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  • Endothelial, pores (fenestrations), BM, and podocytes
  • PAS stain
  • Mesangium provides support to keep them from wonderin gout of the kidney
  • Need light, immunoflorescant, and electron microscopy
  • Immune complex formation
  • If it is subepi or subendo it will be a grany picture
  • ATN : tubular injury
  • Ths is the only kidney disease that will respond within one week to meds
  • Damage to the podocytes
  • This is the WORST
  • secondary
  • Especially in children
  • D is a kidney
  • Transcript

    • 1. Glomerular and Cystic Diseases Davis Massey, MD PhD Surgical Pathology Anna Vinnikova, MD Nephrology
    • 2. Learning Objectives • Know the mechanisms of glomerular injury. • Know the presented causes of the nephrotic and nephritic syndrome, their clinical presentation, clinical course, pathologic findings, and prognoses. • Know the several types of cystic renal diseases and their clinical and pathologic findings. • Know the features of dialysis acquired renal changes.
    • 3. The Kidney: Gross Anatomy Review • Cortex – Glomeruli – Proximal and distal tubules • Medulla – Collecting ducts and loops of Henle
    • 4. The Glomerulus Urinary Space
    • 5. The Glomerulus Urinary Space
    • 6. Foot Processes
    • 7. Filtration Slit
    • 8. Nephrin
    • 9. Immune complex deposit locations relative to GBM
    • 10. Immune complex deposit locations relative to GBM Subendothelial Subepithelial
    • 11. Immune complex deposit locations relative to GBM Subendothelial Subepithelial Intramembranous
    • 12. Clinical Manifestations of Glomerular Injury Major renal syndromes include: Acute nephritic syndrome : immune complexes Nephrotic syndrome Acute renal failure • due to glomerular, interstitial, vascular injury, ATN or obstruction Chronic renal failure • final common pathway of all chronic renal diseases
    • 13. Biopsy Work-up • Glomeruli – H&E, PAS, silver, trichrome stains – Immunofluorescence – Electron microscopy • Tubules • Interstitium • Vessels
    • 14. Glomerular Injury: Immune Mechanisms • In situ immune complex deposition/formation: – by circulating Ab directed against native glomerular Ag complexes (membranous glomerulonephritis). – by circulating Ab directed against or crossreactive with intrinsic Ag native to the glomerulus (Goodpasture Disease), or directed against or crossreactive with non-native “implanted” antigen trapped in the glomerulus. • Circulating immune complex deposition: – Complexes not native to the glomerulus, which lodge there due to their physicochemical properties; these may be exogenous Ag (infectious – Post Streptococcal glomerulonephritis) or endogenous (host DNA – Lupus nephritis) • Cytotoxic Ab: – direct interaction of Ab with glomerular cell components with a cytotoxic result • Cell-mediated damage: – Sensitized T cells, macrophages • Alternative complement pathway activation
    • 15. Glomerular Injury: Immune Mechanisms • Other mechanisms: – Ab to visceral epithelial cells (causing proteinuria) – Toxins (including some drugs) – Cytokines – Conditions promoting nephron loss leads to the “tipping point” (30 – 50%), with eventual renal failure – The unknown (unidentified circulating factors)
    • 16. Mediators of Glomerular Injury • After immune reactants or sensitized T cells localize to glomerulus, how is damage brought about ? – Neutrophils releasing proteases in response to complement activation; T cells, macrophages releasing other biologically active substances (cytokines and other proteases) – Resident glomerular cells such as mesangial cells stimulated to produce pro-inflammatory mediators – Soluble mediators of inflammation (chemotactic cytokines, other cytokines, coagulation factors, etc)
    • 17. Mechanisms of Glomerular Disease Progression • Outcome of damage depends on: – Initial severity of renal damage – Nature and persistence of Ag – Host immune status, age, genetic susceptibilities • Once any renal disease has destroyed sufficient nephron mass to reduce GFR to about 30% to 50% of normal, the tipping point is reached and progression to ESRD continues steadily regardless of the activity of the initiating stimulus.
    • 18. Mechanisms of Glomerular Disease Progression • Two major histologic characteristics of progressive renal damage are 1) focal segmental glomerulosclerosis (FSGS) which may be either a primary idiopathic disease (more later) or a change secondary to other stimuli (next), and 2) tubulointerstitial fibrosis (TIF).
    • 19. Mechanisms of glomerular disease progression • Secondary FSGS: – Glomerulosclerosis caused by maladaptive changes that occur in the unaffected glomeruli of diseased kidneys; maladaptive changes include: • Compensatory glomerular hypertrophy • Glomerular hypertension (often systemic HTN too) – These changes damage epithelial and endothelial cells causing increased glomerular permeability to proteins, accumulation of proteins in the mesangium promoting unwanted mesangial cell proliferation, infiltration by macrophages, increases in extracellular matrix, and inevitable progressive (segmental) sclerosis (“fibrosis”) of glomeruli, all of which further reduces nephron mass, and promotes the spiraling toward worsening glomerulosclerosis.
    • 20. Mechanisms of glomerular disease progression • Tubular injury – Many acute and chronic glomerulonephritides have tubular injury as a component. – Tubular injury may be due to ischemia (reduces amt of O2) from upstream sclerotic glomeruli, acute and chronic inflammation in the adjacent interstitium, damage to peritubular capillaries, and to proteinuria which may directly injure tubular epithelium. • These lead to tubulointerstital fibrosis (TIF). – TIF contributes to disease progression of both immune and non- immune glomerular diseases (FSGS, diabetes); TIF often correlates better with renal function decline than does the severity of glomerular damage.
    • 21. Nephrotic Syndrome • Minimal Change Disease (MCD) • Focal Segmental Glomerulosclerosis (FSGS) • Membranous Glomerulonephropathy (MGN)
    • 22. Minimal Change Disease Case presentation • Danielle is a 21 year old VCU student referred by Student Health for proteinuria. She developed edema to thighs 3 wks ago. She has been previously healthy. She takes no medications except for an occasional Excedrin. • Exam: BP 101/63, exam normal except for 2+ pitting lower extremity edema bilaterally
    • 23. Minimal Change Disease Case presentation • Labs: urine prot 4+, alb 2.2, cholesterol 498, creat 0.6 • Diagnosis: Nephrotic syndrome • Patient started on prednisone 60 mg daily. Returns 1 wk later – edema resolved and urine protein is down to trace. • Diagnosis: Minimal Change Disease
    • 24. Minimal change disease • Definition: Histopathologic lesion with normal glomeruli on light microscopy and diffuse foot process fusion on electron microscopy, associated with nephrotic syndrome.
    • 25. Minimal Change Disease • Pathogenesis: – leading hypothesis: immune dysfunction leads to release of a cytokine – the cytokine (“permeability factor”) targets podocytes, disrupting GBM charge barrier and causing proteinuria
    • 26. Minimal Change Disease • Morphology: – Normal glomeruli by light microscopy (LM) – Abnormal glomeruli by electron microscopy (EM) with foot process effacement; no deposits found – Proximal tubular epithelial cells often filled with lipid and protein (“lipoid nephrosis”) due to hyperlipidemia – Immunofluorescence microscopy (IF) studies are negative
    • 27. normal
    • 28. Minimal Change Disease images
    • 29. Minimal Change Disease • Epidemiology: – Most common cause of primary nephrotic syndrome in children – Less common in adults • Ethiology: – Primary - idiopathic – Secondary: • Drugs: NSAIDs • Tumors: lymphomas • Immune modulation: vaccinations
    • 30. Minimal Change Disease • Clinical characteristics and treatment: – Abrupt onset of florid nephrotic syndrome – Normal blood pressure – Renal function usually remains good – 90% respond rapidly to corticosteroids, adults are slower to respond than children – Relapses are characteristic and respond to re- treatment
    • 31. Minimal Change Disease • Clinical characteristics and treatment: – Frequently relapsing or steroid-resistant cases respond to other immunosuppressive agents (mycophenolate, cyclosporine, cyclophosphamide) – Some become steroid dependent until puberty, when most cases finally remit – Long term prognosis is excellent
    • 32. Minimal Change Disease Case follow-up • Patient was treated with a 4 months prednisone taper with complete resolution of proteinuria. However, 1 mo after stopping prednisone, her proteinuria increased to 3+, which indicated a relapse. Started on CellCept (Mycophenolate), again with resolution of proteinuria after 1 wk. Pt then treated with CellCept x 1 year. She remains in complete remission.
    • 33. Nephrotic Syndrome • Minimal Change Disease (MCD) • Focal Segmental Glomerulosclerosis (FSGS) • Membranous Glomerulonephropathy (MGN)
    • 34. Focal Segmental Glomerulosclerosis Case presentation • Robert is a laboratory technician at St Mary’s Hospital, who has diagnosed himself with nephrotic syndrome over Christmas break • He is a 50 year old African American male w h/o HTN, who developed progressively increasing lower extremity edema since summer
    • 35. Focal Segmental Glomerulosclerosis Case presentation • He was seen by his PCP several times, and his medications were adjusted. However, in spite of proteinuria on UA, no diagnosis was made • Medications: verapamil and lasix • On exam, his BP is 145/91, remainder unremarkable except for tight 4+ LE edema
    • 36. Focal Segmental Glomerulosclerosis Case presentation • Labs 9 mo prior: – 2+ protein on UA – serum albumin 4 – cholesterol 300, LDL 180 • Current labs: – serum albumin 2.8 – cholesterol 396, LDL 270 and – creatinine 1.2 – Urinalysis 4+ protein and a few granular casts – Urine protein/creatinine ratio 12
    • 37. Focal Segmental Glomerulosclerosis Case presentation • Diagnosis: Nephrotic syndrome • Kidney biopsy was performed, demonstrating focal segmental glomerulosclerosis
    • 38. Focal Segmental Glomerulosclerosis • Definition: Histopathologic lesion with sclerosis of some but not all (hence focal) glomeruli that involves a portion (segment) of the glomerular tuft
    • 39. Focal Segmental Glomerulosclerosis • Morpology: – Sclerotic segments show basement membrane collapse, increased matrix, trapping of plasma proteins in glomerular capillary walls by light microscopy – Effacement of VEC in sclerotic and non-sclerotic segments by EM; no deposits. – pronounced tubular atrophy and interstitial fibrosis
    • 40. normal
    • 41. segmentally collapsed unaffected Focal Segmental Glomerulosclerosis
    • 42. Focal Segmental Glomerulosclerosis GBM collapse and foot process fusion less affected segment
    • 43. Focal Segmental Glomerulosclerosis • Ethiology and pathogenesis: – Primary: • presumed due to a circulating factor (?cytokine) that damages VEC – Secondary (associated with other conditions): • HIV, heroin addiction, sickle cell disease, massive obesity. • maladaptive response to nephron loss – Inherited • linked to mutations of the proteins nephrin, podocin, or α-actinin4, causing “podocytopathy”.
    • 44. Focal Segmental Glomerulosclerosis • Epidemiology: most common cause of primary nephrotic syndrome in African-American adults • Clinical characteristics: – Nephrotic syndrome (primary disease or HIV nephropathy) or nephrotic range proteinuria (most secondary forms) – Proteinuria is non-selective (can have other proteins other than just albumin) in contrast with minimal change disease – Hypertension, reduced GFR – Slow and variable response to steroids – Progression to chronic glomerulosclerosis; 50-80% to ESRD within several years – Children have better prognosis than adults – Recurrence post transplant is common in idiopathic FSGS leading to graft failure
    • 45. Focal Segmental Glomerulosclerosis • Treatment: – Only idiopathic FGSG has a chance to respond to immunosuppressive treatment. Therefore, it is imperative to determine whether the disease is primary or secondary – Primary disease: • Steroids • Immunosuppressive cytotoxic agents - Cyclosporine, Tacrolimus, Mycophenolate – Primary and secondary disease: • ACE/ARB and anti-lipid agents – HIV-associated FSGS • Antiretroviral medications
    • 46. Focal Segmental Glomerulosclerosis Case follow-up • Patient was started on prednisone. Two weeks later he was admitted with bacteremia. His prednisone was tapered and he was started on cyclosporine. Patient was unable to tolerate medication, switched to CellCept. This medication was stopped after several months due to lack of efficacy.
    • 47. Focal Segmental Glomerulosclerosis Case presentation • His proteinuria increased to 40 g/24 hrs, and serum creatinine progressively increased to 3. Patient failed other immunosuppressive medications, and had multiple infectious complications. He also had severe complications of nephrotic syndrome – resistant anasarca (total body edema), deep venous thrombosis from hypercoagulable state, pericardial effusion, and chronic hypotension due to low plasma oncotic
    • 48. Focal Segmental Glomerulosclerosis Case presentation • He was started on dialysis to control edema, but could not tolerate fluid removal due to hypotension. After hospitalization that lasted 4 months, patient finally agreed to have bilateral renal artery embolization, a procedure called “chemical nephrectomy”. He is now hemodialysis-dependent, and has much improved clinically.
    • 49. Now let’s see if you’ve been paying attention…
    • 50. Patient has nephrotic syndrome, biopsy below. Which statement about this disease is INCORRECT: A. It is the most common cause of nephrotic syndrome in children B. It is characterized by sudden onset of florid nephrotic syndrome C. It is poorly responsive to steroids D. It can be caused by NSAIDs
    • 51. Which statement about this disease is INCORRECT: A. It is the most common cause of nephrotic syndrome in children B. It is characterized by sudden onset of florid nephrotic syndrome C. It is poorly responsive to steroids D. It can be caused by NSAIDs
    • 52. Nephrotic Syndrome • Minimal Change Disease (MCD) • Focal Segmental Glomerulosclerosis (FSGS) • Membranous Glomerulonephropathy (MGN)
    • 53. Membranous Glomerulonephropathy Case presentation • Danny is a 28 yo previously healthy VCU security guard, who was referred for evaluation of proteinuria. He noticed LE edema several weeks prior. He was hypertensive at 155/90. His serum creatinine was 0.9, alb 2.2, cholesterol 311 w LDL 173, Urine - 5g protein/24 hrs.
    • 54. Membranous Glomerulonephropathy Case presentation • Kidney biopsy showed Membranous Glomerulopathy. • Clinical course: patient was treated w immunosuppressive regimen consisting of prednisone and cyclophosphamide for 6 months, and responded with markedly decreased proteinuria (0.5 g/24 hrs).
    • 55. Membranous Glomerulonephropathy Case presentation • He was seen in follow-up several years later and had trace proteinuria and normal creatinine. He said: “I hope I would never hear from my membranous nephropathy again”
    • 56. Membranous Glomerulonephropathy • Definition: Histopathologic lesion characterized by glomerular basement membrane thickening due to immune complex entrapment, associated with nephrotic syndrome
    • 57. Membranous Glomerulonephropathy normal
    • 58. Membranous Glomerulonephropathy normal
    • 59. Membranous Glomerulonephropathy • Pathology: light microscopy: diffuse, uniform thickening of basement membrane with small subepithelial projections ("spikes") of basement membrane in capillary loops.
    • 60. Membranous Glomerulonephropathy • “Spike” formation on subepithelial (urinary) side of GBM, (silver stain)
    • 61. Membranous Glomerulonephropathy • Immunofluorescence microscopy: diffuse, coarsely granular pattern along capillary loops.
    • 62. Membranous Glomerulonephropathy • Subepithelial electron-dense immune deposits
    • 63. Membranous Glomerulonephropathy
    • 64. Membranous Glomerulonephropathy • Pathogenesis: A chronic immune-complex nephritis caused by: – Ab directed against intrinsic GBM Ag (primary) – circulating Ag-Ab complex entrapment in the GBM (secondary) – Both activate complement, which damages podocytes and makes them leaky
    • 65. Membranous Glomerulonephropathy • Epidemiology: – most common cause of primary nephrotic syndrome in Caucasian adults • Ethiology: – Primary – Secondary: • Drugs: penicillamine, captopril, gold • Malignancy (solid tumors) • Infection: hepatitis B, syphilis • Autoimmune disease: systemic lupus erythematosus (SLE), rheumatoid arthritis (RA)
    • 66. Membranous Glomerulonephropathy • Clinical features: – insidious onset of nephrotic syndrome, usually without identifiable preceding illness; – variable, but often indolent course • Prognosis: “Rule of thirds” (without treatment): – 1/3 – Spontaneous remission – 1/3 – Partial remission / slow deterioration – 1/3 – Progress to ESRD
    • 67. Membranous Glomerulonephropathy • Predictors of poorer outcome are: – tubulointerstitial fibrosis – elevated cr at diagnosis – male sex – hypertension – older age – and heavy proteinuria. • Treatment: – Steroids alone are not very effective – Prednisone alternating with Cyclophosphamide – Cyclosporin
    • 68. Now let’s see if you’ve been paying attention…
    • 69. Patient has nephrotic syndrome and biopsy is depicted below. Which statement is INCORRECT: A. It is the most common cause of idiopathic nephrotic syndrome in African American adults B. It is characterized by slow and variable response to steroids C. It can be associated with HIV D. In primary form, EM would show foot process fusion only in sclerotic segments
    • 70. Patient has nephrotic syndrome and biopsy is depicted below. Which statement is INCORRECT: A. It is the most common cause of idiopathic nephrotic syndrome in African American adults B. It is characterized by slow and variable response to steroids C. It can be associated with HIV D. In primary form, EM would show foot process fusion only in sclerotic segments
    • 71. Nephritic Syndrome • Membranoproliferative Glomerulonephritis (usually combined nephrotic-nephritic) • Acute Post-streptococcal Glomerulonephritis • Rapidly Progressive (Crescentic) GN • IgA Nephropathy
    • 72. Membranoproliferative Glomerulonephritis (Type I) Case presentation • Harry is a 48 year old African American male with h/o polysubstance abuse, admitted to the hospital with generalized swelling, hypertensive urgency and pulmonary edema. He was homeless, but is currently living at Rubicon drug treatment center.
    • 73. Membranoproliferative Glomerulonephritis (Type I) Case presentation • His serum cr in 2, serum albumin is 2.5, urine protein to creatinine ratio is 10, UA showed proteinuria and hematuria. Further workup revealed that patient is positive for hepatitis C and cryoglobulins.
    • 74. Membranoproliferative Glomerulonephritis (Type I) Case presentation • Kidney biopsy revealed membranoproliferative glomerulonephritis (MPGN), type I. • Patient was not a candidate for treatment due to poor social situation and history of non-compliance. His renal function has deteriorated and he became dialysis- dependent within 6 months.
    • 75. Membranoproliferative Glomerulonephritis (Type I) • Definition: histopathologic lesion characterized by mesangial proliferation and interposition into the glomerular capillary wall with double contours (“tram tracking”) of GBM on light microscopy
    • 76. Membranoproliferative Glomerulonephritis (Type I) • Light microscopy: – glomerular hypercellularity and lobular simplification. Splitting of GBM ("tram-track“) is characteristic. • Immunofluorescence microscopy: • coarse granular staining along capillary loops. • Electron Microscopy: • Subendothelial deposits with new formation of GBM (splitting).
    • 77. Membranoproliferative Glomerulonephritis (Type I)
    • 78. Tramtracking (GBM “splitting”)
    • 79. Membranoproliferative Glomerulonephritis (Type I) Deposits by IF (C3)
    • 80. Membranoproliferative Glomerulonephritis (Type I)
    • 81. Membranoproliferative Glomerulonephritis (Type I)
    • 82. Membranoproliferative Glomerulonephritis (Type I) • Pathogenesis: deposition of immune complexes in glomerulus with abnormal activation of complement, production of “nephritic factors” and glomerular injury
    • 83. Membranoproliferative Glomerulonephritis (Type I) • Epidemiology: – Primary – children and young adults, rare – Secondary – adults, more common • Ethiology: – Primary (idiopathic) – Secondary (seen in association with other disorders) • SLE, hepatitis C (often with cryoglobulinemia), endocarditis • Malignancy (lymphoma, leukemia)
    • 84. Membranoproliferative Glomerulonephritis (Type I) • Clinical characteristics – Nephrotic/nephritic – Depressed serum complement levels – Few remissions, usually unrelenting course – 50% with renal failure in 10 years
    • 85. Membranoproliferative Glomerulonephritis (Type I) • Treatment: – Primary in children – immunosuppression – Secondary – treat the original disease (antiviral or antibacterial agents), antiplatelet agents, immunomodulation in some cases
    • 86. Now let’s see if you’ve been paying attention…
    • 87. Which statement regarding the disease with IF picture below (depicting granular IgG staining along GBM) is INCORRECT: A. This is the most common cause of primary nephrotic syndrome in Caucasian adults B. 2/3 of patients will develop spontaneous or partial remission without treatment C. Can be associated with solid tumors D. EM would show reduplication of GBM with “tram tracking”
    • 88. Which statement regarding the disease with IF picture below (depicting granular IgG staining along GBM) is INCORRECT: A. This is the most common cause of primary nephrotic syndrome in Caucasian adults B. 2/3 of patients will develop spontaneous or partial remission without treatment C. Can be associated with solid tumors D. EM would show reduplication of GBM with “tram tracking”
    • 89. Nephritic Syndrome • Membranoproliferative Glomerulonephritis • Acute Post-streptococcal Glomerulonephritis • Rapidly Progressive (Crescentic) GN • IgA Nephropathy
    • 90. Acute Post-Streptococcal Glomerulonephritis Case presentation • Wyatt is transferred to VCU from outside hospital for acute glomerulonephritis. He is a 16 year old Caucasian male with h/o tonsillectomy at age 5. Ten days prior to admission he had strep throat with positive rapid strep test, and was started on augmentin by his PCP.
    • 91. Acute Post-Streptococcal Glomerulonephritis Case presentation • He was referred for admission after he developed tea colored urine, and was found to have hematuria, proteinuria and HTN. Pt reports 20 lbs wt gain in 3 days w periorbital and upper body edema, and abdominal pain. He now denies any sore throat.
    • 92. Acute Post-Streptococcal Glomerulonephritis Case presentation • SH is significant for tobacco, alcohol and marijuana use • Exam: BP 175/77, ps 49. Young athletic wm in no acute distress. Lungs were clear and heart was regular, with 2/6 systolic murmur at base. Abdomen was soft, diffusely tender, with liver and spleen edges palpable. Trace LE edema. No rash.
    • 93. Acute Post-Streptococcal Glomerulonephritis Case presentation • Labs showed cr 1.3, albumin 2.7, urinalysis 178 rbc and 25 wbc, 3+ protein and several red blood cell casts. ASO titer and streptozyme were positive. C3 complement level was low. • Diagnosis: Acute post-streptococcal GN.
    • 94. Acute Post-Streptococcal Glomerulonephritis Case presentation • Due to worsening renal function, we performed renal biopsy, which confirmed the above diagnosis, but also showed acute interstitial nephritis likely secondary to augmentin. That medication was stopped, and patient was treated w diuretic and ace inhibitor. Patient’s condition improved and he was discharged to follow-up in renal clinic.
    • 95. Acute Post-Streptococcal Glomerulonephritis Case presentation • His creatinine normalized after 1 mo. After 4 months, he was off antihypertensives, however his UA still showed 3+ blood and 2+ protein. He was lost to follow-up since that visit.
    • 96. Acute Proliferative (Poststreptococcal, Postinfectious) GN • Definition: acute nephritic syndrome that develops following infection by nephritogenic strains of strep or other organisms
    • 97. Acute Proliferative (Poststreptococcal, Postinfectious) GN • Epidemiology and ethiology: – Most common GN in children – Incidence declines with age – Usually 1 – 4 weeks post infection casued by nephritogenic strains of strep (usually group A strep) – Also reported with pneumococcal and staphylococcal infections, some viral diseases (mumps, measles, chickenpox, and hepatitis B and C).
    • 98. Acute Proliferative (Poststreptococcal, Postinfectious) GN • Clinical features: – history of infection 1-4 wks prior – abrupt onset of nephritic syndrome – oliguria – hematuria (tea-colored urine) – Edema : due to kidneys not working – hypertension – azotemia
    • 99. Acute Proliferative (Poststreptococcal, Postinfectious) GN – urinalysis usually reveals proteinuria, red cells, white cells, and casts – High antistreptolysin O (ASO) titers in post-streptococcal cases
    • 100. Acute Proliferative (Poststreptococcal, Postinfectious) Glomerulonephritis • Pathogenesis: Deposition of IgG immune complexes in capillary loops, with complement (C3) activation. Pathogenic Ag is unknown. Uncertain whether circulating Ag-Ab complex or in situ Ag-Ab complex formation occurs. Implicated antigens are endostreptosin and nephritis-plasmin-binding protein.
    • 101. Acute Proliferative (Poststreptococcal, Postinfectious) GN • Pathology: light microscopy: enlarged, hypercellular glomeruli with endothelial and mesangial cell proliferation. Neutrophils may be present. Crescents may be seen.
    • 102. Acute Proliferative (Poststreptococcal, Postinfectious) GN • Immunofluorescence microscopy: coarsely granular (“lumpy-bumpy”) pattern along capillary loops.
    • 103. Acute Proliferative (Poststreptococcal, Postinfectious) GN • Electron microscopy: subepithelial very large "hump-like" deposits.
    • 104. Acute Proliferative (Poststreptococcal, Postinfectious) GN
    • 105. Acute Proliferative (Poststreptococcal, Postinfectious) GN • Treatment: supportive – Diuretics – Antihypertensives – Antibiotics do not change course in post-strep GN • Prognosis: – majority (especially children) become clinically asymptomatic – some may develop rapidly progressive GN – adults can progress to chronic GN
    • 106. Now let’s see if you’ve been paying attention…
    • 107. Which diagnosis can you suspect from the light microscopy below: A. Membranous nephropathy B. Minimal change disease C. FSGS D. Membranoproliferative Glomerulonephritis (MPGN)
    • 108. Which diagnosis can you suspect from the light microscopy below: A. Membranous nephropathy B. Minimal change disease C. FSGS D. Membranoproliferative Glomerulonephritis (MPGN)
    • 109. Nephritic Syndrome • Membranoproliferative Glomerulonephritis • Acute Post-streptococcal Glomerulonephritis • Rapidly Progressive (Crescentic) Glomerulonephritis (RPGN) • IgA Nephropathy
    • 110. Rapidly Progressive Glomerulonephritis Case presentation • William is a 50 year old music teacher who is transferred from outside hospital for rapidly progressive renal failure with hematuria and proteinuria. He was very fit and healthy until several weeks prior to admission, when he developed a protracted upper respiratory illness requiring several visits to PCP and emergency rooms and several courses of antibiotics.
    • 111. Rapidly Progressive Glomerulonephritis Case presentation • He was finally admitted after he was found to have bilateral pulmonary infiltrates, gross hematuria and elevated creatinine. His condition deteriorated and he required mechanical ventilation for acute respiratory failure. • Bronchoscopy was consistent with pulmonary hemorrhage.
    • 112. Rapidly Progressive Glomerulonephritis Case presentation • His renal function deteriorated and he was started on hemodialysis. • His C-ANCA were positive at high titer. • Kidney biopsy was performed and showed crescentic pauci-immune glomerulonephritis. • Diagnosis: Wegener’s granulomatosis with alveolar hemorrhage and rapidly progressive glomerulonephritis.
    • 113. Rapidly Progressive Glomerulonephritis Case presentation • Clinical course: He was treated with intravenous steroids, cyclophosphamide and plasmapheresis with gradual improvement in respiratory and renal function. He recovered completely and several months later arranged his music department to give a concert at MCV Hospital to thank those who saved his life.
    • 114. Rapidly Progressive Glomerulonephritis • Definition: acute nephritic syndrome associated with rapidly deteriorating renal function (over weeks). Histopathologically this is crescentic GN. • Ethiology: 1. Anti-GBM disease 2. Immune complex-mediated crescentic GN (any GN that has gone severe - lupus nephritis, post-infectious GN, IgA nephropathy) 3. Pauci-immune GN 4. 9dont see any immune complexes) (can be found in : vasculitic diseases – Wegeners granulomatosis, microscopic polyangiitis)
    • 115. Rapidly Progressive (Crescentic) Glomerulonephritis • Clinical features: Rapid and progressive loss of renal function with severe oliguria and even death from renal failure within weeks to months is the course in untreated cases. • Treatment: heavy immunosuppression with steroids and cytotoxic agents (cyclophosphamide, mycophenolate), many times plasmapheresis is used to remove antibodies quickly • Prognosis: May be related to the number of crescents; those with >80% crescents do more poorly. Recurrence post-transplant is unusual.
    • 116. Rapidly Progressive (Crescentic) Glomerulonephritis
    • 117. Anti-GBM Disease • Type I, also referred to as anti- GBM disease (Goodpasture’s disease), in which IF reveals linear (not granular) deposition of IgG and C3 along the GBM; EM shows no deposits; least common type.
    • 118. Anti-GBM Disease • In some cases IgG and C3 may also bind the pulmonary alveolar capillary basement membranes, producing a syndrome (Goodpasture’s syndrome) of pulmonary hemorrhage and renal failure.
    • 119. Anti-GBM Disease • Circulating anti-GBM antibodies are found in the serum. Plasmapheresis may be used to treat these patients, in order to remove the circulating Ab.
    • 120. Immune-Complex-Mediated Crescentic GN • Type II, or immune-complex- mediated crescentic GN, which may be associated with any immune-complex type GN including SLE, IgA nephropathy, or postinfectious GN.
    • 121. Immune-Complex-Mediated Crescentic GN • IF will reveal a coarse, granular or “lumpy-bumpy” staining pattern. Treatment is directed at the underlying disease. “Linear” “Granular”
    • 122. Immune-Complex-Mediated Crescentic GN • EM usually shows deposits
    • 123. Pauci-Immnune Type GN • Type III, or pauci-immnune type GN, which as the name implies shows no anti-GBM Ab or immune-type complexes, either by IF or EM.
    • 124. Pauci-Immnune Type GN • Associated with antineutrophil cytoplasmic antibodies (ANCA) and are a feature of Wegener granulomatosis, microscopic polyangiitis, or other vasculitic diseases.
    • 125. Now let’s see if you’ve been paying attention…
    • 126. Which statement regarding the disease depicted on electron micrograph below is INCORRECT: A. This disease has poor prognosis B. This disease is treated in supportive fashion with diuretics and antihypertensives C. Light microscopy would show proliferative GN
    • 127. Which statement regarding the disease depicted on electron micrograph below is INCORRECT: A. This disease has poor prognosis B. This disease is treated in supportive fashion with diuretics and antihypertensives C. Light microscopy would show proliferative GN
    • 128. Nephritic Syndrome • Membranoproliferative Glomerulonephritis • Acute Post-streptococcal Glomerulonephritis • Rapidly Progressive (Crescentic) Glomerulonephritis (RPGN) • IgA Nephropathy
    • 129. IgA Nephropathy (Berger’s Disease) Case presentation • Kelly is a 24 year old white female with history of hypertension and depression, who is 16 wks pregnant. She is referred by her OB for proteinuria, hematuria and hypertension. Patient has a history of gross hematuria following upper respiratory infections.
    • 130. IgA Nephropathy (Berger’s Disease) Case presentation • Her BP is 155/90, she has trace LE edema, and her UA shows 3+ protein and 20 rbc. Her renal function is normal. She is managed conservatively with labetalol for BP control and bed rest. Her proteinuria is monitored and remains stable throughout the pregnancy. She is delivered via C- section at 37 weeks gestation.
    • 131. IgA Nephropathy (Berger’s Disease) Case presentation • 6 weeks post-partum her proteinuria remains unchanged at 3g/24 hrs. Kidney biopsy is performed and shows IgA nephropathy with 50% glomerulosclerosis and moderate interstitial fibrosis. She is started on ACE-I, fish oil and prednisone.
    • 132. IgA Nephropathy (Berger’s Disease) • Definition: Histopathologic lesion of a glomerulonephritis characterized by prominent IgA deposits in the mesangium detected by IF microscopy.
    • 133. IgA Nephropathy (Berger’s Disease)
    • 134. IgA Nephropathy (Berger’s Disease) • Immunofluorescence microscopy: IgA most prominently and consistently; diffuse and granular in mesangium.
    • 135. IgA Nephropathy (Berger’s Disease) • Electron microscopy: electron-dense deposits within the mesangium.
    • 136. IgA Nephropathy (Berger’s Disease)
    • 137. IgA Nephropathy (Berger’s Disease) • Pathogenesis: – Error of IgA production and clearance; those with IgAN have an abnormally high production of IgA in the marrow, and plasma clearance of IgA by the liver may be reduced by an abnormal glycosylation, leading to its deposition as immune complexes in the mesangium; there it activates complement. – Possible genetic or acquired abnormality of immune regulation causing increased mucosal IgA production in response to respiratory or GI exposure to environmental Ag; IgAN occurs with increased frequency in those with gluten enteropathy (celiac disease). – There may be a familial tendency linked to HLA and complement phenotypes.
    • 138. IgA Nephropathy (Berger’s Disease) • Epidemiology: the most common primary GN worldwide • Clinical features: • The classic presentation is gross hematuria, occurring coincidentally with a upper respiratory infections. Hematuria subsides and recurs every few months. • In the background, there is indolent development of mild nephritic or nephrotic features • Very rarely develops crescentic RPGN
    • 139. IgA Nephropathy (Berger’s Disease) • May be associated with Henoch-Schoenlein purpura, a systemic disorder of children that includes purpuric skin lesions, abdominal pain and arthralgia. • Prognosis: variable, with many patients maintaining normal renal function for many years; but slow progression to chronic renal failure in 40%. Recurrence post-transplant is frequent.
    • 140. Now let’s see if you’ve been paying attention…
    • 141. Look at biopsy slides below. Which statement about this disease is INCORRECT: A. Plasmapheresis should be started to remove circulating antibodies B. This disease can be associated with pulmonary hemorrhage C. This disease is associated with Antinuclear Cytoplasmic antibodies (ANCA) D. This disease clinically presents as RPGN
    • 142. Look at biopsy slides below. Which statement about this disease is INCORRECT: A. Plasmapheresis should be started to remove circulating antibodies B. This disease can be associated with pulmonary hemorrhage C. This disease is associated with Antinuclear Cytoplasmic antibodies (ANCA) D. This disease clinically presents as RPGN
    • 143. Chronic Glomerulonephritis (CRGN) Case presentation • Will is a 25 year old VCU student with history of HTN self-referred to VCU renal clinic to have his “kidneys checked”. He reports that he was seen by a private nephrologist in town 2 years prior and had a kidney biopsy, which showed “chronic changes”. He did not have insurance and could not afford to pay medical bills, therefore he has not followed up. He is not taking any medications.
    • 144. Chronic Glomerulonephritis (CRGN) Case presentation • Patient is asymptomatic • Blood pressure is 170/110, and physical exam is normal apart from trace LE edema. His BUN is 55 and creatinine 6.2. Urinalysis demonstrates 3+ protein, 5 rbcs per hpf, and some broad granular casts. Renal ultrasound demonstrates 9 cm kidneys bilaterally with thin echogenic cortex. • Diagnosis: chronic glomerulonephritis
    • 145. Chronic Glomerulonephritis (CRGN) • Pathology: kidneys are grossly shrunken, and microscopically show significant and widespread global glomerular sclerosis, with interstitial fibrosis and tubular atrophy, “end- stage kidney”.
    • 146. Chronic Glomerulonephritis (CRGN) • Epidemiology: an important cause of end- stage renal disease. It is usually first noted in young to middle-age adults. • Pathogenesis: usually at time of diagnosis, glomerular changes of CRGN are so far advanced that determination of exactly how they became sclerotic is impossible to work out. It may therefore be the end-stage of such processes as FSGS, MGN, RPGN, or MPGN.
    • 147. Chronic Glomerulonephritis (CRGN)
    • 148. Chronic Glomerulonephritis (CRGN) • Clinical features and lab findings: usually insidious onset, and discovered late in its course with renal insufficiency. Patients usually have edema, HTN and heavy proteinuria.
    • 149. Chronic Glomerulonephritis (CRGN) • Treatment – Control of BP – Use of ACE inhibitor – Control of hyperlipidemia – Avoidance of other nephrotoxic substances – Cessation of smoking
    • 150. Chronic Glomerulonephritis (CRGN) • Prognosis: poor renal prognosis and patient needs to be prepared for dialysis or kidney transplantation
    • 151. Now let’s see if you’ve been paying attention…
    • 152. This IF staining pattern is in: A. Mesangial distribution B. Granular capillary loop distribution C. Linear capillary loop distribution
    • 153. This IF staining pattern is in: A. Mesangial distribution B. Granular capillary loop distribution C. Linear capillary loop distribution
    • 154. Autosomal Dominant Polycystic Kidney Disease (Adult) • Autosomal dominant disease related to defect on chromosome 16 (PKD-1) in 85% of cases • Progressive cystic dilation of nephrons leading to renal failure • ESRD by the 4th or 5th decade.
    • 155. Autosomal Dominant Polycystic Kidney Disease (Adult) • Polycystin-1 on surface of tubular epithelial cells (TEC) probably integral to cell-cell and cell-matrix interaction in growth and differentiation. • Cysts detach from TEC and continue to proliferate and secrete fluid thereby enlarging. • May be asymptomatic until late stages, when pain may occur.
    • 156. Autosomal Dominant Polycystic Kidney Disease (Adult) • Larger masses (up to 4kg) may be apparent by palpation. • Hematuria, proteinuria, polyuria, hypertension. • Patients may survive for years with azotemia but ultimately progress to uremia.
    • 157. Autosomal Dominant Polycystic Kidney Disease (Adult) • 40% also have polycystic liver disease (from biliary epithelium) • Also intracranial berry aneurysms at the Circle of Willis; lead to death in 4 – 10% of cases due to subarachnoid hemorrhage
    • 158. Autosomal Dominant Polycystic Kidney Disease (Adult) • Mitral valve prolapse in 20 – 50% (usually asymptomatic) • 40% die of coronary or hypertensive heart disease
    • 159. Autosomal Dominant Polycystic Kidney Disease (Adult) • Dialysis or transplant usually successful, does not recur • Nephrectomy if painful or infected
    • 160. Autosomal Recessive Polycystic Kidney Disease (Childhood) • Rare and distinct from ADPKD • Usually presents at birth with serious complications • Enlarged kidneys may interfere with pulmonary development - stillbirth • Rapid renal failure may follow • Defect on chromosome 6 (PKHD1) which encodes protein fibrocystin
    • 161. Autosomal Recessive Polycystic Kidney Disease (Childhood) • Fibrocystin may function in biliary and renal collecting duct differentiation • Kidneys are enlarged with smooth external surface and many small cysts on cut section arranged at right angles to cortical surface • Spongelike appearance
    • 162. Autosomal Recessive Polycystic Kidney Disease (Childhood) • Liver also has cysts • Progressive hepatic fibrosis and bile duct proliferation in older children (“congenital hepatic fibrosis”)
    • 163. Simple cysts • May be multiple • Usually 1 – 5cm, maybe bigger • Translucent, straw colored fluid • Commonly found post- mortem • By imaging have smooth contours with no vascularity, unlike tumors
    • 164. Acquired (dialysis-associated) cystic disease • With prolonged dialysis may form many cortical and medullary cysts • Clear fluid filled • Probably result from tubule obstruction due to fibrosis or calcification
    • 165. Acquired (dialysis-associated) cystic disease • May develop renal cell carcinoma in cyst wall (7% over 10 years)
    • 166. Pathology Laboratory Images • Selected images from the path website. • Understand the pathogenesis/cause. • OK to memorize the image, but be able to recognize similar changes in other images. • You should be familiar with the images you have seen in lectures and will see in lab.

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