ACCME/Disclosure. Case #1. Case History. Dr. Bracamonte has nothing to disclose

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Case #1 ACCME/Disclosure Dr. Erika Bracamonte Associate Professor of Pathology University of Arizona, College of Medicine Banner University Medical Center, Tucson Dr.

1 Case #1 ACCME/Disclosure Dr. Erika Bracamonte Associate Professor of Pathology University of Arizona, College of Medicine Banner University Medical Center, Tucson Dr. Bracamonte has nothing to disclose Case History 14 year old girl with ESRD due to obstructive uropathy underwent cadaveric renal transplant Post transplant course Multiple UTI s Leukopenia, anemia, reticulocytopenia Serology positive: Dx: Aplastic anemia secondary to Parvovirus Case History 6 months post transplant Bilateral native nephrectomies due to UTI s 1 year post transplant Allograft dysfunction: SCr 1.2 mg/dl 1

RBC s Urine culture: Negative Case History Serology: Negative: CMV, EBV, BK, HIV, Hepatitis Positive: (IgG and

2 Case History CBC: WBC: Normal RBC: 4.13 (borderline low), low Hgb and Hct Urinalysis: Mild protein: 30 mg/dl Minimal blood No casts or dysmorphic RBC s Urine culture: Negative Case History Serology: Negative: CMV, EBV, BK, HIV, Hepatitis Positive: (IgG and IgM) HLA Antibody Testing Positive: Class I and Class II Donor Specific Antibodies detected A2 (7,313 MFI) DQA1*01:03 (1,839 MFI) Cw7 (1,086 MFI) Allograft Biopsy #1 1 year post transplant 2

3 3

4 IgG Lambda 4

5 Diagnoses Acute antibody mediated rejection Immune complex mediated glomerulonephritis Features suggestive of early transplant glomerulopathy? 5

endothelial tissue 85% adults have serologic evidence of prior infection Children: Erythema infectiosium Adults: Polyarthropathy, myalgia, headache, fever, anemia Pregnant women May cross placenta

6 Immune complex GN De novo No features of autoimmune disease or other infections Possibly associated with infection? Kidney biopsy sent for testing by PCR Positive Single stranded DNA virus Tropism for erythroid progenitor cells which express parvovirus receptor Receptor also found in synovial, heart, renal, endothelial tissue 85% adults have serologic evidence of prior infection Children: Erythema infectiosium Adults: Polyarthropathy, myalgia, headache, fever, anemia Pregnant women May cross placenta severe fetal anemia Sickle cell disease Aplastic crisis Renal Disease Link reported 1978 Markenson et al: Sickle disease, nephrotic syndrome and hypoplastic crisis Renal lesion: focal segmental glomerulosclerosis 1997 Moudgil et al: Transplant patient with PVB19 and collapsing glomerulopathy 6

Renal Disease PB19 associated renal disease Adult and pediatric patients Female predominance (67%) Renal dysfunction + evidence of PVB19 infection Positive blood

2001: 23 pts with collapsing GN Increased incidence PVB19 detected in blood (vs HIVAN, FSGS) PVB19 DNA detected in 78% renal biopsies by PCR» 25% normal controls

Thrombotic microangiopathy With and without associated proliferative features Renal Biopsy Lesions Proliferative GN Immunofluorescence IgM (70%) > IgG (63%) > IgA

7 Renal Disease PB19 associated renal disease Adult and pediatric patients Female predominance (67%) Renal dysfunction + evidence of PVB19 infection Positive blood serology and/or tissue PCR Reported cases Native kidneys: 75% Allograft kidneys: 25% Renal Biopsy Lesions Native Kidneys Collapsing glomerulopathy Moudgil et al, 2001: 23 pts with collapsing GN Increased incidence PVB19 detected in blood (vs HIVAN, FSGS) PVB19 DNA detected in 78% renal biopsies by PCR» 25% normal controls also positive Proliferative GN Endocapillary (55%) > mesangial (15%) > mesangial + endocapillary (12%) Occasionally crescentic Occasionally with associated FSGS Thrombotic microangiopathy With and without associated proliferative features Renal Biopsy Lesions Proliferative GN Immunofluorescence IgM (70%) > IgG (63%) > IgA (40%) Predominantly capillary loops C3 (80%) C1q (20%) Electron Microscopy Subendothelial immune deposits (92%) Mesangial deposits (50%) Subepithelial deposits (25%) 7

Transplant kidneys Renal Biopsy Lesions Most common lesion:

Nephrologie & Therapeutique 8 (2012) 5 12.

medium sized vessel vasculitis Collapsing GN/FSGS PVB19 Detected:

FSGS Endothelium Thrombotic microangiopathy, vasculitis Immune

(Hep C) Association vs direct causality PVB19 positive IHC/ISH

8 Transplant kidneys Renal Biopsy Lesions Most common lesion: Thrombotic microangiopathy (66%) Brodin Sartorius A et al: Nephrologie & Therapeutique 8 (2012) Transplant Kidneys Renal Biopsy Lesions Other lesions: Small and medium sized vessel vasculitis Collapsing GN/FSGS PVB19 Detected: Parietal and visceral epithelial cells Collapsing glomerulopathy, FSGS Endothelium Thrombotic microangiopathy, vasculitis Immune complex mediated proliferative GN Precedent for viral etiologies (Hep C) Association vs direct causality PVB19 positive IHC/ISH only rarely demonstrated in glomerular tissue with proliferative GN Ardalan et al: Exp and Clin Transpl. 6(2)

9 Our patient De novo immune complex GN would be more consistent with native kidney No other features of infection, autoimmune disease Due to inadequate immunosuppression? AMR Treatment: Plasmapheresis, IVIG Repeat biopsy 4.5 months later 9

10 10

11 IgG C4d 3 rd Biopsy 3 years post transplant 11

12 IgM 12

13 C4d 13

14 Take Home Points PVB19 associated glomerular injury may occur or be exacerbated in transplant setting Morphologic distinction from lesions of rejection (acute glomerulitis, transplant glomerulopathy, vasculitis) can be challenging Clinical significance and contribution of PVB19 to graft dysfunction and overall clinical picture is unclear Acknowledgement Beth Braunhut, MD References Ardalan MR, Shoja MM, Tubbs RS, Jayne D. Microepidemic in Renal Transplant Recipients with Thrombotic Microangiopathy and Allograft Vasculitis. Exp Clin Transplant Jun;6(2): Ardalan MR, Shoja MM, Tubbs RS, Esmaili H, Keyyani H. Postrenal transplant hemophagocytic lymphohistocytosis and thrombotic microangiopathy associated with parvovirus B19 infection. Am J Transplant Jun 8(6) Brodin Sartorius A, Mekki Y, Bloquel B, Rabant M, Legendre C. Infection par le apres transplantation renale. Nephrologie & Therapeutique 8 (2012) Moudgil, Nast CC, Bagga A, Wei L, Cohen AH, Jordan SC, Toyoda M. Association of parvovirus B19 infection with idiopathic collapsing glomerulopathy. Kidney Int 2001 Jun;59(6): Moudgil A, Shidban H, Nast CC, Bagga A, Aswad S, Graham SL, Mendez R, Jordan SC. infection related complications in renal transplant recipients: treatment with intravenous immunoglobulin. Transplantation Dec 27;64(12): Murer L, Zacchello G, Bianchi D, Dall Amico R, Montini G, Andreetta B, Perini M, Dossi E, Zanon G, Zacchello F. Thrombotic Microangiopathy Associated with Infection after Renal Transplantation. J Am Soc Nephrol 11: , 2000 Waldman M, Kopp J. Parvovirus B19 associated complications in renal transplant recipients. Nat Clin Prac Nephrol (Oct. 2007): p

RENAL EVENING SPECIALTY CONFERENCE

RENAL EVENING SPECIALTY CONFERENCE Harsharan K. Singh, MD The University of North Carolina at Chapel Hill Disclosure of Relevant Financial Relationships No conflicts of interest to disclose. CLINICAL HISTORY