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Contrasting features of acute nephritic and nephrotic glomerulus, renal interstitium, calyceal system, ureter, bladder, 649 Table 20.7 syndromes. prostate, urethra, and underlying bleeding disorder, congenital F...

Contrasting features of acute nephritic and nephrotic glomerulus, renal interstitium, calyceal system, ureter, bladder, 649 Table 20.7 syndromes. prostate, urethra, and underlying bleeding disorder, congenital FEATURE ACUTE NEPHRITIC NEPHROTIC abnormalities of the kidneys or neoplasia. Glomerular SYNDROME SYNDROME haematuria is indicated by the presence of red blood cells, red CHAPTER 20 cell casts and haemoglobin in the urine. Glomerular haematuria 1. Proteinuria Mild (< 3 gm per Heavy (> 3 gm per is frequently associated with asymptomatic proteinuria. 24 hrs) 24 hrs) 2. Hypoalbuminaemia Uncommon Present Clinical Manifestations of Renal GIST BOX 20.5 3. Oedema Mild, in loose Marked, generalised Diseases tissues peripheral  In general, different glomerular diseases fall in to one or 4. Mechanism of Na+ and water plasma osmotic more of 6 clinical syndromes: nephritic and nephrotic oedema retention pressure, Na+ and syndromes; acute and chronic renal failure; asymptomatic water retention proteinuria and haematuria.  Acute nephritic syndrome is acute onset of microscopic The Kidney and Lower Urinary Tract 5. Haematuria Present, Absent microscopic haematuria, mild proteinuria, hypertension, oedema and 6. Hypertension Present Present in advanced oliguria following an infective illness about 10 to 20 days disease earlier. 7. Hyperlipidaemia Absent Present  Nephrotic syndrome is characterised by findings of massive proteinuria, hypoalbuminaemia, oedema, hyper- 8. Lipiduria Absent Present lipidaemia, lipiduria, and hypercoagulability. 9. Oliguria Present Present in advanced disease 10. Hypercoagulability Absent Present PATHOGENESIS OF GLOMERULAR INJURY Most forms of primary GN and many of the secondary glomeru- III. ACUTE RENAL FAILURE As already described above, lar diseases in human beings have immunologic pathogenesis. acute renal failure (ARF) is characterised by rapid decline in This view is largely based on immunofluorescence studies of renal function. ARF has many causes including glomerular GN in humans which have revealed glomerular deposits of disease, principally rapidly progressive GN and acute diffuse immunoglobulins and complement in patterns that closely proliferative GN. resemble those of experimental models. The consequences of injury at different sites within the glomerulus in various IV. CHRONIC RENAL FAILURE Glomerular causes of glomerular diseases can be assessed when compared with chronic renal failure (CRF) have already been described. the normal physiologic role of the main cells involved i.e. These cases have advanced renal impairment progressing over endothelial, mesangial, visceral epithelial, and parietal epithe- years and is detected by significant proteinuria, haematuria, lial cells as well as of the GBM as summed up in Table 20.8. hypertension and azotaemia. Such patients generally have Immunologic mechanisms underlying glomerular injury small contracted kidneys due to chronic glomerulonephritis. are primarily antibody-mediated (immune-complex disease). V. ASYMPTOMATIC PROTEINURIA Presence of proteinu- There is evidence to suggest that cell-mediated immune ria unexpectedly in a patient may be unrelated to renal reactions in the form of delayed type hypersensitivity can disease (e.g. exercise-induced, extreme lordosis and also cause glomerular injury in some conditions. In addition, orthostatic proteinuria), or may indicate an underlying mild a few secondary mechanisms and some non-immunologic glomerulonephritis. Association of asymptomatic haematuria, mechanisms are involved in the pathogenesis of some forms of hypertension or impaired renal function with asymptomatic glomerular diseases in human beings (Table 20.9). proteinuria should raise strong suspicion of underlying glomerulonephritis. I. IMMUNOLOGIC MECHANISMS VI. ASYMPTOMATIC HAEMATURIA Asymptomatic micro- Experimental studies and observations in humans have scopic haematuria is common in children and young adole- revealed that immunologic mechanisms, most impor- scents and has many diverse causes such as diseases of the tantly antigen-antibody complexes, underlie most forms of Table 20.8 Relationship of physiologic role of glomerular components with consequences in glomerular injury. COMPONENT PHYSIOLOGIC FUNCTION CONSEQUENCE OF INJURY RELATED GLOMERULAR DISEASE 1. Endothelial cells i) Maintain glomerular perfusion Vasoconstriction Acute renal failure ii) Prevent leucocyte adhesion Leucocyte infiltration Focal/diffuse proliferative GN iii) Prevent platelet aggregation Intravascular microthrombi Thrombotic microangiopathies 2. Mesangial cells Control glomerular filtration Proliferation and increased matrix Membranoproliferative GN 3. Visceral epithelial cells Prevent plasma protein filtration Proteinuria Minimal change disease, FSGS 4. GBM Prevents plasma protein filtration Proteinuria Membranous GN, ? MPGN 5. Parietal epithelial cells Maintain Bowman’s space Crescent formation RPGN tahir99 - UnitedVRG - vip.persianss.ir 650 Table 20.9 Pathogenetic mechanisms in glomerular diseases. MECHANISM RELATED GLOMERULAR DISEASE I. IMMUNOLOGIC MECHANISMS SECTION III A. Antibody-mediated glomerular injury 1. Immune-complex disease Immune-complex mediated GN (Acute diffuse proliferative GN, membranous GN, membranoproliferative GN, IgA nephropathy; secondary glomerular disease in SLE, malaria etc.) 2. Anti-glomerular basement membrane (Anti-GBM) disease Goodpasture’s disease 3. Alternate pathway disease Membranoproliferative GN type II 4. Other mechanisms (anti-neutrophil cytoplasmic antibodies or Vasculitis ANCA, anti-endothelial cell antibodies or AECA) Systemic Pathology B. Cell-mediated glomerular injury Pauci-immune GN (type III RPGN) C. Secondary pathogenetic mechanisms Mediate glomerular injury in various primary and secondary glomerular diseases II. NON-IMMUNOLOGIC MECHANISMS 1. Metabolic Diabetic nephropathy, Fabry’s disease 2. Haemodynamic Hypertensive nephrosclerosis, FSGS 3. Deposition Amyloid nephropathy 4. Infectious HIV-nephropathy, immune-complex GN in SABE 5. Drugs NSAIDs-associated minimal change disease 6. Inherited Alport’s syndrome, nail-patella syndrome glomerular injury. The general principles of these mechanisms immunoglobulins (IgG, IgM and IgA) and complement (mainly in different forms of glomerular diseases are discussed below, C3). Based on the experimental models and studies in human while specific features pertaining to individual types of GN are beings, the following 3 patterns of glomerular deposits of described separately later. immune complexes in various glomerular diseases have been observed as illustrated in Fig. 20.11: A. Antibody-Mediated Glomerular Injury i) Exclusive mesangial deposits are characterised by very mild 1. IMMUNE COMPLEX DISEASE Majority of cases of form of glomerular disease. glomerular disease result from deposits of immune complexes ii) Extensive subendothelial deposits along the GBM are (antigen-antibody complexes). The immune complexes are accompanied by severe hypercellular sclerosing glomerular represented by irregular or granular glomerular deposits of lesions. Figure 20.11 Diagrammatic representation of ultrastructure of a portion of glomerular lobule. It shows three patterns of irregular or granular glomerular deposits in immune-complex disease. tahir99 - UnitedVRG - vip.persianss.ir iii) Subepithelial deposits are seen between the outer surface of anti-GBM disease is Masugi nephritis (nephrotoxic serum 651 the GBM and the podocytes. nephritis) produced in rats by injection of heterologous Deposits may be located at one or more of the above sites in antibodies against GBM prepared in rabbits by immunisation any case of glomerular injury. with rat kidney glomerular tissue. CHAPTER 20 It was widely believed earlier that glomerular deposits Anti-GBM disease is classically characterised by interrupted result from circulating immune complexes. Now, it has been linear deposits of anti-GBM antibodies (mostly IgG; rarely IgA shown that glomerular deposits are formed by one of the and IgM) and complement (mainly C3) along the glomerular following two mechanisms: basement membrane. These deposits are detected by i) Local immune complex deposits Classic experimental immunofluorescence microscopy or by electron microscopy. model to understand human in situ immune complex Anti-GBM disease is characteristically exemplified by GN is Heymann nephritis. In this, rats were injected with glomerular injury in Goodpasture’s syndrome in some cases of homologous kidney homogenates that resulted in a chronic rapidly progressive GN. About half to two-third of the patients glomerular disease manifested by heavy proteinuria. It was due with renal lesions in Goodpasture’s syndrome have pulmonary haemorrhage mediated by cross-reacting autoantibodies The Kidney and Lower Urinary Tract to autoimmunity induced by antibodies to intrinsic glomerular antigens resulting in formation of in situ immune deposits on against alveolar basement membrane (page 475). glomerular basement membrane. The intrinsic antigen in the 3. ALTERNATE PATHWAY DISEASE As apparent from the experiment was found in epithelial brush borders of proximal above mechanisms, the complement system, in particular convoluted tubules and has been named megalin. C3, contributes to glomerular injury in most forms of GN. Similar phenomenon is seen in human membranous Deposits of C3 are associated with the early components C1, glomerulonephritis. In humans, the corresponding autologous C2 and C4 which are evidence of classic pathway activation non-basement membrane antigen is identified as gp330 (glyco of complement. But in alternate pathway activation, there is protein with a mass of 330 kD) or nonglomerular antigens decreased serum C3 level, decreased serum levels of factor B planted on glomeruli (e.g. certain drugs, endotoxins, parasitic and properdin, normal serum levels of C1, C2 and C4 but C3 products etc). It is located on the podocytes and coated on and properdin are found deposited in the glomeruli without pits of proximal tubular epithelial cells. Antibodies are formed immunoglobulin deposits, reflecting activation of alternate against such planted antigens. Main antigen-antibody reaction pathway of complement. Such patients have circulating anti- takes place at soles of the foot processes of podocytes and the complementary nephritic factor (C3NeF) which is an IgG immune complexes get deposited at the lamina rara externa of antibody and acts as an autoantibody to the alternate C3 the basement membrane. Correspondingly, in membranous convertase, leading to persistent alternate pathway activation. glomerulonephritis, granular IgG deposits are found along the The deposits in alternate pathway disease are charac- subepithelial side of basement membrane. Similarly, electron teristically electron-dense under electron microscopy; dense deposits are found on the epithelial side of basement glomerular lesions in such cases are referred to as dense-deposit membrane. disease. Currently, this mechanism is considered responsible for Alternate pathway disease occurs in most cases of type most cases of immune complex GN. II membranoproliferative GN, some patients of rapidly ii) Circulating immune complex deposits This mechanism progressive GN, acute diffuse proliferative GN, IgA nephropathy used to be considered important for glomerular injury earlier and in SLE. but now it is believed that circulating immune complexes cause glomerular damage under certain circumstances only. 4. OTHER MECHANISMS OF ANTIBODY-MEDIATED These situations are: their presence in high concentrations for INJURY A few autoantibodies have been implicated in some prolonged periods, or when they possess special properties that patients of focal segmental glomerulosclerosis and few other cause their binding to glomeruli, or when host mechanisms are types of GN. These antibodies include the following: defective and fail to eliminate immune complexes. The antigens i) Anti-neutrophil cytoplasmic antibodies (ANCA) About evoking antibody response may be endogenous (e.g. in SLE) or 40% cases of rapidly progressive GN are deficient in may be exogenous (e.g. Hepatitis B virus, Treponema pallidum, immunoglobulins in glomeruli (pauci-immune GN) and are Plasmodium falciparum and various tumour antigens). The positive for ANCA against neutrophil cytoplasmic antigens in antigen-antibody complexes are formed in the circulation and their circulation. ANCA causes endothelial injury by generation then trapped in the glomeruli where they produce glomerular of reactive oxygen radicals. ANCA-mediated vasculitis is injury after combining with complement. also seen in Wegenger’s granulomatosis and Churg-Strauss Immune complex GN by either of the above mechanisms is syndrome. observed in the following human diseases: ii) Anti-endothelial cell antibodies (AECA) Autoantibodies i) Primary GN e.g. acute diffuse proliferative GN, memb- against endothelial antigens have been detected in circulation ranous GN, membranoproliferative GN, IgA nephropathy and in several inflammatory vasculitis and glomerulonephritis. some cases of rapidly progressive GN and focal GN. These antibodies increase the adhesiveness of leucocytes to ii) Systemic diseases e.g. glomerular disease in SLE, malaria, endothelial cells. syphilis, hepatitis, Henoch-Schonlein purpura and idiopathic mixed cryoglobulinaemia. B. Cell-mediated Glomerular Injury (Delayed-type Hypersensitivity) 2. ANTI-GBM DISEASE Less than 5% cases of human GN are associated with anti-GBM antibodies. The constituent of There is evidence to suggest that cell-mediated immune GBM acting as antigen appears to be a component of collagen reactions may be involved in causing glomerular injury, IV of the basement membrane. The experimental model of particularly in cases with deficient immunoglobulins (e.g. in tahir99 - UnitedVRG - vip.persianss.ir 652 pauci-immune type glomerulonephritis in RPGN). Cytokines 1. Metabolic glomerular injury e.g. in diabetic nephropathy and other mediators released by activated T cells stimulate (due to hyperglycaemia), Fabry’s disease (due to sulfatidosis). cytotoxicity, recruitment of more leucocytes and fibrogenesis. 2. Haemodynamic glomerular injury e.g. systemic hyper- CD4+ T lymphocytes recruit more macrophages while CD8+ tension, intraglomerular hypertension in FSGS. cytotoxic T lymphocytes and natural killer cells cause further SECTION III 3. Deposition diseases e.g. amyloidosis. glomerular cell injury by antibody-dependent cell toxicity. 4. Infectious diseases e.g. HBV, HCV, HIV, E. coli-derived Soluble factor derived from T lymphocytes is implicated in nephrotoxin. proteinuria in minimal change disease and focal GS. However, cell-mediated injury is yet less clear than 5. Drugs e.g. minimal change disease due to NSAIDs. antibody-mediated glomerular injury. 6. Inherited glomerular diseases e.g. Alport’s syndrome, nail- patella syndrome. C. Secondary Pathogenetic Mechanisms The evolution of end-stage renal failure in glomerular injury (Mediators of Immunologic Injury) is explained on the basis of adaptive glomerular hypertrophy of unaffected glomeruli that results in increased glomerular blood Systemic Pathology Secondary pathogenetic mechanisms are a number of mediators of immunologic glomerular injury operating in man flow and increased glomerular capillary pressure inducing and in experimental models. These include the following: intraglomerular hypertension. These events lead to increased deposition of mesangial matrix and proliferation of mesangial 1. NEUTROPHILS Neutrophils are conspicuous in certain cells, endothelial and epithelial cell injury, and eventually to forms of glomerular disease such as in acute diffuse prolife- progressive glomerulosclerosis and end-stage renal failure. rative GN, and may also be present in membranoproliferative GN and lupus nephritis. Neutrophils can mediate glomerular injury by activation of complement as well as by release of GIST BOX 20.6 Pathogenesis of Glomerular Diseases proteases, arachidonic acid metabolites and oxygen-derived free radicals. These agents cause degradation of GBM and cell  Most forms of glomerular diseases in human beings have injury. immunologic pathogenesis—antibody-mediated or cell- mediated. 2. MONONUCLEAR PHAGOCYTES Many forms of  Antibody-mediated glomerular injury is often immune- human and experimental proliferative GN are associated complex disease, either local (in situ) or circulating with glomerular infiltration by monocytes and macrophages. deposits. Anti-GBM disease and alternate pathway activa- Accumulation of mononuclear phagocytes is considered an tion of complement are the other antibody mechanisms. important constituent of hypercellularity in these forms of GN A few autoantibodies (ANCA, AECA) are also implicated in aside from proliferation of mesangial and endothelial cells. certain glomerular diseases with vasculitis. Activated macrophages release a variety of biologically active  Cell-mediated immune reactions by delayed type hyper- substances which take part in glomerular injury. sensitivity can also cause glomerular injury. 3. COMPLEMENT SYSTEM The pathogenetic role of  Secondary mechanisms involve role of neutrophils, classical and alternate pathway of activation of complement monocytes, complement, platelets, mesangial cells and has already been highlighted above. Besides the components of activation of coagulation system. complement which mediate glomerular injury via neutrophils  Non-immunologic mechanisms have role in certain forms already mentioned, C5bC6789 (MAC, acronym for membrane of metabolic, infiltrative and inherited glomerular diseases. attack complex, also called terminal complex) is capable of inducing damage to GBM directly. SPECIFIC TYPES OF GLOMERULAR DISEASES 4. PLATELETS Platelet aggregation and release of Classification of different forms of glomerular diseases into mediators play a role in the evolution of some forms of GN. primary and secondary is already presented in Table 20.4. Increased intrarenal platelet consumption has been found to Features of individual types are described below and a occur in some forms of glomerular disease. summary of major forms of primary glomerulonephritis is 5. MESANGIAL CELLS There is evidence to suggest that given in Table 20.11 at the end of this discussion. mesangial cells present in the glomeruli may be stimulated to produce mediators of inflammation and take part in glomerular I. PRIMARY GLOMERULONEPHRITIS injury. Acute Glomerulonephritis 6. COAGULATION SYSTEM The presence of fibrin in early (Synonyms: Acute Diffuse Proliferative GN, crescents in certain forms of human and experimental GN Diffuse Endocapillary GN) suggests the role of coagulation system in glomerular damage. Fibrinogen may leak into Bowman’s space and act as stimulus Acute GN is known to follow acute infection and charac- for cell proliferation. Crescents usually transform into scar teristically presents as acute nephritic syndrome. Based on tissue under the influence of fibronectin which is regularly etiologic agent, acute GN is subdivided into 2 main groups: present in crescents in human glomerular disease. acute post-streptococcal GN and acute non-streptococcal GN, the former being more common. II. NON-IMMUNOLOGIC MECHANISMS ACUTE POST-STREPTOCOCCAL GN Though most forms of GN are mediated by immunologic Acute post-streptococcal GN, though uncommon and mechanisms, a few examples of glomerular injury by non- sporadic in the Western countries, is a common form of GN immunologic mechanisms are found: in developing countries, mostly affecting children between tahir99 - UnitedVRG - vip.persianss.ir