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NEPHRITIC SYNDROMENephritic Syndrome The nephritic Syndrome is a clinical complex, usually of acute onset. Is caused by inflammatory lesions of glomeruli. Characterized by; 1) Hematuria with red cells(dysmorphic) & red blood cell casts in urine (hallmark) . 2) Some degree of oliguria and azotemia. 3) Hypertension. 4) Proteinuria (subnephrotic range 0.3–3 g/d). 5) Edema, if present, in dependent (e.g., periorbital or scrotal) areas.(due to less fluid excreted0 Retention of metabolites Azotemia Hypertension Edema + Oliguria + azotemia escape of red cells into the urine The lesions that cause the nephritic syndrome have in common proliferation of the cells within the glomeruli, accompanied by a leukocytic infiltrate NEPHRITIC SYNDROME Acute diffuse proliferative GN. Acute Proliferative Glomerulonephritis associated with influx of leukocytes , especially neutrophils. This inflammatory reaction injures the capillary walls, permitting escape of red cells into the urine, and induces hemodynamic changes that lead to a reduction in the GFR. These lesions are typically caused by immune complexes. The inciting antigen may be exogenous or endogenous. The prototypic exogenous antigen-induced disease pattern is post infectious glomerulonephritis. An example of an endogenous antigen-induced disease is the nephritis of SLE. The most common underlying infections are streptococcal, but the disorder also has been associated with other infections like pneumococcal ,staphylococcal infections, viral diseases such as mumps, measles, chicken-pox, and hepatitis B and C. The classic case, a young child abruptly develops malaise, fever, nausea, oliguria, and hematuria (smoky or cola-colored urine) 1 to 2 weeks after recovery from a sore throat. The patients have red cell casts in the urine, mild proteinuria (usually less than 1 gm/day), periorbital edema, and mild to moderate hypertension. post-streptococcal glomerulonephritis Poststreptococcal glomerulonephritis occurs most frequently in children 6 to 10 years of age, but adults of any age can also be affected. Only certain strains of group A β-hemolytic streptococci are nephritogenic. The initial infection is localized to the pharynx or skin (impetigo) appears 1 to 4 weeks after a streptococcal infection. It is an immune complex disease, when the nature of the pathogenic antigen remains not clear whether circulating complexes or those formed in situ deposited on the GBM (subepithelial) complement activation inflammatory reaction in glomeruli glomerular injury. enlarged, diffuse hypercellular glomeruli . (1) Infiltration by leukocytes, both neutrophils and monocytes. (3) In severe cases crescent formation. Neutrophil exudation, and red cell casts within tubules. Electron microscopy shows subepithelial immune complex deposits (humps) . Immunofluorescence shows granular deposits of IgG, IgM, and C3 throughout the glomerulus (staphylococcal infection produce IgA). Low power H & E This glomerulus is large hypercellular and capillary loops are poorly defined. This is a type of proliferative glomerulonephritis Sub epithelial electron-dense deposits or “humps” Clinical course; Fever, nausea & nephritic syndrome (mild). There is usually gross hematuria due to oxidation of hemoglobin to methemoglobin. In children; Complete recovery occurs in most cases(spontaneously resolves). In some cases the proteinuria is severe--- nephrotic syndrome. Few develop crescentic GN or CRF. In adults; 15-50% develop CRF in 10-20 years. Blood tests: -Decreased complement( hypocomplementemia) (Note: Post infectious GN due to staphylococcal infection , Note the red cell casts in the tubules. - NEPHRITIC SYNDROME Acute diffuse proliferative GN. 2- Systemic disorders such as SLE. *Approximate prevalence of primary disease is 95% of the cases in children and 60% in adults. Approximate prevalence of systemic disease is 5% of the cases in children and 40% in adults. IgA Nephropathy (Berger disease) (Disease That Present Mostly With Asymptomatic Hematuria) . It usually affects children & young adult, men affected more common than women. Begins by gross hematuria that occurs within 1-2 days of upper respiratory tract infection. Hematuria subsides after days & recurs every few months. IgA nephropathy is the commonest cause of recurrent gross hematuria or microscopic hematuria & is the most common glomerular disease worldwide. • The pathogenic hallmark is the deposition of IgA in the mesangium. Some have considered IgA nephropathy to be a localized variant of Henoch-Schönlein purpura, also characterized by IgA deposition in the mesangium. In contrast to IgA nephropathy, which is purely a renal disorder, Henoch-Schönlein purpura is a systemic syndrome involving the skin (purpuric rash), gastrointestinal tract (abdominal pain), joints (arthritis), and kidneys. • Pathogenesis: • IgA is present in plasma at low concentration normally. Mostly present in mucosal secretion. • There are two subclasses of IgA molecules in humans (IgA1 and IgA2), only IgA1 forms the nephritogenic deposits of IgA nephropathy. An abnormally glycosylated IgA1 (i.e., galactose- deficient IgA1 [Gd-IgA1]) immunoglobulin is thought to play a central role in the pathogenesis. Pathogenesis,cont’d, antigens (e.g., viruses, bacteria, food proteins) lead to increased IgA synthesis, some of which is abnormally glycosylated bind to IgG and form antiglycan antibodies forming IgA-containing immune complexes which deposited with IgA in the mesangium. The presence of C3 points to activation of the alternative complement pathway proinflammatory cytokines and initiate glomerular injury. Patients with IgA nephropathy may have increased production of IgA ,this occurs in cases of celiac disease due to presence of mucosal defect and in cases of liver diseases where there is defective hepatobiliary clearance of IgA complexes (secondary IgA nephropathy). Genetic influence is suggested by the occurrence of this condition in families. Morphology: show: glomeruli(FGN) , or electron-dense deposits in the mesangium. By immunofluorescence microscopy with C3 and properdin and lesser amounts of IgG or IgM. mesangial widening and inflammation Clinical course The disease can be suspected by light microscopic examination, but the diagnosis is made only by immunocytochemical techniques . Many patients present with gross recurrent hematuria(red or cola-coloured urine) 1-2 days after an infection of the respiratory or, less commonly, gastrointestinal or urinary tract. The hematuria typically lasts for several days and then subsides, only to return every few months. 30% to 40% have only microscopic hematuria, with or without proteinuria. 5% to 10% develop a typical acute nephritic syndrome. Many patients maintain normal renal function for decades. Slow progression to chronic renal failure occurs in 15% to 40% of cases over a period of 20 years. Onset in old age, heavy proteinuria, hypertension, and the extent of glomerulosclerosis on biopsy are clues to an increased risk of progression. Lab findings: Serum IgA level (50%), normal serum complement level . Indications of renal biopsy in IgA nephropathy : • It is better to be earlier if there is indication .what indication? • Recurrent hematuria with proteinuria or any degrees of renal dysfunction or hypertension . • But if patient presented only with isolated hematuria with no or mild proteinuria( or less than 1gm) ,and normal RFT no biopsy, and should follow up the pt. • Relative renal biopsy indication , if pt with isolated hematuria come with relative as a donor for renal transplantation , so biopsy may done. . Acute diffuse proliferative GN. RAPIDLY PROGRESSIVE (CRESCENTIC) It is a clinical syndrome assoc. with sever,intense glomerular injury, characterized by rapid progressive loss of renal function(uremia) & severe oliguria and signs of nephritic syndrome. It does not denotes a specific etiologic form of GN. If untreated , renal failure occurs in weeks or months. Usually in adults 50s -60s. The most common histologic picture is the presence of crescents in most glomeruli . Classification and Pathogenesis RPGN may be caused by a number of different diseases, some restricted to the kidney and others systemic. Although no single mechanism can explain all cases, there is little doubt that in most cases the glomerular injury is immunologically mediated. A practical classification divides RPGN into three groups on the basis of immunological findings . In each group the disease may be associated with a known disorder, or it may be idiopathic. Type I RPGN; (Anti-GBM), 12% May be idiopathic or in cases of Goodpasture syndrome. Patients benefit from plamapharesis. Anti-GBM antibodies in serum. Type II RPGN; (Immune complex), 44% May be idiopathic or may complicate any of the immune complex nephritis as in cases of SLE, post-infectious GN, IgA nephropathy, Henoch-Schonlein purpura. This type shows cellular proliferation and influx of leukocytes within the glomerular tuft, in addition to crescent formation. There is granular deposits of immunoglobulins in GBM and/or mesangium and/or complement on immunofluorescence studies. This disorder usually does not respond to plasmapheresis. • Type III RPGN; (Pauci-immune), 44% May be idiopathic or in some cases of systemic vasculitis such as Wagener granulomatosis, microscopic polyarteritis. No immune deposits ( lack of anti-GBM antibodies or significant immune complex deposition). ANCA antibodies in serum. • The common denominator in all types of RPGN is severe glomerular injury. GOODPASTURE SYNDROME(autoimmune disease) IgG) directed against basement membrane (anti-GBM antibodies) ,which results in damage of the lungs and the kidneys ,because anti- GBM antibodies also bind to (Cross reaction) pulmonary alveolar capillary basement membranes to produce the clinical picture of pulmonary hemorrhages associated with renal failure. -The Goodpasture antigen is the noncollagenous component of type IV collagen. Morphology of RPGN; Kidneys are enlarged, pale with petechial hemorrhages on cortical surfaces Microscopically Depending on the underlying cause, the glomeruli may show cellular proliferation outside the capillary loops, sometimes in association with segmental capillary necrosis, breaks in GBM, and deposition of fibrin in Bowman’s space . More than half of the glomeruli show crescents. Crescents are formed by proliferation of parietal cells of Bowman's capsule & by migration of monocytes and macrophages into the urinary space. Fibrin strands are frequently prominent between the cellular layers in the crescents. Crescents may obliterate Bowman's space & compress the glomeruli tuft. The escape of fibrinogen into Bowman space and its conversion to fibrin are an important contributor to crescent formation. Crescentic glomerulonephritis (PAS stain). Note the collapsed glomerular tufts. Crescent between Bowman capsule and glomerular tuft. • Electron microscopy Regardless of type, electron microscopy may show distinct ruptures in the GBM, indicating severe injury that allows leukocytes, proteins, and inflammatory mediators to reach the urinary space, where they trigger the crescent formation. In time, most crescents undergo sclerosis, but restoration of normal glomerular architecture may be achieved with early aggressive therapy. -In type II, electron dense immune complex deposits are seen within the glomeruli. Electron micrograph showing characteristic complement, granular immune deposits; deposition of immune reactants. (-ve) Linear IF Clinical Course RPGN is a clinical entity with features of the nephritic syndrome (hematuria , dysmorphic RBC, RBC casts, hypertension , ..) with rapid loss of renal function and progress rapidly to renal failure(uremia ). range may occur. In Goodpasture syndrome the course may be dominated by recurrent hemoptysis or even life- threatening pulmonary hemorrhage. Serum analyses for anti-GBM antibodies, antinuclear antibodies, and ANCAs are helpful in the diagnosis of specific subtypes. • The prognosis can be roughly related to the number of crescents ,those with crescent are present in less than 80% of the glomeruli have a more favorable prognosis than those in whom the percentage of crescents is higher, and it has poor prognosis if not treated early. Treatment: • Plasma exchange(in association with immunosuppressants) may be of benefit in those with anti-GBM antibody GN and in some cases of ANCA-related pauciimmune crescentic GN. • Immunosuppressants . NEPHRITIC SYNDROME Acute diffuse proliferative GN. HEREDITARY NEPHRITIS A collection of genetic diseases which principally involve glomeruli . Alport syndrome (triad of nephritis, nerve deafness, and eye disorders) X-linked dominant disorder having mutation in alpha -5 chain of type IV collagen located on X- chromosome. It affects males more severely than females . It has systemic manifestations. • Slowly progressive, terminating in chronic kidney disease in the 2nd to 3rd decades of life. The presenting features are persistent or recurrent hematuria accompanied by erythrocyte casts, proteinuria and hypertension. interstitium glomerular sclerosis, tubular atrophy and interstitial fibrosis. • Electron microscope: The GBM shows irregular foci of thickening alternating with attenuation (thinning),with longitudinal splitting and lamination of lamina densa, often producing a distinctive basket-weave Appearance(due to defective GBM production). Similar alterations can be found in the tubular basement membranes. • Treatment: ACE inhibitors and transplantation. NEPHRITIC SYNDROME Acute diffuse proliferative GN. Lupus nephritis: Renal manifestations of systemic lupus erythematosus (SLE) are termed lupus nephritis. Lupus nephritis affects up to 50% of SLE patients. It occurs between 20 & 30 years. Common in females, F:M ratio=10:1. SLE gives rise to a heterogenous group of glomerular lesions & clinical presentations. The principal mechanism of injury is immune complex deposition in the glomeruli, tubular or peritubular capillary basement membranes, or larger blood vessels. It activate complements. Other injuries may include thrombi in glomerular capillaries, arterioles, or arteries, often associated with antiphospholipid antibodies. All of the glomerular lesions are the result of deposition of immune complexes that are regularly present in the mesangium causing cellular proliferation with infiltration of PMNs ,or along the entire basement membrane and sometimes throughout the glomerulus . The immune complexes consist of DNA and anti-DNA antibodies, but other antigens such as histones have also been implicated.(TYPE III HS). Classes of Lupus Nephritis (WHO classification) Class I: Lupus with no renal lesion (20%) Class II: Mesangial ("mesangial proliferative") lupus nephritis (10%) Class III: Focal proliferative lupus nephritis (10%) Class IV: Diffuse proliferative lupus nephritis (50%) Class V: Diffuse membranous lupus nephritis (10%) Class VI: Sclerosing lupus nephritis . Class III, IV, V may show Focal necrosis of capillary wall & PNL infiltrate Fibrinoid deposits Capillary thrombi Crescent formation Class I: Minimal lesions • On light microscopy, these cases do not show any abnormality. But examination by electron microscopy and immunofluorescence microscopy shows deposits within the mesangium which consist of IgG and C3. • No clinical finding. These cases have mild clinical manifestations, and characterized by mesangial cell proliferation and immune complex deposition without involvement of glomerular capillaries. By light microscopy, there is increase in the number of mesangial cells and amount of mesangial matrix. Electron microscope and immunofluorescence studies reveal granular mesangial deposits of IgG and C3; sometimes IgA and IgM are also present in the deposits. Class III: Focal segmental lupus nephritis(focal proliferative LN) • Is defined by less than half glomeruli are involved . The lesions may be segmental or global. • By light microscope: Focal and segmental proliferation of endothelial and mesangial cells, together with infiltration by macrophages and sometimes neutrophils. • Clinically, class II and III, come with mild to moderate proteinuria and hematuria. Lupus nephritis, focal proliferative type. There are two focal necrotizing lesions in the glomerulus (arrows). Class IV: Diffuse proliferative lupus nephritis • all the morphologic manifestations of lupus are present in most advanced form .This is the most severe and the most common form of lupus nephritis (occurring in 35% to 60% of patient). • Clinically, combination of nephrotic and nephritic syndrome. • light microscopy. diffuse proliferation of endothelial, mesangial, and sometimes epithelial cells, involving most or all glomeruli with crescent formation . -Subendothelial immune complex deposits may create a circumferential gross thickening of the capillary wall, forming “wire-loop” structures on light microscopy. due to immune complexes deposition. • Electron microscopy shows large electron-dense deposits in the mesangium and in the subendothelial region. Endothelial proliferation . • Immunofluorescence are positive for IgG; sometimes also for IgA or IgM, and C3. Lupus nephritis, diffuse proliferative type. Note the marked increase in cellularity throughout the glomerulus. wire-loop” structures • These lesions resemble those of idiopathic membranous GN. • light microscopy :These consist of diffuse thickening of glomerular capillary wall. Mesangial hypercellularity is present in some cases. • Electron microscope ,IF: show subendothelial deposits of immune complexes containing IgG, IgM and C3. • Is usually accompanied by severe proteinuria or nephrotic syndrome, or diffuse lupus nephritis. • Clinically Nephrotic syndrome. Class VI: Sclerosing lupus nephritis: • This is chronic kidney disease of SLE. Similar to chronic GN. • Most glomeruli are sclerosed and hyalinised and there may be remnants of preceding lesions. Clinical features: -Lupus nephritis more commonly manifested as nephrotic syndrome , but many cases presented as niphritic syndrome (according to location of injury and extent of lesion). - Although in a given case, the lesions in lupus nephritis fit into one of the classes described above, it is not unusual to find overlapping and progressive transformation of lupus lesions during the course of disease, or progressed to RPGN renal failure. • Diagnosis is typically require kidney biopsy which establish the pattern of injury and guide immunosuppressive therapy. -Hypocomplementamia (specially C3, C4 due to overuse). • Treatment: • Class I and II: No treatment required. • Class III,IV,V: Immunosuppression (corticosteroids, cyclophosphamide and |or azathioprine) • Note: Renal lesion severity often determines overall prognosis of SLE patients. • Henoch-Schönlein Purpura • Type of vasculitis, causing purpuric skin lesions characteristically involving the extensor surfaces of arms and legs as well as buttocks and abdominal manifestations, nonmigratory arthralgia; and renal abnormalities. The renal manifestations occur in one third of patients and include gross or microscopic hematuria, nephritic syndrome, and nephrotic syndrome, or some combination of these. • On histologic examination, the renal lesions vary from mild focal mesangial proliferation to diffuse mesangial proliferation and/or endocapillary to crescentic rapidly progressive GN • IF: Deposition of IgA, sometimes with IgG and C3, in the mesangial region. • recurrences of hematuria may persist for many years after onset. Most children have an excellent prognosis(self limited). Patients with the more diffuse lesions, crescents, or the nephrotic syndrome have a somewhat poorer prognosis. Why do patients with nephritic syndrome develop oliguria and azotemia?-GFR?-Tubular function? • 1- Inflamed glomeruli decrease GFR • 2- Tubular function is intact, so reabsorbing fluid to make up for decreased GFR What is seen in the urine sediment of patients with nephritic syndrome? • RBC casts • Dysmorphic RBC • IgG, IgM, C3 • Presents 2-3 weeks after strep infection In nephritic syndrome, neutrophils invade and damage the glomeruli. What would be seen on a biopsy? • Hypercellular, inflamed glomeruli- • Hypercellularity due to invading neutrophils-Inflamed due to damage from neutrophils Post-Strep Glomerulonephritis: Only certain strains of GAS are able to cause glomerulonephritis. What pathogenic factor must be present for this to develop? • Only strains with M protein Post-Strep Glomerulonephritis: How is this diagnosed? • Anti-DNAse antibodies • What is seen on EM? • Subepithelial humps-Immune complexes deposit in the subepithelial layer What is Rapidly Progressive Glomerulonephritis :?-What does this rapidly progress to? • Nephritic syndrome that rapidly progresses to renal failure-Weeks to months Rapidly Progressive Glomerulonephritis :What is the characteristic findings on LM? • Crescents in Bowman's space Rapidly Progressive Glomerulonephritis : All types of these will show crescents in Bowman's capsule. How can you differentiate between the different types? • Differentiate based on clinical picture and immunofluorescence Rapidly Progressive Glomerulonephritis :Wegener’s granulomatosis can cause RPGN with a negative IF. What antibodies is this associated with? • Goodpasture’s syndrome composed of? • Crescents are composed of fibrin and macrophages-Also C3b and glomerular parietal cells Rapidly Progressive Glomerulonephritis : What are the possible causes of granular IF? • Post-strep glomerulonephritis that progressed Diffuse proliferative glomerulonephritis IgA Nephropathy (Berger's Disease):Because the excess IgA can't be cleared fast enough, it is able to form immune complexes. Where do these immune complexes deposit? • Deposit in the mesangium of the glomeruli IgA Nephropathy (Berger's Disease):What is the prognosis? • Slowly progresses to chronic renal failure IgA Nephropathy (Berger's Disease):Does this affect adults or kids? • Affects both adults and kids IgA Nephropathy (Berger's Disease):What is seen on IF? • IgA immune complexes seen in mesangium IgA Nephropathy (Berger's Disease):IgA immune complexes deposit in the mesangium of the glomeruli. How does this present? • Episodic hematuria and RBC casts-Usually following a respiratory/GI infection Specific Glomerular Diseases (sammary) • Acute GN is known to follow acute infection (poststreptococcal) and characteristically presents as acute nephritic syndrome in children. • RPGN is an acute reduction in renal function resulting in acute renal failure rapidly and is characterised…