Case Presentation Turki Al-Hussain, MD Director, Renal Pathology Chapter Saudi Society of Nephrology & Transplantation Consultant Nephropathologist & Urological Pathologist Department of Pathology & Laboratory Medicine King Faisal Specialist Hospital & Research Centre 1
Clinical History A 74 year-old man underwent kidney transplantation from related living donor in September 2010. His primary disease was unknown. H/O hypertension and diabetes mellitus type 2 H/O mitral valve replacement He is on regular follow up with stable renal function Two years after transplant, he developed nephrotic syndrome Physical examination: Temperature: 36.8 C, respiratory rate: 18/MIN, blood pressure: 160/68 mmhg and heart rate: 88/MIN He had pitting lower limb edema, fine basal crackles in the chest 2
Laboratory Data Urinalysis: 3+ protein, 1+ blood, 0-5 WBC/HPF, 0-5 RBC/HPF, No RBC cast. 24 hrs. urine protein: 4 g/24 hrs. Urine culture: negative Serum creatinine: 60 μmol/l, Urea: 6 mmol/l, Albumin: 28 g/l 3
Renal Biopsy was Performed 4
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IF: IgG 14
IF: C3 15
IF: Kappa and Lambda Light chains 16
Immunofluorescene IgG: 3+ IgA: 1+ IgM: negative Kappa light chain: 3+ Lambda light chain: 3+ C3: 3+ C1q: trace Fibrinogen: negative 17
Immunohistochemistry C4d: negative in peritubular capillaries SV40 large T antigen: negative in tubular epithelial cells 18
EM 19
EM 20
EM 21
EM 22
EM 23
EM 24
Final Diagnosis Membranous Glomerulopathy, stage 3 (De novo VS Recurrent) No evidence of acute rejection 25
Recurrent Glomerular Diseases Recurrent glomerulonephritis is the third most common cause of allograft failure (after death with functioning graft and chronic rejection) Fairhead and Knoll. Curr Opin Nephrol Hypertens 2010; 19:578-85 26
Recurrent Glomerular Diseases Membranous glomerulopathy Focal segmental glomerulosclerosis Membranoproliferative glomerulonephritis type 1 Dense Deposit Disease IgA nephropathy 27
Recurrent Glomerular Diseases Fairhead and Knoll. Curr Opin Nephrol Hypertens 2010; 19:578-85 28
Recurrent Membranous Glomerulopathy Usually develops within the first few months or weeks Recurrence rate: 10-40% Graft loss: up to 50% at 10 years Patients usually have severe proteinuria 29
Focal Segmental Glomerulosclerosis Recurrence rate: 30% May occur within minutes in the form of heavy proteinuria. Histologic changes appear 4-6 weeks post transplant. Risk factors: younger recipient age, history of rapid progression to ESRD, prior nephrectomy for FSGS, and a second transplant after allograft loss from recurrence. 30
Membranoproliferative glomerulonephritis type 1 Recurrence rate: 30-50% Usually occurs early (in 1 st year) DDx: transplant glomerulopathy Risk factors: younger recipient age, aggressive disease in the native kidney, and persistently low complement levels. 31
Dense Deposit Disease Recurrence rate: 80-100% Can be very rapid (as early as 12 days) BUT with slow progression. Serum C3 can be normal (35%). 32
IgA nephropathy Recurrence rate: 15-50% Can be only immunopathologic i.e., discovered on a protocol biopsy of an asymptomatic patient. 33
De Novo Glomerular Diseases Development of glomerular disease in allograft that is different from the native kidney disease. De novo membranous glomerulopathy De novo focal segmental glomerulosclerosis De novo antiglomerular basement membrane disease 34
De Novo Membranous Glomerulopathy The most common de novo glomerulonephritis in renal transplant. Prevalence: 0.5-9% Usually appears after the first year of transplantation. Patients may have nephrotic range proteinuria (1/3), mild proteinuria, or no proteinuria. 35
De novo Membranous Glomerulopathy The dominant IgG subclass is IgG1. No anti-pla2r antibodies In most cases, the cause is unknown. Sporadic cases reported in recipients with renal infarction, Alport s syndrome, ureteral obstruction, or recurrent IgA nephritis, and even the posttransplant emergence of cancer.? Sirolimus 36
Frequently associated with signs of antibodymediated rejection, such as peritubular capillaritis and C4d deposition in peritubular capillary or transplant glomerulopathy. Evidence is presented that many of the cases of socalled de novo MGN may be a complication of transplant glomerulopathy rather than being caused by mechanisms totally independent from rejection. [Truong L, Gelfand J, D'Agati V et al. De novo membranous glomerulonephropathy in renal allografts: a report of ten cases and review of the literature. Am J Kidney Dis. 1989;14:131-44]. 37
Post-transplant de novo MN was frequently accompanied by the histological findings of AMR, and some of the patients with de novo MN were positive for DSA. In one case of the de novo MN with DSA, double IF staining revealed that the HLA-DR and donor-specific HLA class I molecules (A11) were present in the subepithelial deposits combined with IgG. Although in the limited number of cases, these observations suggested that the antibodies against donor HLAs might play some roles for the pathogenesis of de novo MN after kidney transplantation in some patients. Honda K et al. 38
De novo MN is not caused by an immunologic response to a single antigen, but may be triggered by widely different antigens. The frequent association of de novo MN with signs of allograft rejection, viral hepatitis, or non immune-mediated kidney diseases strongly suggests that alloimmune responses, viral infections, and possibly mechanical injuries may produce an environment in the kidney allograft that predisposes to the exposure of hidden (cryptic) autologous podocyte-related antigens and thereby stimulate the production of circulating auto- or allo-antibodies (typically of the IgG1 subclass) eventually leading to in situ immune complex formation, subepithelial deposits, and the morphological lesion of MN. Ponticelli C, Glassock RJ. De novo membranous nephropathy (MN) in kidney allografts. A peculiar form of alloimmune disease? Transpl Int. 2012 ;25:1205-10. 39
De Novo Focal Segmental Glomerulosclerosis Usually develops years after transplantation. Related to progressive nephron loss and glomerular hyperfiltration injury. Reported following rapamycin. 40
De Novo Antiglomerular Basement Very rare Membrane Disease Occurs in patients with Alport syndrome (2-5%) Antibodies against alpha-3 subunit of type IV collagen in the donor kidney. 41
References 1. Marinaki S et al. Glomerular Disease Recurrence in the Renal Allograft: A Hurdle But Not a Barrier for Successful Kidney Transplantation. Transplant Proc. 2013; 45:3-9. 2. Fairhead T et al. Recurrent glomerular disease after kidney transplantation. Curr Opin Nephrol Hypertens. 2010; 19:578-85. 3. Ponticelli C et al. De novo membranous nephropathy (MN) in kidney allografts. A peculiar form of alloimmune disease? Transpl Int. 2012 ;25:1205-10. 4. Honda K et al. De novo membranous nephropathy and antibodymediated rejection in transplanted kidney. Clin Transplant. 2011; 25:191-200. 5. Truong L et al. De novo membranous glomerulonephropathy in renal allografts: a report of ten cases and review of the literature. Am J Kidney Dis. 1989;14:131-44. 42
THANK YOU 43