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Pathogenesis of Glomerulonephritis
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- 2. OUTLINE • INTRODUCTION • EPIDEMIOLOGY •RELEVANT ANATOMY • DEFINITION OF TERMS • CLASSIFICATION • PATHOGENESIS • HISTOLOGY • MANAGEMENT • CONCLUSION
- 3. INTRODUCTION • GN canbe defined as a spectrum of renal diseases of varied etiology and clinical presentations that are characterized by clinical and histological evidence of glomerular damage. •Note that despite the “itis” in GN, inflammation per se may not feature in many GNs. Associated terms include: •Glomerulonephritides •Glomerulopathy •Nephritis GLOMERULONEPHRITIDES–ThepathophysiologyGLOMERULONEPHRITIDES–Thepathophysiology
- 4. INTRODUCTION The term Glomerulonephritisand Glomerulopathy are usually used interchangeably to denote glomerular injury, although some authorities reserve the former term for injury with evidence of inflammation such as leucocyte infiltration, antibody deposition, and complement activation •It encompasses a group of disorders with wide- ranging clinical presentations,severity,causes and immunopathogenetic mechanisms •GN is an important cause of both acute and chronic kidney Disease worldwide.
- 5. STRUCTURE OF THEKIDNEY •The functioning unit of the kidney is the nephron •Each kidney has about one million nephrons •The number of nephrons is established during prenatal development. •After birth, no new nephron can develop and a lost nephron cannot be replaced.
- 6. Gross Anatomy •KIDNEYS – Paired organ – Each weigh 120 – 200g – Dimensions: 10 – 12 cm vertically, 5 -7 cm transversely, and 3 cm anteroposteriorly. – The outer surface can be divided into anterior side, dorsal side, upper pole and lower pole – The lateral surface is convex. – The medial surface is concave, deeply grooved (renal sinus) and forms the renal hilum – The ureter/renal pelvis, renal artery, renal vein, lymphatic vessels and nerves enter or exit through the renal hilum the kidney.
- 7. GENERAL ARCHITECTURE OFTHE KIDNEY •Kidney –Outer cortex –Inner medulla •Vasculature –the arterial system –Venous system –the resistance vessels •THE GLOMERULUS •Structural characteristics of the glomerular capillary wall –the endothelial cell –the glomerular visceral epithelial cell –the mesangial cell –the extracellular matrix: basement membrane, (GBM’s and mesangial matrix) •Filtration depends on –Hydrostatic pressure difference –Size of the molecule –Charge on the molecule
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- 9. EPIDEMIOLOGY •GN is recognizedas the second commonest cause of CKD worldwide. •In developed countries, it is still the 3rd commonest cause of ESRD in many countries. •In developing countries, it ranks 2nd or 1st •For every patient with clinically apparent GN receiving medical care, an estimated additional 5 to 10 patients have undiagnosed sub-clinical disease.
- 10. EPIDEMIOLOGY ... NIGERIA •GNis more common in the male than in the female population 1.4 : 1 •Peak incidence for AGN is usually October – January ( Etuk et al) •Case average of 7.5/year calabar - to 14.5/year in UPTH. •GN is the commonest cause of CKD in Nigeria from available reports
- 11. GLOSSARY OF DESCRIPTIVETERMS •All glomeruli –Diffuse: Involving ≥ 50% of the glomeruli –Focal: Involving <50% of glomeruli •Individual glomerulus –Global: if all or almost all of the glomerular tuft are involved –Segmental: if only part of the glomerulus is involved.
- 12. GLOSSARY OF DESCRIPTIVETERMS •Sclerosis refers to an increase in the amount of homogenous non-fibrillar extracellular material of similar composition to GBM and mesangial matrix. •Fibrosis refers to deposition of collagen type I and III and is more commonly a consequence of healing of crescents or tubulointerstitial inflammation.
- 13. GLOSSARY OF DESCRIPTIVETERMS •Proliferative is used to describe an increase in glomerular cell number, which can be either –true proliferation of resident glomerular cells or –glomerular hypercellularity caused by infiltration of leucocytes. •Proliferation of resident glomerular cells is classified as – intracapillary or endocapillary when referring to endothelial or mesangial cells and –extracapillary when referring to cells in Bowman’s
- 14. GLOSSARY OF DESCRIPTIVETERMS •A crescent is a half-moon-shaped collection of cells in Bowman’s space, usually composed of proliferating parietal epithelial cells and infiltrating macrophages. •Because crescentic GN is often associated with renal failure that progresses rapidly over weeks to months, the clinical term rapidly progressive GN and the pathologic term crescentic GN are often used interchangeably.
- 15. GLOSSARY OF DESCRIPTIVETERMS •Sub-epithelial – Located between the glomerular basement membrane and the podocytes. •Intra-membranous – within the basement membrane •Sub-endothelial - Between the glomerular basement membrane and the endothelium •Mesangial – within the mesangium
- 16. CLASSIFICATION ACCORDING TO AETIOLOGY •Primary:idiopathic but usually immune mediated •Secondary: there is a known cause
- 17. CLASSIFICATION ACCORDING TO CELLULARRESPONSE/APPEARANCE OF THE GLOMERULAR TUFT •Non-proliferative •Proliferative
- 18. CLASSIFICATION ACCORDING TO HISTOLOGIC PATTERN •Focalsegmental •Diffuse •MCD •Membranous •Menbranousproliferative
- 19. CLASSIFICATION OF ACCORDING TODURATION OF DISEASE •Acute GN refers to glomerular injury occurring over days to weeks. •Sub-acute or rapidly progressive GN refers to glomerular injury occurring over weeks or a few months. •Chronic GN refers to glomerular injury occurring over months or years.
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- 21. GN….BASIC DIVISION •Non- Proliferative •Minimalchange •Membranous •FSGS •Diabetes •Amyloidosis •Proliferative •Diffuse proliferative •(crescents) •Mesangiocapillary •Focal and segmental proliferative. All these are Histological patterns and NOT a diagnosis
- 22. PATHOGENESIS OF GLOMERULAR INJURY •Pathogenesisof glomerular injury involves a complex interplay between •Genetic factors eg congenital Nephrotic syndrome •Acquired: Immune and Non—immune Factors Immune Mechanisms –Cellular immunity –Humoral immunity –Complement system/cascade –Coagulation cascade –Soluble factors
- 23. Mechanisms of Glomerulonephritis Cell-mediatedimmune mechanismsAntibody deposits Compliment activation Influx of circulating leucocytes and cytokine and growth factor synthesis Glomerulonephritis Activation of resident cells Change in matrix On-off switch Scarring Resolution Persistant inflamation Exit of inflammatory molecules and leukocytes Genetic factors Hemodynamic factors PATHOPHYSIOLOGY.
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- 25. Genetic Factors • CongenitalNephrotic Syndrome - Mutations in nephrin - Mutation in podocin - Mutation in alpha Actinin 4 • Alport Syndrome • Thin basement membrane Disease
- 26. Immune Factors •Central tothe pathogenesis GN is inflammation which is often immune mediated. •Glomeruli have three properties that make them vulnerable to immunological attack: –they “filter” and trap immune complexes –they contain immunologically competent cells capable of processing antigen –they have structures like the GBM and mesangial cells which can act as “targets” for antibodies
- 27. Circulating Immune Complex •In conditions such as - SLE - HBV Infection - Malaria P. Falciparum and Malariae - Syphillis - Strptococcal infection • Deposition of immune complexes in the glomerulus which leads to complement activation, leucocytes recruitment, coagulation cascade activation and inflammation ensues
- 28. In-Situ Immune Complexes •Seen in Anti-GBM Ab GN • Ab directed to fixed antigens on the GBM • Ab may also react in situ with previously planted non- glomerular antigens such as DNA, IgG, bacterial products • Ab deposition shows a linear pattern while planted antigens induce a granular pattern of immunoglobulin deposition on immunoflorescence • Ant-GBM can also cross react with alveolar basement membrane leading to simultaneous kidney/lung lesions as obtained in GoodPasture Syndrome. • Α3 chain of type IV collagen is the target antigen in anti- GBM disease (Goodpasture’s syndrome
- 29. Cell mediated ImmuneGN •Cell-mediated immune mechanisms •A direct role of T cells in mediating proteinuria and crescent formation been suggested •T cells sensitized to endogenous or exogenous antigen present in the glomeruli recruit macrophages, resulting in a local delayed type hypersensitivity reaction. •There maybe no ab or immune complex deposition and and when present may not correlate with disease severity.
- 30. Mediators Of ImmuneInjury •Main pathway of Ab-mediated injury is complement- leucocyte mediated •Acute injury: Predominant infiltrating cells are neutrophils and monocytes •Chronic injury:Predominant cells are monocytes/macrophages and T cells. •The primary mechanism for attracting these cells is the secretion of chemokines and the expression of leucocyte adhesion molecules by local endothelial and resident cells; •Local release of complement activation fragments (C5a) is very crucial(Chemotactic agent)
- 31. Soluble Factors •Soluble factorsplay a role in the pathogenesis of glomerular disease. •Examples of soluble factors are; cytokines, chemokines, growth factors vasoactive mediators, reactive oxygen species, proteases, proteins in the coagulation cascade •These factors –promote recruitment and activation of inflammatory cells, –activate resident glomerular cells, –directly cause tissue injury, –stimulate production of matrix proteins (which forms the basis of scarring).
- 32. Non-immune Factors • PodocyteInjury • Nephron Loss - Any renal condition causing significant nephron destruction and reduced GFR - Adaptive changes in the kidney such as hypertrophy to remain renal fxn occurs - Associated maladaptive haemodynamic changes utimately perpertutes renal damage and a vicious cycle ensues
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- 40. LIGHT MICROGRAPH OFA NORMAL GLOMERULUS. There are only 1 or 2 cells per capillary tuft, the capillary lumens are open, the thickness of the glomerular capillary wall (long arrow) is similar to that of the tubular basement membranes (short arrow), and the mesangial cells and mesangial matrix are located in the central or stalk regions of the tuft (arrows).
- 41. HISTOLOGY ....MESANGIAL PROLIFERATIVE Normal glomerulusMesangial proliferative
- 42. HISTOLOGY ....MESANGIAL PROLIFERATIVE •Normal •Mesangialproliferative Light micrograph in membranoproliferative glomerulonephritis showing a lobular appearance of the glomerular tuft with focal areas of increased glomerular cellularity (large arrows), mesangial expansion (*), narrowing of the capillary lumens, and diffuse thickening of the glomerular capillary walls (small arrows).
- 43. HISTOLOGY .... DIFFUSE •Normalglomerulus Diffuse endocapillary hypercellularity: post-streptococcal GN
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- 45. HISTOLOGY ..... FOCALSEGMENTAL GLOMERULOSCLEROSIS
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- 48. PATHOGENESIS – CHRONIC PROGRESSIVEPHASE •Renal damage in the chronic-progressive phase of GN is mediated by non-immune mechanisms that develop as a result of loss of filtering-surface with accompanying increases in glomerular pressures in remaining nephrons. •These features lead to glomerular sclerosis as well as to chronic interstitial fibrosis, which is a consequence of multiple injurious events including ischaemia, glomerular cytokine release, and toxic effects of increased protein filtration on tubules
- 49. MGT:HISTORY •Family history ofkidney disease and hearing difficulties (Alport syndrome) •Medication e.g NSAID’s ACEI, penicillamine, gold, mercury in some skin lightening creams. •Recent throat infection PSGN or Viral Wegener’s granulomatosis, IgA. •Cancer - Solid tumors, Hodgkin’s (minimal change) or non Hodgkin’s (MPGN)
- 50. PHYSICAL EXAMINATION •Inspection –appearance, colour, pitting oedema, xanthelasma, alopecia, facial rash, purpura, clubbing, livedo reticularis •Palpation – pulse, hepatomegaly, palpable kidneys, splenomegaly, palapable bladder •Percussion – hepatomegaly, splenomegaly •Auscultation – renal artery bruits, other bruits, cardiac lesions, hypertension,
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- 52. CLINICAL FEATURES OFGN • .
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- 54. Useful Blood Testsin Investigations of Glomerular Disease •FBC – High white cell count in vasculitis, infections. •E &U,Cr – assesses severity of renal impairment •Total serum protein, albumin – Low in those with nephrotic syndrome •Immunoglobulins – High in vasculitis, SLE •Complement •Low C3, normal C4 in MPGN (type II) and sometimes SLE. •high C3, C4 in systemic vasculitis •Antiglomerular BM antibody – Goodpasture’s disease •Anti-dsDNA antibodies – SLE •C3 nephritic factor – MPGN (type II)
- 55. Investigations… •Urinalysis •Urine Microscopy forcellular elements and casts •24 hr urinary protein estimation •Creatinine clearance or estimated GFR •Renal ultrasound •HBsAg, anti-HCV, HIV •ANCA (antineutrophil cytoplasmic antibodies) •Renal Biopsy –Light microscopy –Electron microscopy –Immunofluorescence
- 59. Treatment •Control of bloodpressure –ACE inhibitors ± ARBs –Other anti-hypertensives •Blood pressure goal < 125 / 75 mm Hg if proteinuria is > 1 g /day and < 130 / 80mmHg if proteinuria is < 1 g / day. •Corticosteroids –Are effective in several types of GN owing to their ability to inhibit activity of the transcription factor nuclear factor ĸB and consequently inhibit the proinflammatory effects of cytokines known to promote glomerular inflammation actively, including interleukin 1β and tumour necrosis factor α. –Are useful in several types of GN •Lipid lowering agents e.g. statins
- 60. TREATMENT •Corticosteroids •Inhibits activity ofthe transcription nuclear factors kB and consequently inhibit the pro-inflammatory effects of cytokines, known to promote glomerular inflammatory actively, including IL-Iβ and TNFα •Immunosuppressive therapies – crescentic GN, proliferative GN, FSGS, MCD, MN, IgAN with deteriorating renal function and proteinuria. •Plasmapheresis – removal of preformed antibodies from the circulation – Goodpasture’s disease
- 61. TREATMENT •Immunosuppressives e.g. cyclophosphamide, azathioprine,chlorambucil, mycophenolate mofetil, sirolimus –Are of proven benefit in crescentic GN, proliferative lupus nephritis, focal and segmental glomerulosclerosis, minimal change disease, membranous nephropathy, and in cases of IgA nephropathy with deteriorating renal function and proteinuria.
- 66. Conclusion • Glomerulonephritis refersto a spectrum of aetiopathogenesis and varied clinical presentations following glomerular damage • Results from complex interplay of genetic, immunologic and environmental factors • Histologic difference abound depending mostly on aetiology • May result in Acute or Chronic kidney disease • Leading cause of CKD worldwide, commonest Cause in Nigeria and Sub-Sahara Africa • Management requires early recognition by meticulous hx taking, examination and appropriate investigation • Some would require Steroid +/- Immunosuppressants
- 67. References • Basic PathologyBy Robins, 8th ed • Harrison’s Principles of Internal Medicine By Longo et al, 18th ed • WACP Revision Course, 2011 • www.pubmed.gov
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Editor's Notes
- #45 Showing diffuse thickening