Rapidly progressive glomerulonephritis

Rapidly progressive glomerulonephritis (RPGN) is a syndrome of the kidney that is characterized by a rapid loss of renal function,[4][5] (usually a 50% decline in the glomerular filtration rate (GFR) within 3 months)[5] with glomerular crescent formation seen in at least 50%[5] or 75%[4] of glomeruli seen on kidney biopsies. If left untreated, it rapidly progresses into acute renal failure[6] and death within months. In 50% of cases, RPGN is associated with an underlying disease such as Goodpasture syndrome, systemic lupus erythematosus or granulomatosis with polyangiitis; the remaining cases are idiopathic. Regardless of the underlying cause, RPGN involves severe injury to the kidneys' glomeruli, with many of the glomeruli containing characteristic glomerular crescents (crescent-shaped scars)

1. RAPIDLY PROGRESSIVE CRESCENTIC GLOMERULONEPHRITIS BY: NIMMY ANN SHIBU GROUP-4

2. Rapidly progressive glomerulonephritis (RPGN) is a syndrome of the kidney that is characterized by a rapid loss of renal function. usually a 50% decline in the glomerular filtration rate (GFR) within 3 months with glomerular crescent formation seen in at least 50 % or 75 % of glomeruli seen on kidney biopsies. In 50% of cases, RPGN is associated with an underlying disease such as Goodpasture syndrome, systemic lupus erythematosus or granulomatosis with polyangiitis ; the remaining cases are idiopathic . RPGN involves severe injury to the kidneys' glomeruli , with many of the glomeruli containing characteristic glomerular crescents (crescent-shaped scars ) INTRODUCTION

3. Proliferative extracapillary glomerulonephritis (GN) or crescentic GN is not a specific disease , but a histologic manifestation of severe glomerular damage. The term “ extracapillary proliferation ” is used to designate the cellular and/or fibrous proliferation that occupies the Bowman’s space, arising from its capsule . Extracapillary indicate that proliferation occur outside of capillary tuft . Definition of crescent is the presence of at least two layers of cells that are filling totally (circumferential) or partially (circumscribed) the Bowman’s space . CRESCENTIC GLOMERULONEPHRITIS

4. Crescents are formed by a variable proportion of epithelial cells and monocytes (macrophages); according to the evolution of crescent the predominant cells are monocytes (earlier phase) or epithelial cells (later phases). In cases with segmental necrosis and/or rupture of the Bowman’s capsule usually there are more monocytes, and in cases of immune complexes disease there are more epithelial cells . Crescents are associated to rupture of capillary walls and fibrin in the urinary space . This fibrin and other proteins of the plasma seem to have the capacity to stimulate epithelial cells so that they proliferate , in addition, the mediators released by monocytes and platelets would contribute to the cellular proliferation and, probably, to posterior fibrosis. Crescents may evolve to fibrosis (fibrous crescent) or disappear (by apoptosis ). Fibrosis is mediated by infiltration of fibroblasts from the periglomerular interstitium through spaces in the Bowman’s capsule . When the crescents contain only cells, without collagen, is called : epithelial crescent when cellular components are mixed with collagen the lesion is called : fibroepithelial crescent

5. Hematuria Red blood cell casts in the urine Proteinuria - sometimes exceeding 3 g protein/24 h, a range associated with nephrotic syndrome. H ypertension E dema Oliguria or anuria SIGN AND SYMPTOMS

6. In the pathophysiology of RPGN the anti-neutrophil cytoplasmic antibodies (ANCA) interact with antigens in cytoplasm of neutrophils . It is thought that ANCA causes an early degranulation giving way to release of lytic enzymes at site of injury. ANCA are linked to the pathogenesis of glomerulonephritis, anti-neutrophil cytoplasmic antibodies specificity is determined via (ELISA), with pANCA (antibody) directed against MPO PATHOPHYSIOLOGY

7. RPGN can be classified into three types, based upon the immunofluorescence patterns : Type I– Anti-glomerular basement membrane antibody associated RPGN. Type II – Immune complex RPGN Type III-- Pauci immune associated RPGN CLASSIFICATION

8. Accounting for approximately 20% of RPGN, type I RPGN is characterized by the presence of autoantibodies directed against the glomerular basement membrane (GBM ). It is also called anti-GBM glomerulonephritis. The antibodies are directed against a particular protein found in the GBM, type IV collagen . some cases of type I RPGN are also associated with antibodies directed against the basement membrane of lung alveoli, producing Goodpasture syndrome . TYPE 1

9. RPGN caused by the deposition of immune complexes accounts for 25% of RPGN and is classified as type II . These diseases include systemic lupus erythematosus , acute proliferative glomerulonephritis, Henoch – Schönlein purpura and IgA nephropathy . TYPE 2

10. Also known as pauci -immune RPGN, type III RPGN accounts for 55% of RPGN and features neither immune complex deposition nor anti-GBM antibodies . the glomeruli are damaged in an undefined manner, perhaps through the activation of neutrophils in response to ANCA . Type III RPGN may be isolated to the glomerulus (primary, or idiopathic) or associated with a systemic disease (secondary ). The systemic disease is an ANCA-associated vasculitis such as granulomatosis with polyangiitis , microscopic polyangiitis or eosinophilic granulomatosis with polyangiitis TYPE 3

11. Goodpasture syndrome (GPS) is a rare autoimmune disease in which antibodies attack the basement membrane in lungs and kidneys, leading to bleeding from the lungs and kidney failure . It attack the alpha-3 subunit of type IV collagen . Goodpasture syndrome may quickly result in permanent lung and kidney damage, often leading to death. GOODPASTURE SYNDROME

12. 60 to 80% of those with the condition experience both lung and kidney involvement; 20-40% have kidney involvement alone, and less than 10% have lung involvement alone. Lung symptoms usually antedate kidney symptoms and usually include: coughing up blood , chest pain (in less than 50% of cases overall), cough, and shortness of breath . Kidney symptoms usually include blood in the urine, protein in the urine, unexplained swelling of limbs or face, high amounts of urea in the blood, and high blood pressure . oliguric or anuric renal failure, macro or microhematuria , and other unspecific general symptoms. According to sodium retention and volume expansion, hypertension may be detected. SIGN AND SYMPTOMS

13. HISTOPATHOLOGY Histopathological presentation in renal tissue is similar for anti-GBM and pauci -immune crescentic GN. There is glomerular inflammation with necrotizing lesions; GN is usually focal and segmental , but it may be global and diffuse. Necrotizing lesions are invariably accompanied by crescents. In the tuft (in addition to necrosis ) capillary collapse , mesangial matrix increase, and karyorrhexis can be identified . Frequently there is segmental or extensive destruction of Bowman’s capsul e in these cases it is usual to find granulomas and multinucleated cells surrounding the glomerulus.

14. Figure 1. This case corresponds to a 58-years-old patient with rapidly progressive GN. See proliferation of cells occupying the entire Bowman’s space (green arrows) and compressing the tuft (red arrows). The Bowman’s capsule is indicated by the blue arrows. This is the characteristic aspect of an epithelial crescent, in this case circumferential. Cells forming the crescent may be epithelial, monocytes o r other inflammatory cells

15. In epithelial crescents the proliferating cells are not accompanied by fibrous or collagen tissue. Methenamine -silver stain emphasizes the compressed tuft and rupture of capillary walls (arrows). This capillary damage is an important pathogenic phenomenon in the generation of the extracapillary proliferation. ( Methenamine -silver, X400).

16. In fibroepithelial crescents we can see a mixture of large cells, with cleared nucleus, prominent nucleolus, and ample cytoplasm, that are mixed with fibrous or collagen tissue that is highlighted with the silver stains (like in this photo) and with the trichrome stains. The blue arrows indicate the tuft compressed and distorted ; the red arrows indicate large, active, proliferating cells , and green arrows mark the fibrosis replacing many areas of this crescent ; this combination of lesions indicates a process that evolves to chronicity. ( Methenamine -silver, X400 ).

17. . When advancing the destructive process of glomeruli the crescent becomes more fibrous (or scarred) and the cells composing it diminish progressively until disappearing, being replaced by fibroblasts . Stains for fibrous tissue, like trichrome and silver, emphasize this component (green arrows), in this case without epithelial component; the blue arrows indicate remains of glomerular tuft. ( Methenamine -silver, X400).

18. Systemic lupus erythematosus (SLE), also known simply as lupus, is an autoimmune disease in which the body's immune system mistakenly attacks healthy tissue in many parts of the body . Symptoms vary between people and may be mild to severe . Common symptoms include painful and swollen joints, fever, chest pain, hair loss, mouth ulcers, swollen lymph nodes, feeling tired, and a red rash which is most commonly on the face . The mechanism involves an immune response by autoantibodies against a person's own tissues . These are most commonly anti-nuclear antibodies and they result in inflammation . SYSTEMIC LUPUS ERYTHEMATOSUS

19. Kidneys Painless passage of blood or protein in the urine may often be the only presenting sign of kidney involvement. Acute or chronic renal impairment may develop with lupus nephritis, leading to acute or end-stage kidney failure. Because of early recognition and management of SLE, end-stage renal failure occurs in less than 5%of cases; except in the black population, where the risk is many times higher. The histological hallmark of SLE is membranous glomerulonephritis with "wire loop" abnormalities. This finding is due to immune complex deposition along the glomerular basement membrane , leading to a typical granular appearance in immunofluorescence testing .

20. HISTOPATHOLOGY

21. Example of a glomerulus that contains a focal cellular crescent and expanded mesangium . Thickened capillary loops suggest double contouring of the basement membrane

22. Membranoproliferative glomerulonephritis ("MPGN"), also known as mesangiocapillary glomerulonephritis, is a type of glomerulonephritis caused by deposits in the kidney glomerular mesangium and basement membrane (GBM) thickening , activating complement and damaging the glomeruli . MPGN accounts for approximately 4% of primary renal causes of nephrotic syndrome in childreN and 7% in adults . Membranoproliferative glomerulonephritis involves deposits at the intraglomerular mesangium . It is also the main hepatitis C associated nephropathy . The GBM is rebuilt on top of the deposits, causing a "tram tracking" appearance under the microscope . Mesangial cellularity is increased. MEMBRANOPROLIFERAIVE GLOMERULONEPHRITIS

23. Type I Type I the most common by far, is caused by immune complexes depositing in the kidney. It is characterised by subendothelial and mesangial immune deposits. It is believed to be associated with the classical complement pathway . Type II The preferred name is "dense deposit disease ".Most cases of dense deposit disease do not show a membranoproliferative pattern , A 2012 review considers DDD to be in a continuum with C3 glomerulonephritis , Type III Type III is very rare, it is characterized by a mixture of subepithelial deposits and the typical pathological findings of Type I disease.

24. HISTOPATHOLOGY

25. Glomerulus from a case of MPGN type I with crescent.

26. Henoch – Schönlein purpura (HSP ), also known as IgA vasculitis , anaphylactoid purpura , purpura rheumatica,and Schönlein – Henoch purpura . is a disease of the skin, mucous membranes , and sometimes other organs that most commonly affects children. In the skin, the disease causes palpable purpura (small, raised areas of bleeding underneath the skin), often with joint pain and abdominal pain . With kidney involvement , there may be a loss of small amounts of blood and protein in the urine ( hematuria and proteinuria ) HENOCH SCHONLEIN PURPURA

27. HSP is a systemic vasculitis and is characterized by deposition of immune complexes containing the antibody immunoglobulin A (IgA ); it usually resolves within several weeks and requires no treatment apart from symptom control but may relapse in a third of cases and cause irreversible kidney damage in about one in a hundred cases . Henoch – Schönlein purpura is a small-vessel vasculitis in which complexes of immunoglobulin A (IgA ) and complement component 3 (C3) are deposited on arterioles, capillaries, and venules . HSP is more predominant among children. HSP involves the skin and connective tissues, scrotum, joints, gastrointestinal tract and kidneys

28. HISTOPATHOLOGY

29. Glomerular arteriol e showing a vasculitis with fibrinoid necrosis of the vessel wall (arrow) and swelling of the endothelial cells (E). Surrounding the vessel there is granulomatous inflammation (G )

30. . Renal biopsy . (A) The glomerulus shows segmental necrosis with fibrin exudation and a small cellular crescent (arrow). Note also endocapillary hypercellularity and neutrophil polymorph exudation. Haematoxylin & eosin (H&E). (B ) There is fibrin within several capillary loops and Bowman's space (arrows). The remaining capillary loops on the left show mild hypercellularity only. Silver trichrome . Direct immunofluorescence microscopy for IgA (C) and C3 ( D) shows strong granular mesangial and peripheral capillary wall staining.

31. Also known as IgA nephritis , Berger disease or synpharyngitic glomerulonephritis , is a disease of the kidney (or nephropathy); specifically it is a form of glomerulonephritis or an inflammation of the glomeruli of the kidney . IgA nephropathy is the most common glomerulonephritis worldwide. IgA nephropathy is characterized by deposition of the IgA antibody in the glomerulus . IgA NEPHROPATHY

32. Hematuri a- which usually starts within a day or two of a non-specific upper respiratory tract infection. proteinuria IgA nephropathy may show mesangial widening and focal and segmental inflammation . Diffuse mesangial proliferation or crescentic glomerulonephritis may also be present. Immunoflourescence shows mesangial deposition of IgA often with C3 and properdin and smaller amounts of other immunoglobulins ( IgG or IgM ) In IgA nephropathy, there is abnormally glycosylated IgA1. Anti-glycan antibodies form and lead to immune complexes deposited within the mesangium of the glomeruli. These complexes attach to fibronectin or type IV collagen in the extracellular matrix and activate mesangial cells to produce extracellular matrix, leading to mesangial hypercellularity , segmental glomerulosclerosis or adhesion, tubular atrophy, and interstitial fibrosis.

33. HISTOPATHOLOGY

34. The IgA is deposited mainly within the mesangium , which then increases mesangial cellularity as shown at the arrow .

35. Formerly known as Wegener's granulomatosis (WG ) is a long-term systemic disorder that involves both granulomatosis and polyangiitis . It is a form of vasculitis that affects small- and medium-size vessels in many organs but most commonly affects the upper respiratory tract and the kidneys . The signs and symptoms of GPA are highly varied and reflect which organs are supplied by the affected blood vessels. Typical signs and symptoms include nosebleeds, stuffy nose and crustiness of nasal secretions, and inflammation of the uveal layer of the eye . Damage to the heart, lungs and kidneys can be fatal . GRANULOMATOSIS WITH POLYANGITIS

36. Kidney: rapidly progressive glomerulonephritis (75%), leading to chronic kidney failure . Upper airway, eye and ear disease : Ears: conductive hearing loss due to auditory tube dysfunction, sensorineural hearing loss Oral cavity: strawberry gingivitis, underlying bone destruction with loosening of teeth, non-specific ulcerations throughout oral mucosa. Lungs : pulmonary nodules (referred to as "coin lesions"), infiltrates (often interpreted as pneumonia), cavitary lesions, pulmonary haemorrhage causing haemoptysis , and rarely bronchial stenosis . Arthritis: Pain or swelling (60%), often initially diagnosed as rheumatoid arthritis Skin: subcutaneous nodules (granulomas) on the elbow, purpura , various others (see cutaneous vasculitis ) Nervous system : occasionally sensory neuropathy (10%) and rarely mononeuritis multiplex Heart, gastrointestinal tract, brain ,

37. Classic microscopic features of GPA include inflammation of blood vessels associated with poorly formed granulomas, necrosis, and many giant cells . It is now widely presumed that the anti-neutrophil cytoplasmic antibodies (ANCAs) are responsible for the inflammation in GPA . The typical ANCAs in GPA are those that react with proteinase 3 , an enzyme prevalent in neutrophil granulocytes . ANCAs can activate neutrophils, increase their adherence to endothelium, and induce their degranulation that can damage endothelial cells .

38. Well-developed cellular crescent with collapse of small amount of remaining glomerular tuft with segmental fibrinoid necrosis and extracapillary fibrin and necrosis in pauci -immune crescentic glomerulonephritis, consistent with Wegener's granulomatosis or microscopic polyangiitis . Immunofluorescence studies were negative

39. Electron microscopy shows the absence of deposits along the capillary wall in a case of pauci -immune crescentic glomerulonephritis, consistent with Wegener's granulomatosis . The glomerular basement membrane break, which is the unit lesion leading to exudation of plasma proteins which stimulates proliferation of parietal epithelial cells, leading to crescent formation , is illustrated

40. FOCAL SEGMENTAL PROLIFERATIVE, NECROTIZING AND SCLEROSING PAUCI-IMMUNE GLOMERULONEPHRITIS WITH FOCAL (30%) CRESCENT FORMATION . NECROTIZING GRANULOMATOUS ARTERITIS INVOLVING INTRALOBULAR SIZED ARTERIES AND ARTERIOLES . FOCAL ACUTE TUBULAR INJURY WITH INTERSTITIAL EDEMA AND PATCHY ACUTE AND CHRONIC INTERSTITIAL INFLAMMATION

41. Microscopic polyangiitis is an ill-defined autoimmune disease characterized by a systemic, pauci -immune, necrotizing, small-vessel vasculitis without clinical or pathological evidence of necrotizing granulomatous inflammation . Clinical features may include constitutional symptoms like fever , loss of appetite, weight loss, fatigue, and kidney failure . A majority of patients may have blood in the urine and protein in the urine . Rapidly progressive glomerulonephritis may occur T he process is begun with an autoimmune process of unknown cause that triggers production of p-ANCA. These antibodies will circulate at low levels until a pro-inflammatory trigger — such as infection, malignancy, or drug therapy. The trigger upregulates production of p-ANCA . MICROSCOPIC POLYANGITIS

42. The large number of antibodies make it more likely that they will bind a neutrophil. Once bound, the neutrophil degranulates . The degranulation releases toxins that cause endothelial injury. Results from blood vessel inflammation that can result in damage to organ systems. Areas most commonly affected by MPA include the kidneys, lung, nerves, skin, and joints . Have common features with another form of vasculitis called granulomatosis with polyangiitis

43. The case of this microphotography corresponds to a 62-year-old man with microscopic polyangiitis . In an intrarenal artery we demonstrated this vascular lesion. The arterial wall i s pointed with green arrows, and the lumen with asterisks. In the central zone we can see an area with fibrinoid necrosis of the wall , polymorphous and cellular detritus (blue arrows). These lesions are not very frequent in intrarenal arteries, but its presence helps much in the vasculitis diagnosis.

44. Crescentic glomerulonephritis .

45. Focal segmental glomerulonephritis .

46. Also known as Churg -Strauss syndrome (CSS) or allergic granulomatosis , is an extremely rare autoimmune condition that causes inflammation of small and medium-sized blood vessels ( vasculitis ) in persons with a history of airway allergic hypersensitivity ( atopy ). The early ( prodromal) stage is marked by airway inflammation; almost all patients experience asthma and/or allergic rhinitis. The second stage is characterized by abnormally high numbers of eosinophils ( hypereosinophilia ), which causes tissue damage, most commonly to the lungs and the digestive tract . The third stage consists of vasculitis , which can eventually lead to cell death and can be life-threatening. EOSINOPHILLIC GRANULOMATOSIS WITH POLYANGITIS

47. It is a type of systemic necrotizing vasculitis . An EGPA-like syndrome is a rare complication that develops in steroid-dependent patients with asthma who have their oral steroid dose reduced after they start treatment a leukotriene receptor antagonist ( eg , montelukast , zafirlukast ). The vasculitic phase usually develops within 3 years after the onset of asthma, although it may be delayed for several decades. The most prominent symptoms and signs are those related to pulmonary, cardiac, dermatologic, renal, and peripheral nerve involvement. Mononeuritis multiplex is a major clinical finding . Asthma is one of the cardinal features of EGPA. Kidney-- Glomerulonephritis Kidney-- Hypertension

48. Micrograph showing an eosinophilic vasculitis consistent with Churg –Strauss syndrome. H&E stain. One of the American College of Rheumatology criteria for Churg –Strauss syndrome is extravascular eosinophil infiltration on biopsy .

49. http:// www.kidneypathology.com/English_version/Crescentic_GN.html Wikipedia Google images Medscape REFERENCES

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