Case Presentation

1. Case Presentation By ABEER SHAHBA Assistant lecturer Internal Medicine Dep. Tanta University

9. History • A 18 years old male patient (smoker) • 2 years ago, he was presented by: • Heamaturea • Heamoptysis • Dyspnea • Pallor • Hypotension

10. Bronchoscope • Biopsy • Central venous line  Pneumothorax  Surgical emphysema  intercostal tube

11. Serum Creatinine was 2.3 mg/dl • Hb gradually decreased till 3 gm/dl • Anti-GBM antibodies +ve • ANCA +ve • Plasmapheresis (16 settings) • Fever, convulsions & coma for 2 days then recoverd • Renal biopsy • Oligurea & hematurea • Lasix

12. Serum Creatinine increased till reached 16 mg/dl • Hemodialysis • Referred to our hospital to continue hemodialysis waiting for kidney transplantation • Anti-GBM antibodies -ve • ANCA -ve

13. Differential diagnosis? Diagnosis? Management ?

14. Clinical Diagnosis Pulmonary – Renal syndrome consistent with Goodpasture syndrome

15. Differential diagnosis of diffuse alveolar hemorrhage

19. Major Cause of Acute Nephritis

20. Alport’s Syndrome, Goodpasture’s Syndrome, and Type IV Collagen • Basement membranes form a complex surface on which epithelial cells reside. • These membranes provide morphogenic cues that determine the fate of cells, the polarization of subcellular constituents, and the location of cell receptors and transporters.

21. Basement membranes are assembled through an interweaving of type IV collagen (collagen IV) with laminins, nidogen, and sulfated proteoglycans • Collagen IV belongs to a family of collagenous proteins that has at least 25 distinct members.

23. Damage to collagen IV due to mutation (in Alport’s syndrome) or an immune attack (in Goodpasture’s syndrome) disrupts the function of attached epithelia and leads to organ impairment. • Alport’s syndrome consists of: • Hematuria • Proteinuria (less than 1 to 2 g/day) • Progressive renal failure, and sensorineural deafness • Lenticonus of the anterior lens capsule (positive “oil droplet sign”) • Retinopathy (dot and fleck reflections) • Rarely, mental retardation or leiomyomatosis

24. Histopathological Features of Kidneys in Alport’s Syndromes An electron micrograph of a glomerular capillary from a patient with Alport’s syndrome and proteinuria demonstrates the multilamellations and lucent spaces resulting in the split appearance of the basement membrane (arrows).

25. TreatmentofAlport’s syndrome • Antihypertensive drugs and ACE inhibitors to attenuate proteinuria and slow progression, • Patients who require dialysis are candidates for renal transplantation. Although the development of nephritis with anti–GBM alloantibodies in the transplanted kidney is not very common.

26. Goodpasture’s syndrome • It is a multigenic disorder. Hudson and coworkers identified the α3(IV) NC1 domain as the Goodpasture autoantigen. • This target antigen must be present as a component of the native α3.α4.α5(IV) network of selected basement membranes in order for pulmonary and renal disease to develop. • It is a rare disease only one person in a million develops it each year.

27. Human GBM antibodies, usually of the IgG class (or, rarely, IgA), are of particularly high affinity and remain attached to GBM for prolonged periods. • Environmental factor, such as exposure to hydrocarbons or tobacco smoke, is required in order to reveal cryptic epitopes to the immune system. Endogenous oxidants can open this privileged site.

29. The mechanism of renal injury in Goodpasture’s syndrome is complex. • GBM antibodies bind GBM, they activate complement and proteases  disrupts the filtration barrier and Bowman’s capsule  proteinuria and facilitating crescent formation. • CD4+ and CD8+ T cells and intrinsic renal epithelium induce the migration of macrophages and neutrophils into the kidney. • IL-12 and INF- mediate crescent formation. • This initial inflammatory reaction in the glomerulus produces proteinuria, interstitial nephritis, and fibrosis.

30. Findings on kidney biopsy • Renal biopsies typically show: • Focal or segmental glomerular necrosis • Destruction of the glomerular basement membrane • Cellular proliferation • Crescent formation • Breakdown of the Bowman’s capsule by periglomerular inflammation • Vasculitis on renal biopsy suggests the presence of ANCA-related disease • As these lesions progress, there is concomitant interstitial nephritis with fibrosis and tubular atrophy

32. A B Histopathological Features of Kidneys Goodpasture’s Syndromes. Panel A (hematoxylin and eosin) shows focal, segmental necrosis of the glomerular tuft in a kidney from a patient with Goodpasture’s syndrome. Panel B (hematoxylin and eosin) shows the crescent formation of the glomerular tuft in such a kidney.

34. Goodpasture’s syndrome: massive intra-pulmonary bleeding has led to opacities (white-out) of both mid- and lower zones on chest X-ray. • The mortality rate is high as a result of pulmonary and renal involvement.

35. Sectioned surface of the lung at autopsy, with extensive hemorrhagic consolidation

36. Pulmonary Capillaritis with alveolar walls thickened or replaced by neutrophils and nuclear dust. • Alveoli are engorged with blood.

37. Typical splenic lesion of Wegener's granulomatosis or polyarteritis nodosa and does not occur in Goodpasture's syndrome. • The appearance of a fleckmilz, numerous discrete foci of yellow necrosis involved the spleen, which was slightly enlarged.

38. Clinical presentation • Goodpasture’s syndrome occurs primarily in young men in their late 20s and in men and women over 60 years of age. • In the younger age group, the disease is usually eruptive, with hemoptysis, a sudden decrease in the hemoglobin level, pallor, cough, fever, dyspnea, hematuria, non-nephrotic proteinuria, and red-cell casts. • Chest radiography shows diffuse alveolar infiltrates. • Hemoptysis is largely confined to smokers.

39. In testing serum in anti–GBM assays, it is important that the α3(IV) NC1 domain be used as the sole target, because assays that use all collagen IV fragments cannot distinguish Goodpasture antibodies from antibodies against the α1(IV) NC1 domain in patients with a paraneoplastic syndrome. • Approximately 25 % of patients with Goodpasture’s syndrome also produce ANCA, mainly against myeloperoxidase

40. Prognosis and Treatment • Prognosis is worse if there is oliguria, advanced fibrosis or > 50 % crescents on renal biopsy, a serum creatinine concentration of > 5.7 mg /dl, or a need for dialysis. • Most patients with advanced disease do not have a response to plasmapheresis or immunosuppression. • Patients with end-stage kidney disease who present with hemoptysis should be treated for lung hemorrhage, which does respond to plasmapheresis.

41. Patients who have the fewest features known to predict a poor outcome typically have a response when given 8 to 10 treatments with plasmapheresis during the first two weeks, accompanied by oral prednisone and cyclophosphamide therapy. • Patients who have a response to treatment involving an enduring absence of anti–GBM antibodies can have their dose of prednisone tapered after a few months, while continuing to receive cyclophosphamide for varying periods of up to a year.

42. Kidney transplantation is possible, but because there is a risk of recurrence, experience has suggested that patients should wait for 6 months until anti–GBM antibodies are undetectable in serum. • Work with experimental models of anti–GBM disease already predicts a role for • Co-stimulatory blockade of T-cell activation • Immune modulation with IL- 4 and IL-10 • Inhibition of macrophage migration • The future will be interesting, and work in this area will provide a new understanding of collagen- related diseases

43. Thank You Thank you