of patients progress to ESRD disease within 10 to 20 years.
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    Focal Segmental Glomerulosclerosis- LM • Focal and segmental lesions may involve only a minority of the glomeruli and may be missed if the biopsy specimen contains an insufficient number of glomeruli. • The lesion initially tends to involve the juxtamedullary glomeruli and subsequently becomes generalized. In the sclerotic segments there is collapse of capillary loops, increase in matrix and segmental deposition of plasma proteins along the capillary wall (hyalinosis). • The hyalinosis may become so pronounced as to occlude the capillary lumen. Lipid and foam cells are often present. • Glomeruli that do not show segmental lesion usually appear normal. •
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    Focal Segmental Glomerulosclerosis- LM Biopsy from a patient with FSGS: One of the glomeruli shows segmental sclerosis while others appear unremarkable Tubular atrophy is also seen.
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    Focal Segmental Glomeruloscerosis narrowingof capillary lumens, proliferation and swelling of visceral epithelial cells, and prominent accumulation of intracellular protein absorption droplets in the visceral epithelial cells.
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    Focal Segmental Glomerulosclerosis– Variants Glomerular Tip Lesion Characterized by a consolidation of the glomerular segment adjacent to the origin of proximal tubule - characterized by a "tip" (from the glomerular tip). There are adhesions and sclerosis, hyaline deposits and endocapillary hypercellularity.
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    FSG – ElectronMicroscopy Early FSG. There is mild segmental prominence of the mesangium (upper third) & vacuolization of the epithelial cell cytoplasm. A lipid-laden intracapillary cell with foamy cyto plasm is also seen (arrows).
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    Membraneous nephropathy • Commoncause of nephrotic syndrome in adults. • Characterized by diffuse accumulation of electron dense, Ig- containing deposits along the sub-epithelial side of basement membrane. [Formation of membrane attack protein (C5b-C9) causes the capillary damage and hence leakage of proteins]. • In about 85% of patients, no associated condition can be uncovered and are considered idiopathic. In about 15% patients there is another systemic condition associated with it and is referred to as secondary membranous glomerulopathy.
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    Membranous Nephropathy • Secondarytype is a form of chronic immune complex-mediated disease. • The inciting antigens can sometimes be identified in the immune complexes. For eg exogenous antigen (hepatitis B or Treponema), Endogenous nonrenal antigens (thyroglobin), Endogenous renal antigens (membrane protein antigen). • The most notable associations are seen with: a) Infections - Hepatitis B, Hepatitis C, Syphilis, malaria. b) Drugs - Penicillamine, Captopril, Gold NSAIDs c) Malignant tumors - Ca lung, Ca colon , Melanoma d) SLE - 10%-15% of glomerulonephritis in SLE is of membranous type e) Auto immune disorders - Thyroiditis.
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    Membranous Nephropathy • Uniform,diffuse thickening of the glomerular capillary wall. • Basement membrane material is laid down between these deposits, appearing as irregular spikes which protrude from the GBM. • These spikes are best seen by silver stains, which color the basement membrane black.
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    • The courseof the disease is variable but generally indolent. • Although proteinuria persists in more than 60% of patients, only about 10% die or progress to renal failure within 10 years, • And no more than 40% eventually develop renal insufficiency. Membranous Nephropathy
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    Normal capillaries withthin walls Membranous capillaries with thick walls Membranous Nephropathy - LM Marked diffuse thickening of the capillary walls without an increase in the number of cells. There are prominent spikes projecting from basement membrane.
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    Membranous Nephropathy -Immunofluorescence Granular deposits contain both immunoglobulins & complement .
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    Membranous Nephropathy -EM Electron micrograph showing electron dense deposits along the epithelial side of the basement membrane. There is effacement of
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    Membranoploliferative GMN • Accountsfor 10% to 20% of cases of nephrotic syndrome. • MPGN is characterized by alteration of glomerular cells and leukocyte infiltration. Persistent and slowly progressive. • Proliferation is predominantly in the mesengium and involves capillary loops and thus the synonym mesengiocapillary glomerulonephritis is used.
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    Membranoploliferative - Classification •Primary MPGN :- when the cause is idiopathic. • Secondary MPGN :- when associated with other systemic disorders. • On the basis of distinct ultra structural, immunofluorescence and pathological findings it is divided into:- • A) Type I MPGN • B) Type II MPGN (dense deposit disease) • C) Type III MPGN (very rare, it is characterized by a mixture of subepithelial deposits and the typical pathological findings of Type I disease)
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    Membrano-proliferative -Type 1MPGN • Account for 5% of the cases of end stage renal disease. • Children and young adults are more frequently involved. • Approx one third of patients present with nephritic syndrome. Approx two thirds of the patients develop hypocomplementemia with predominant depletion in C3 levels. • Evidence of immune complexes in the glomerulus and activation of both classical and alternative complement pathways are usually present. • Antigens involved are unknown, but sometimes believed to be protein derived from infectious agents like hepatitis C and B viruses.(planted antigens)
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    Membranoploliferative -Type 2MPGN (Dense Deposit Dx) • Rarer than type 1. • Shows unique morphological appearance of basement membrane best seen by electron microscopy. • Type II MPGN tends to present with nephritis while MPGN type I presents more often with nephrotic features. • There is activation of alternative complement pathway. Serum levels of C3 remains low for a longer period than type I disease. • More than 70% of patients have a circulating antibody termed C3 nephiritic factor ( C3NeF ).
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    Membranoploliferative - LM •Light microscopy of both types of MPGN are similar, but the cellular proliferation, and especially the circumferential mesengeal interposition is less prominent in type 2 MPGN. • Glomeruli are large and hypercellular. • Hypercellularity is produced both by proliferation of cells in the mesengium and endocapillary also.
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    Thickening of capillary walls(global & diffuse) with hypercellularity. Much of this hypercellularity is mesangial proliferation, and some of the capillary wall thickening is caused by mesangial interposition into the subendothelial zone of the capillary loops. Membranoploliferative - LM
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    • Glomeruli havelobular appearance due to proliferating mesengial cells and increased mesengeal matrix. • The GBM is thickened, often segmentally. • The glomerular capillary wall often show a double contour or tram-track appearance especially evident in silver or PAS stains. This is caused by splitting of GBM. Membranoploliferative - LM
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    Membranoploliferative – TypeI C3, IgG and IgM deposits – frequently C3 . These deposits are granular in the capillary walls. Often they are elongated and smooth in their external edge because they are subendothelial and they are molded to the GBM.
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    Membranoploliferative – TypeII Immunofluorescence The bright deposits scattered along capillary walls and in the mesangium with antibody to complement component C3 are typical for type II membranoproliferative glomerulonephritis.
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    IgA Nephropathy • Itis the commonest form of glomerulonephritis resulting in ESRD throughout the world. Male predominance. • Also known as IgA nephritis, Berger's disease, Synpharyngitic glomerulonephritis • Frequent cause of gross and microscopic hematuria • Characterized by the presence of prominent IgA deposits in the mesengeal region. • Suspected by light microscopy, but diagnosis is made only by immunochemical method.
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    IgAN Pathogenesis • Abnormalitiesof immune regulation leads to increased IgA synthesis in response to respiratory or gastrointestinal exposure to environmental agents. • IgA1 (nephritogenic form) and IgA1-containing immune complexes are then trapped in the mesangium, where they activate the alternative complement pathway and initiate glomerular injury. • IgA nephropathy occurs with increased frequency in individuals with gluten enteropathy and in liver diseases (defective hepatobiliary clearance of IgA complexes)
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    IgAN Light Microscopy Glomeruli maybe normal or may show mesangial widening and endocapillary proliferation. The mesangial widening is due to cell proliferation, accumulation of matrix and immune deposits.
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    IgAN Immunofluorescence The IF pattern parallelsthe distribution of deposits seen by EM. It shows deposits of IgA often with C3 and properdin and lesser amounts of IgG or IgM. Early complement components are usually absent.
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    IgAN Electron Microscopy Portion ofa glomerulus from a patient with IgA nephropathy showing electron-dense mesangial deposits
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    Alport’s Syndrome • AlportsSyndrome is a primary basement membrane disorder manifested by progressive nephritis (hematuria and proteinuria), deafness and ocular abnormalities. • Approximately 80%-85% of patients have X linked form of syndrome resulting from mutation of COL4A5. • Gross or microscopic hematuria is the most common and earliest manifestation.
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    Nonspecific findings. There isfocal and segmental glomerular hypercellularity of the mesangial and endothelial cells. Renal interstitial foam cells can be found and represent lipid-laden macrophages which can be seen in many renal diseases. Alport’s Syndrome - LM
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    Alports Syndrome Glomerular capillaryloop showing diffuse, irregular thickening of GBM . The lamina densa is split into multiple interwoven lamellae
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    Summary • Overview ofglomerular diseases was discussed • It was noted that numerous inflammatory and non inflammatory diseases affect the glomerulus and lead to alterations in glomerular permeability, structure and function. • However, not all glomerular diseases is caused by GN and other causes were noted in its differential diagnosis inclusive of diabetic nephropathy, amyloidosis, hereditary nephropathies and Alports syndrome •
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    References Becker D (2008).Minimal change disease. Nephrology Rounds, 6, 8; http://www.nephrologyrounds.org/crus/nephus_10_08.pdf . Coward RJ, Foster RR, Patton D et al. (2005). Nephrotic plasma alters slit diaphragm-dependent signaling and translocates nephrin, podocin, and CD2 associated protein in cultured human podocytes. J Am Soc Nephrol, 16: 629–637. Greenbaum LA, Benndorf R, Smoyer WE (2012). Childhood nephrotic syndrome—current and future therapies. Nat. Rev. Nephrol. 8, 445–458. Greka A, Mundel P (2012). Cell Biology and Pathology of Podocytes. Annu. Rev. Physiol., 74:299–323. Healy H (2002).Treatments conferring renoprotection in patients with nephrotic syndrome. Nephrology, 7: S16-S20. Herve C, Dantal J (2006). Possible new perspectives for our understanding of nephrotic syndrome recurrence. Nephrol Dial Transplant, 21: 10–13. Lahdenkari A-T, Kestila M, Holmberg et al (2004). Nephrin gene (NPHS1) in patients with minimal change nephrotic syndrome (MCNS). Kidney International, 65: 1856–1863. Tryggvason K, Patrakka J, Wartiovaara J et al (2006). Hereditary Proteinuria Syndromes and Mechanisms of Proteinuria. N Engl J Med, 354:1387-401. Kemper MJ, Gellermann J, Habbig S et al (2011). Long-term follow-up after rituximab for steroid-dependent idiopathic nephrotic syndrome. Nephrol Dial Transplant (20112011) 0: 1–6 doi: 10.1093/ndt/gfr548.