AN ANALYSIS OF TRANSPLANT GLOMERULOPATHY AND THROMBOTIC MICROANGIOPATHY IN KIDNEY TRANSPLANT BIOPSIES
K Joshi*, S Sreedharanunni*, R Duggal*, R Nada*, V Sakhuja#, M Minz**
Departments of Histopathology*, Nephrology# and Transplant Surgery**, Postgraduate Institute of Medical Education and Research, Chandigarh, India
Objectives: 1) To determine the incidence of transplant glomerulopathy (TG) and Thrombotic Microangiopathy (TMA) in a large cohort of renal transplant recipients studied by biopsies performed for evaluation of graft dysfunction. 2) To evaluate the histological and ultrastructural features of TG and TMA. 3) To assess the relationship between the two glomerular lesions
Methods: A total of 1792 indicated renal transplant biopsies received over 5 years (2006 to 2010) were reviewed independently by four pathologists and assessed for glomerular pathology. 266/1792 biopsies (of 249 patients)had significant glomerular pathology and were further analyzed; along with EM and IF on 44 cases, IF alone on 89 and EM alone on 3 cases. C4d immunostain was done on paraffin sections. Appropriate correlations and tests of significance were derived using SPSS software.
Results: TG is the most common glomerular lesion in renal allograft biopsies constituting 5.97% of all allograft biopsies and 40.23% of all allograft biopsies with significant glomerular lesions. Banff score of TG was cg1, cg2, cg3 in 26.2%, 29.0% and 44.9% biopsies respectively. TG was associated with antibody mediated rejection (AMR) in 67.3% of biopsies. In biopsies of TG which are PTC C4d positive, tubular atrophy and interstitial fibrosis are less common, whereas PTC dilatation and capillaritis are more common as compared to the C4d negative group. There is no difference between Cg1, Cg2 and Cg3 in terms of tubular atrophy, interstitial inflammation, interstitial fibrosis, or PTC capillaritis. C4d immunostaining of glomerular capillary loops is a common finding in TG. Peritubular capillary basement membrane multilamination is a common association with TG. However, multilamination of glomerular basement membrane is less frequent. EM reveals remodelling of GBM, mesangial interposition and sub-endothelial fluffy material.
TMA is the 2nd most common glomerular lesion (34.2% of all glomerular lesions). The morphological appearance of TMA can be variable. Endothelial swelling, vacuolation and subendothelial widening are the most common morphological features. Collapsing glomerulopathy, segmental sclerosis and presence of crescents in a transplant setting, can also be manifestations of TMA. The most common cause of TMA in our study was AMR, followed by cyclosporine toxicity and rarely CMV infection. TMA can be associated with other glomerular lesions like IgA nephropathy. In 19/266 biopsies TG was associated with TMA, manifested in different glomeruli or in the same glomerulus. The electron microscopic findings seen in TG often overlap with that of TMA. The concept that TG is a chronic smouldering TMA is supported by our findings. A combination of TG with other glomerular pathologies such as IgAN and DDD can occur and should be looked for.
Conclusions: Glomerular diseases contribute significantly to allograft dysfunction and a complete diagnosis needs proper evaluation of HE and PASM stained sections together with other special stains, immunohistochemistry, electron microscopy, and detailed clinical data including pre-transplant history.
Since AMR is significantly associated with glomerular lesions of both TG and TMA which are the two most common glomerular pathologies, strategies have to be developed to control both acute as well as ongoing AMR. Since IF does not contribute to the diagnosis of TG or TMA, newer ancillary modalities have to be developed to distinguish TG from TMA. Our findings suggest an overlap between the two lesions and support the concept that TG evolves from a smouldering TMA.