IgA NEPHROPATHY (CLOSING THE LOOP) - Pathogenesis & Clinical guide

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IgA NEPHROPATHY (CLOSING THE LOOP) m Pathogenesis & Clinical guide :

IgA NEPHROPATHY (CLOSING THE LOOP) m Pathogenesis & Clinical guide Mohammed Abdel Gawad

Historical View:

Historical View 2 It was described in 1968 by Jean Berger (it has also been called Berger’s disease).

OBJECTIVES:

Normal IgA formation & function Pathogenesis of IgAN Epidemiology Is IgA a familial disease? Age & Sex Clinical presentation Associations Investigations Would you biopsy? Pathology Prognostic markers OBJECTIVES 3

OBJECTIVES:

Normal IgA formation & function Pathogenesis of IgAN Epidemiology Is IgA a familial disease? Age & Sex Clinical presentation Associations Investigations Would you biopsy? Pathology Prognostic markers OBJECTIVES 4

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5 Mestecky J, Russell MW, Jackson S, Brown TA. The human IgA system: a reassessment.Clin Immunol Immunopathol 1986;40:105-114 Normal IgA Formation & Function

Normal IgA Formation & Function:

Immunoglobulin A (IgA) is an antibody that plays a critical role in mucosal immunity Normal IgA Formation & Function 6 S Fagarasan and T Honjo (2003). "Intestinal IgA Synthesis: Regulation of Front-line Body Defenses". Nat. Rev. Immunology 3 (1): 63–72

Normal IgA Formation & Function:

Polymeric & Secretory IgA Mucosal antigen challenge provokes polymeric IgA ( pIgA ) production by plasma cells of the mucosa-associated lymphoid tissue; the pIgA is then transported across epithelium into mucosal fluids, where it is released after coupling to secretory component as secretory IgA (sIgA). 7 Normal IgA Formation & Function Comprehensive Clinical Nephrology, 4 th edition, Chapter 22, Page 270, 271

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8 Polymeric & Secretory IgA Normal IgA Formation & Function

Normal IgA Formation & Function:

9 Andrea Cerutti , Maria Rescigno , Immunity , volume 28, Issue 6, 13 June 2008, Pages 740–750 Normal IgA Formation & Function Polymeric & Secretory IgA

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IgA Clearance Circulating IgA1 is cleared by the liver through hepatocyte asialoglycoprotein receptors and Kupffer cell Fc α receptors. 10 Normal IgA Formation & Function Comprehensive Clinical Nephrology, 4 th edition, Chapter 22, Page 270, 271

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Normal IgA1 Structure 11 Normal IgA Formation & Function Panel A: The Structure of a Normal IgA1 Molecule Panel B: the Structure of Carbohydrates O-Linked to Serine or Threonine residues within the Hinge Region of Normal IgA1 Donadio JV, Grande JP. N Engl J Med 2002;347:738-748.

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Normal IgA2 Structure IgA2 has no hinge and carries no such sugars . 12 Normal IgA Formation & Function Barratt J, Feehally J, Smith AC. Pathogenesis of IgA nephropathy. Semin Nephrol . 2004;24:197-217.

OBJECTIVES:

Normal IgA formation & function Pathogenesis of IgAN Epidemiology Is IgA a familial disease? Age & Sex Clinical presentation Associations Investigations Would you biopsy? Pathology Prognostic markers OBJECTIVES 13

Pathogenesis:

The pathogenesis of IgA nephropathy remains incompletely understood * Pathogenesis in one word = ABNORMAL GALACTOSYLATED IgA Pathogenesis 14 * Hahn WH, Suh JS, Cho BS, Kim SD. The enabled homolog gene polymorphisms are associated with susceptibility and progression of childhood IgA nephropathy. Exp Mol Med. Nov 30 2009;41(11):793-801.

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Hinge region of the IgA1 molecule in patients with IgAN is often abnormal with reduced galactose and/or sialic acid content . * The mechanisms responsible for this underglycosylation are unclear, but reduced function of the enzyme responsible for performing this glycosylation may be involved. * 15 Pathogenesis – Abnormal Glycosylation * Current Diagnosis & Treatment, Nephrology & Hypertension, Chapter 27, Page 243

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Hepatic clearance of IgA is reduced , possibly as a consequence of the altered molecular characteristics of IgA. 16 Pathogenesis – Hepatic Clearance Comprehensive Clinical Nephrology, 4 th edition, Chapter 22, Page 270, 271

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17 Pathogenesis Donadio JV, Grande JP. N Engl J Med 2002;347:738-748.

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18 Comprehensive Clinical Nephrology, 4 th edition, Chapter 22, Page 270, 271 Pathogenesis

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Studies of renal biopsy specimens in human IgAN also support a role for PDGF and TGF-β .* These mechanisms are not unique to IgAN but are likely to be involved in all forms of mesangial proliferative GN, including those without IgA deposition.* 19 * Floege J, Eitner F, Alpers CE. A new look at platelet-derived growth factor in renal disease. J Am Soc Nephrol . 2008;19:12-23. Pathogenesis – Growth Factors

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Analysis of kidney tissue from patients with IgAN reveals that the glomerular deposits are almost exclusively polymeric IgA1 . 20 Pathogenesis – IgA Type Current Diagnosis & Treatment, Nephrology & Hypertension, Chapter 27, Page 243

IgA Court :

21 IgA Court Case 1: Is the mucosal IgA accused ?! The onset of IgA nephropathy may be associated with infections in the upper respiratory tract. It has therefore been proposed that IgA nephropathy results from hyperactivity of the mucosal immune system. Bene MC, Faure GC. Mesangial IgA in IgA nephropathy arises from the mucosa. Am J Kidney Dis 1988;12:406-409

IgA Court :

The onset of IgA nephropathy may be associated with infections in the upper respiratory tract. It has therefore been proposed that IgA nephropathy results from hyperactivity of the mucosal immune system.[1] However, evidence suggests that mucosal immunity , which is in part directed by IgA, is decreased in patients with IgA nephropathy .[2] In some patients with IgA nephropathy, production of IgA1 in the bone marrow is increased and may be responsible for the observed increase in serum IgA1 levels.[3] IgA Court 22 [1] Bene MC, Faure GC. Mesangial IgA in IgA nephropathy arises from the mucosa. Am J Kidney Dis 1988;12:406-409 [2] Feehally J, Allen AC. Pathogenesis of IgA nephropathy. Ann Med Interne (Paris)1999;150:91-98 [3] Harper SJ, Pringle JH, Wicks AC, et al. Expression of J chain mRNA in duodenal IgA plasma cells in IgA nephropathy. Kidney Int1994;45:836-844 Case 1: Is the mucosal IgA accused ?!

IgA Court :

Serum IgA levels are increased in 50% of patients with IgAN . High serum IgA per se is not, however, sufficient to cause IgAN ; What is the evidence?? High circulating levels of monoclonal IgA (in myeloma) or polyclonal IgA (in AIDS) only infrequently provoke mesangial IgA deposition. IgA Court 23 Case 2: Is elevated serum IgA accused ?! Comprehensive Clinical Nephrology, 4 th edition, Chapter 22, Page 270, 271 Bene MC, Canton P, Amiel C, May T, Faure G. Absence of mesangial IgA in AIDS: a postmortem study. Nephron 1991;58:240-241

IgA Court Verdict :

IgA Court Verdict 24 Studies have focused on potential abnormalities of the IgA molecule as a factor in the pathogenesis of IgA nephropathy not the level of serum IgA. Allen AC, Bailey EM, Brenchley PE, Buck KS,Barratt J, Feehally J. Mesangial IgA1 in IgA nephropathy exhibits aberrant O- glycosylation : observations in three patients. Kidney Int2001;60:969-973

Note: Tonsils & IgA:

Tonsillar pIgA1 production is also increased, although IgAN can occur after tonsillectomy , and the tonsil is a very minor source of IgA production compared with the mucosa or marrow. Note: Tonsils & IgA 25 Comprehensive Clinical Nephrology, 4 th edition, Chapter 22, Page 270, 271

Local or Systemic Disease?:

IgAN is systemic disease Evidence 1 Histologic evidence of recurrent IgA nephropathy is observed in over 35 percent of patients who receive renal allografts as treatment for end-stage renal disease due to IgA nephropathy Local or Systemic Disease? 26 Ponticelli C, Traversi L, Feliciani A, Cesana BM,Banfi G, Tarantino A. Kidney transplantation in patients with IgA mesangial glomerulonephritis.Kidney Int 2001;60:1948-1954

Local or Systemic Disease?:

IgAN is systemic disease Evidence 2 When a kidney obtained from a donor with asymptomatic IgA nephropathy is transplanted into a recipient with end-stage renal disease due to a disease other than IgA nephropathy , the deposits in the donor kidney rapidly disappear. Local or Systemic Disease? 27 Koselj M, Rott T, Kandus A, Vizjak A, Malovrh M. Donor-transmitted IgA nephropathy: long-term follow-up of kidney donors and recipients.Transplant Proc 1997;29:3406-3407 IgA IgA IgA IgA IgA IgA

What is the Antigen ??:

No antigen has been consistently detected in circulating immune complexes containing IgA or in biopsy specimens from the kidneys of patients with IgA nephropathy. What is the Antigen ?? 28 Russell MW, Mestecky J, Julian BA, Galla JH. IgA-associated renal diseases: antibodies to environmental antigens in sera and deposition of immunoglobulins and antigens in glomeruli. J Clin Immunol 1986;6:74-86

OBJECTIVES:

Normal IgA formation & function Pathogenesis of IgAN Epidemiology Is IgA a familial disease? Age & Sex Clinical presentation Associations Investigations Would you biopsy? Pathology Prognostic markers OBJECTIVES 29

Epidemiology :

It is now generally known to be the most common form of primary glomerulonephritis throughout the world in most countries where renal biopsy is widely used as an investigative tool. Epidemiology 30 Levy M, Berger J. Worldwide perspective of IgA nephropathy. Am J Kidney Dis1988;12:340-347 Comprehensive Clinical Nephrology, 4 th edition, Chapter 22, Page 270, 271

OBJECTIVES:

Normal IgA formation & function Pathogenesis of IgAN Epidemiology Is IgA a familial disease? Age & Sex Clinical presentation Associations Investigations Would you biopsy? Pathology Prognostic markers OBJECTIVES 31

Genetic Basis of IgA Nephropathy:

Isolated cases of IgA nephropathy are common, and the disease is not considered to be familial .[1] There have, however, been suggestions that there may be immunogenetic factors that predispose some persons to IgA nephropathy, and familial clustering has been reported . [1] Many association studies have sought genes associated with disease in sporadic IgAN , so far without consistent findings. [2] Genetic Basis of IgA Nephropathy 32 [1] Hsu SI, Ramirez SB, Winn MP, Bonventre JV,Owen WF. Evidence for genetic factors in the development and progression of IgA nephropathy.Kidney Int 2000;57:1818-1835 [2] Hsu SI. Racial and genetic factors in IgA nephropathy. Semin Nephrol . 2008;28:48-57.

OBJECTIVES:

Normal IgA formation & function Pathogenesis of IgAN Epidemiology Is IgA a familial disease? Age & Sex Clinical presentation Associations Investigations Would you biopsy? Pathology Prognostic markers OBJECTIVES 33

Age & Sex:

Primary IgA nephropathy occurs at any age , most commonly with clinical onset in the second and third decades of life. [1] In populations of Caucasian descent, it is more common in males than in females by a ratio of 3 : 1 , whereas the ratio approaches 1 : 1 in most Asian populations. [2] Age & Sex 34 [1] Radford MG Jr , Donadio JV Jr , Bergstralh EJ,Grande JP. Predicting renal outcome in IgA nephropathy. J Am Soc Nephrol 1997;8:199-207 [2] Comprehensive Clinical Nephrology, 4 th edition, Chapter 22, Page 270, 271

OBJECTIVES:

Normal IgA formation & function Pathogenesis of IgAN Epidemiology Is IgA a familial disease? Age & Sex Clinical presentation Associations Investigations Would you biopsy? Pathology Prognostic markers OBJECTIVES 35

Clinical Presentation:

Presentation % of IgA cases Macroscopic Hematuria 40% to 50% of cases Asymptomatic Hematuria ± Proteinuria (<2g/d) 30% to 40% of cases Nephrotic Syndrome 5% of cases Acute Kidney Injury: a- Crescentic IgA nephropathy b- ATN - <5% of all cases - 27% of those older than 65 years Chronic Kidney Disease Older age with long years undiagnosed IgA Clinical Presentation 36 Comprehensive Clinical Nephrology, 4 th edition, Chapter 22, Page 273, 274 Floege J, Feehally J. IgA nephropathy: recent developments. J Am Soc Nephrol2000;11:2395-2403

Hematuria:

Hematuria 37 Synpharyngitic hematuria : Hematuria is usually visible within 24 hours of the onset of the symptoms of infection (upper respiratory tract or occasionally in the gastrointestinal tract. Differentiating it from the 2 to 3 week delay between infection and subsequent hematuria in postinfectious (e.g., poststreptococcal ) GN. Comprehensive Clinical Nephrology, 4 th edition, Chapter 22, Page 273

Hematuria:

Usually brown rather than red. Clots are unusual . The macroscopic hematuria resolves spontaneously in the course of a few days. There is persistent microscopic hematuria between attacks. 38 Hematuria Comprehensive Clinical Nephrology, 4 th edition, Chapter 22, Page 273

Hematuria:

Episodic gross hematuria , often in association with upper respiratory infections, may also be seen in familial glomerular diseases such as thin basement membrane disease or Alport’s syndrome. 39 Hematuria Current Diagnosis & Treatment, Nephrology & Hypertension, Chapter 27, Page 243

Nephrotic Syndrome:

It may be first presentation but very rare. or Alternatively, it may occur as a late manifestation of advanced chronic glomerular scarring . Nephrotic Syndrome 40 Comprehensive Clinical Nephrology, 4 th edition, Chapter 22, Page 273

Crescentic IgA nephropathy:

This may be the first presentation of IgAN , or it may be superimposed on established, less aggressive disease. Crescentic IgA nephropathy 41 Comprehensive Clinical Nephrology, 4 th edition, Chapter 22, Page 273

ATN:

Acute renal failure can occur with mild glomerular injury when heavy glomerular hematuria leads to tubule occlusion by red cells ATN 42 Comprehensive Clinical Nephrology, 4 th edition, Chapter 22, Page 273

Chronic Kidney Disease:

May be first presentation. Usually old patients with long-standing disease that remained undiagnosed because the patient neither had frank hematuria nor underwent routine urinalysis. Chronic Kidney Disease 43 Comprehensive Clinical Nephrology, 4 th edition, Chapter 22, Page 273

Clinical presentations in relation to age:

Clinical presentations in relation to age 44 Comprehensive Clinical Nephrology, 4 th edition, Chapter 22, Page 273

OBJECTIVES:

Normal IgA formation & function Pathogenesis of IgAN Epidemiology Is IgA a familial disease? Age & Sex Clinical presentation Associations Investigations Would you biopsy? Pathology Prognostic markers OBJECTIVES 45

Associations with IgA Nephropathy:

Associations with IgA Nephropathy 46 Comprehensive Clinical Nephrology, 4 th edition, Chapter 22, Page 275

PowerPoint Presentation:

47 Donadio JV, Grande JP. N Engl J Med 2002;347:738-748. Associations with IgA Nephropathy

OBJECTIVES:

Normal IgA formation & function Pathogenesis of IgAN Epidemiology Is IgA a familial disease? Age & Sex Clinical presentation Associations Investigations Would you biopsy? Pathology Prognostic markers OBJECTIVES 48

Investigations:

Serum IgA is increased in 50% of the cases Serum complement components are normal. Neither finding, however, is reliable enough to support the diagnosis without a renal biopsy . Investigations 49 Comprehensive Clinical Nephrology, 4 th edition, Chapter 22, Page 273

OBJECTIVES:

Normal IgA formation & function Pathogenesis of IgAN Epidemiology Is IgA a familial disease? Age & Sex Clinical presentation Associations Investigations Would you biopsy? Pathology Prognostic markers OBJECTIVES 50

Would You Biopsy 1 ?!:

Male 34 years old Macroscopic hematuria History of upper respiratory tract infection since 48 hours Normal serum complement level What is your DD Would You Biopsy 1 ?! 51

Would You Biopsy 2 ?!:

Male 22 years old Macroscopic hematuria HTN History of upper respiratory tract infection since 10 days Low C3, normal C4 Would You Biopsy 2 ?! 52

OBJECTIVES:

Normal IgA formation & function Pathogenesis of IgAN Epidemiology Is IgA a familial disease? Age & Sex Clinical presentation Associations Investigations Would you biopsy? Pathology Prognostic markers OBJECTIVES 53

Pathology - LM:

Pathology - LM 54 Light microscopic findings are variable and can reveal: Mesangial cell proliferation, and increase in mesangial matrix,* Focal or diffuse proliferative glomerulonephritis, * Crescentic glomerulonephritis, * Chronic sclerosing glomerulonephritis,* Membranoproliferative glomerulonephritis type I pattern,* A subset of nephrotic patients with normal appearing glomeruli by light microscopy,* Focal segmental GN ** * Current Diagnosis & Treatment, Nephrology & Hypertension, Chapter 27, Page 243 * *Comprehensive Clinical Nephrology, 4 th edition, Chapter 22, Page 275

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The preglomerular arterial vessels often exhibit wall hyalinosis and subintimal fibrosis even in cases of only mild arterial hypertension. 55 Pathology - LM

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56 Glomerulus from a patient with IgA nephropathy showing mild segmental mesangial hypercellularity in the upper left quadrant of the glomerulus [periodic acid-Schiff (PAS) stain]. Pathology - LM Fundamental of Renal Pathology, Section III, Chapter 6, Page 62

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57 Glomerulus from a patient with IgA nephropathy showing moderate segmental mesangial hypercellularity and increased mesangial matrix in the upper portion of the tuft (PAS stain). Pathology - LM Fundamental of Renal Pathology, Section III, Chapter 6, Page 63

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58 Acute kidney injury in IgA nephropathy. Tubular occlusion by red cells. ( Hematoxylin -eosin; magnification ×300.) This appearance may be associated with only minor glomerular changes. Comprehensive Clinical Nephrology, 4 th edition, Chapter 22, Page 275 Pathology - LM

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59 Mesangial Deposits % of cases Diffuse IgA deposits Hallmark C3 90% IgG 40% IgM 40% Kappa & lambda chain May be present Pathology - IF Comprehensive Clinical Nephrology, 4 th edition, Chapter 22, Page 275

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60 Comprehensive Clinical Nephrology, 4 th edition, Chapter 22, Page 275 Diffuse mesangial IgA. (Indirect immunofluorescence with fluorescein isothiocyanate –anti-IgA; magnification × 3300.) Pathology - IF

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61 Immunofluorescence microscopy demonstrating glomerular mesangial staining for immunoglobulin A (IgA) in a patient with IgA nephropathy. Fundamental of Renal Pathology, Section III, Chapter 6, Page 62 Pathology - IF

DD- IF - Mesangial Proliferative:

DD- IF - Mesangial Proliferative 62 Comprehensive Clinical Nephrology, 4 th edition, Chapter 27, Page 336

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63 Electron microscopy: mesangial electron-dense deposits. The deposits are shown by arrows. (Electron micrograph; magnification ×316,000.) Comprehensive Clinical Nephrology, 4 th edition, Chapter 22, Page 275 Pathology - EM

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64 Fundamental of Renal Pathology, Section III, Chapter 6, Page 63 Electron micrograph of a glomerulus from a patient with IgA nephropathy showing massive electron-dense deposits within the mesangium . The mesangium is on the left of the image and a portion of the capillary loop is on the right. Pathology - EM

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Typically, electron dense deposits are confined to mesangial and paramesangial areas, but, in addition, subepithelial and subendothelial deposits can also be seen. Up to one third of patients will have some focal thinning of GBM . On occasion, there will be extensive GBM thinning , suggesting a coincident diagnosis of thin membrane nephropathy 65 Pathology - EM

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66 A subset of nephrotic patients with normal appearing glomeruli by light microscopy may have only prominent visceral epithelial cell foot process effacement on electron microscopy and appear indistinguishable from patients with minimal change disease. Pathology - EM Current Diagnosis & Treatment, Nephrology & Hypertension, Chapter 27, Page 243

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67 Pathology

OBJECTIVES:

Normal IgA formation & function Pathogenesis of IgAN Epidemiology Is IgA a familial disease? Age & Sex Clinical presentation Associations Investigations Would you biopsy? Pathology Prognostic markers OBJECTIVES 68

Prognostic Markers:

Prognostic Markers 69 Comprehensive Clinical Nephrology, 4 th edition, Chapter 22, Page 277

Summary & Recommendations:

Summary & Recommendations 70

Pathogenesis:

Abnormal Glycosylated pIgA1 Pathogenesis 71

Highly suggestion of IgA:

Highly suggestion of IgA 72 Synpharyngitic hematuria within 24 hours of the onset of the symptoms of infection in 2 nd or 3 rd decade of life with normal serum complement

Other IgA presentations & Pathologies:

Other IgA presentations & Pathologies 73 Other IgA presentations (nephrotic syndrome & cresentic GN) & pathologies rather than mesangial proliferation will be included in the DD of these presentations

DD- IF - Mesangial Proliferative:

DD- IF - Mesangial Proliferative 74 Comprehensive Clinical Nephrology, 4 th edition, Chapter 27, Page 336

Excepted IgA course:

Excepted IgA course 75

Prognostic Markers:

Prognostic Markers 76 Comprehensive Clinical Nephrology, 4 th edition, Chapter 22, Page 277

PowerPoint Presentation:

77 Donadio JV, Grande JP. N Engl J Med 2002;347:738-748. Associations with IgA Nephropathy

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Follow On www.nephrotube.blogspot.com & Facebook Group NephroTube 78

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Gawad 79

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