Workup for chronic allograft nephropathy

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Slide 1 :

Workup for Chronic Allograft Dysfunction Salwa Ibrahim, MD MRCP (London) Professor of Nephrology Cairo University

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Definition of CAD Causes Work up of CAD Agenda

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Chronic allograft dysfunction is a clinically defined by declining renal function (as evidenced by a slow progressive decrease in GFR) associated with de novo or aggravated hypertension It is usually associated with new-onset proteinuria of greater than 0.5 g/24 h or worsening proteinuria in a transplant patient Reliance on s.creatinine alone as a marker underestimate the severity and rate of functional decline particularly when the GFR is between 30 and 70 mL/min Q1: What is Chronic Allograft Dysfunction

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An example of a transplant recipient with a relatively stable serum creatinine (blue) over 10 yr but with first increase then progressive decline in GFR (red) Chapman et al J Am Soc Nephrol 16: 3015–3026, 2005

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Q2: What are the causes of chronic allograft dysfunction Chronic allograft nephropathy Chronic cell mediated rejection Chronic humoral rejection Calcineurin inhibitor toxicity Recurrent and de-novo GN Transplant Glomerulopathy PKV and CMV infection

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Work Up of CAD Urine analysis and cytology 24 hour protein in urine Renal function test e GFR estimation Lipid profile CNI drug level Immune screen Virology work up Renal ultrasonography Renal Duplex examination Renal Biopsy (light microscopy, EM, IF)

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Renal Biopsy is the Gold Standard Approach for Diagnosis of CAD

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Chronic allograft Nephropathy CAN is characterized by progressive renal dysfunction accompanied by chronic interstitial fibrosis, tubular atrophy, vascular occlusive changes and glomerulosclerosis It is the chief cause of kidney transplant failure despite improvement in Immunosuppression

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Extensive intimal Thickening and narrowing of vascular lumen Glomerulosclerosis Expansion of mesangial matrix Interstitial fibrosis and tubular atrophy Chronic Allograft Nephropathy

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The latest meeting of the Banff consensus group (2007) worked towards clearly delineating specific diagnostic entities such as Chronic active antibody-mediated rejection Chronic active cell-mediated rejection Calcineurin inhibitor (CNI) toxicity Interstitial fibrosis and tubular atrophy Banff consensus Update

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Chronic active antibody mediated rejection C4d+ presence of circulating anti-donor antibodies, morphologic evidence of chronic tissue injury such as glomerular double contor and/or peritubular capillary basement membrane multilayering/ tubular atrophy Chronic active T-cell mediated rejection Chronic allograft arteriopathy (arterial intimal fibrosis with mononuclear cell infiltration in fibrosis, formation of neointima) Interstitial fibrosis and tubular atrophy (no evidence of any specific etiology) Include nonspecific vascular and glomerular sclerosis severity graded by tubulointertsitial features I Mild interstitial fibrosis and tubular atrophy (less than 25% of cortical area) II Moderate interstitial fibrosis and tubular atrophy (26 -50% of the cortical area) III severe interstitial fibrosis and tubular atrophy (more than 50% of the cortical area) The 2007 updates on the Banff Classification

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(Prevalence of CAN among 961 kidney transplant protocol biopsy over 10 years) Nankivell et al, NEJM 2003 Interstitial fibrosis and tubular atrophy are almost universal especially grade I by 10 years after transplantation

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C4d deposition in the peritubular capillaries of the kidney have been correlated with slowly failing kidney allograft Chronic humoral rejection

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Chronic active T-cell mediated rejection Chronic allograft arteriopathy (arterial intimal fibrosis and formation of neointima)

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Chronic CNI Toxicity

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Chronic CNI therapy is associated with irreversible kidney damage All the three elements are affected: vessels (arteriolar hyalinosis) tubulo-interstium (tubular atrophy and fibrosis) and glomeruli (thickening and fibrosis of Bowman’s capsule, focal or global sclerosis) Chronic Calcineurin inhibitor nephrotoxicity

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Nodular hyaline arteriolar thickening

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Afferent arteriolar hyalinosis

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Tubular atrophy striped interstitial fibrosis

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D.D The D.D of chronic CNI toxicity from others remain difficult as they may share same nonspecific findings of interstitial fibrosis, tubular atrophy, and renal scarring Even tubular vacuolization or new onset or progressive arteriolar hyalinosis can be seen in other processes Combination of different histological findings is mandatory to make the diagnosis of CNI toxicity

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CMV-BKV Nephropathy

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There is growing evidence that CMV contributes to the pathogenesis of chronic allograft injury CMV enhanced the expression of endothelial TGF-1 and platelet-derived growth factor in renal allograft causing transplant vasculopathy and by up-regulating connective tissue growth factor–induced interstitial fibrosis CMV Infection

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BKV is small Virus with a core of DNA Replication occurs during states of immune suppression This results in large nuclear and perinuclear virus-containing inclusions in the tubule cells Lysis of these infected cells results in viral seepage into the tubule lumen and urine The resultant effect of continued intragraft inflammation, tubular injury and upregulation of profibrotic mediators is allograft dysfunction and loss BKV Nephropathy

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Viruria can be detected by PCR for BKV DNA Cytology for BKV inclusion– bearing epithelial cells termed “decoy cells” Electron microscopy for viral particles A transplant kidney biopsy remains the gold standard for diagnosing BKV nephropathy Interstitial nephritis and tubular cytopathic changes of BKV nephropathy can be focal Therefore, at least two cores including medulla should be examined Diagnosis of BKVN

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Decoy cells and BKV Nephropathy Good correlation between the number of DCs and The presence of BKVN The histological grading of BKVN BKVN is more likely when DCs are associated with an acute increase in serum creatinine False positive 9.6%-false negative 2.9%and

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Recurrence of original kidney disease

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Recurrent GN is the third most important cause of renal allograft loss at 10 years after transplantation Frequency Membranoproliferative GN type II (60-100%) Membranoproliferative GN type I (20-30%) IgA Nephropathy (26-46%) Focal segmental glomerulosclerosis (20-30%) Membranous Nephropathy(10%) HUS (50%) Diabetic nephropathy Oxalosis, Cystinosis Anti GBM, SLE less 5% Recurrence of the original kidney disease

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Recurrent FSGS FSGS can recur as early as a few hours after transplant and as late as two years post-transplant

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Membranous Nephropathy Recurrence of membranous nephropathy in the transplanted kidney is not common. The rates of recurrence with MGN vary from 10 to 30%

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MCGN is suggested by the presence of crescents on light microscopy, stronger staining for C3, and weaker staining for IgM on immunohistology and by the presence of dense subendothelial deposits on electron microscopy D.D chronic transplant glomerulopathy Recurrent MCGN

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Transplant glomerulopathy It is characterized by endothelial cell injury , accumulation of flocculent material in a widened subendothelial space, and mesangial interposition with deposition of new matrix along glomerular capillary walls These progressive changes produce a thickened glomerular capillary profile and the capillary wall “double contours TG has been documented in the context of “chronic rejection” and was strongly correlated with features consistent with chronic/persistent/recurrent antibody-mediated rejection (AMR)

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Rare entity The spectrum of histopathological changes seen in denovo glomerulonephritis does not differ from recurrent glomerulonephritis FSGS (1-9%) Membranous GN (2-9%) De novo GN

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Urine proteomics

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In this study, mass spectrometry was used to analyze differences in urinary polypeptide patterns of 32 cases with chronic allograft dysfunction (14 with pure interstitial fibrosis and tubular atrophy, 18 with chronic antibody mediated rejection) and 18 control subjects (8 stable recipients and 10 healthy controls)

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The study showed good segregation of samples in the 4 different groups that may offer a first step to design a specific non invasive diagnostic tool for chronic allograft dysfunction

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Summary CAD is caused by various disease pathology including chronic allograft nephropathy, chronic CNI toxicity, BKV and recurrence of original kidney disease So far, renal biopsy with IF, c4d staining, E/M examination remain the Gold standard technique to diagnose the exact cause of CAD

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