Afrouzian M1, Thomas P2, Kadambi P3, Solez K4
1
Department of Pathology, University of Texas Medical Branch, Galveston, USA
2
Department of Surgery, Transplantation surgery, University of Texas Medical Branch, Galveston, USA
3
Department of Internal Medicine, Division of Nephrology, University of Texas Medical Branch,
Galveston, USA
4
Department of Pathology, University of Alberta, Edmonton, Canada
Role of peritubular capillary thrombosis in renal allograft rejection
Background: Microthrombus formation in peritubular capillaries (Ptcs) is a
phenomenon that has not been fully explored in renal transplantation pathology.
The only study on human allografts that addresses the presence of thrombi in
Ptcs of rejecting kidneys has been published by Meehan and Haas in 2003 and
since then, this subject has remained untouched. In an earlier animal study, we
have reported the presence of microthrombi in Ptcs of rejecting grafts in the ϒInterferon and the ϒ-Interferon Receptor knock out model. In these mice models
of transplantation, microthrombi appear in Ptcs before the grafts undergo
hemorrhagic/ coagulative necrosis. The significance of this phenomenon is not
known: Whether or not it is associated with ABMR in human allografts or with
other lesions such as bacterial infection, drug toxicity, polyoma virus
nephropathy, are questions that deserve attention.
Objectives: The primary goal of this study was to determine the incidence of this
lesion in human allografts. The secondary goal was to explore its relationship with
antibody- mediated rejection (ABMR), T cell-mediated rejection (TCMR),
thrombotic microangiopathy (TMA), Polyoma virus nephropathy (PVN) and drug
toxicity (CNI tox).
Material and Methods: A total of 84 renal transplant biopsies with renal allograft
dysfunction, reported between January 2012 and April 2013 at the UTMB
Department of Pathology were reviewed by a single pathologist. Thirteen native
kidney biopsies with no evidence of coagulopathy were used as control. To detect
fibrin, all biopsies were stained with Martius-Scarlet –Blue (MSB) and assessed for
presence of microthrombi in Ptcs and in glomeruli. Immunofluorescence and
electron microscopy material were reviewed on all biopsies in search of
intraluminal and sub-endothelial fibrin tactoids, platelet aggregates, and signs of
endothelial injury, including sub-endothelial widening, loss of endothelial cell
fenestration, cytoplasmic swelling, or fragmentation and apoptosis. All allograft
biopsies were studied for the presence of C4d in peritubular capillaries. Finally,
using the Banff diagnostic categories for renal allograft biopsies (2009), findings
were correlated with the following diagnoses: ABMR, TCMR, Borderline changes
(Brd), TMA, CNI tox, PVN, interstitial fibrosis and tubular atrophy (IFTA),
Transplant glomerulopathy (TG), and bacterial pyelonephritis (Pyelo).
Results: Ptc thrombosis was present in: 25/71 (35%) of allograft biopsies; 7/17
cases with Acute AMR; 9/25 cases with TCMR; 1/5 cases of Brd; 10/13 cases of
TMA; one case of atypical HUS; 3/4 cases with PVN; 2/7 cases with IFTA; 2/4 cases
of pyelonephritis and in none of the two cases diagnosed as TG. None of the
native kidney biopsy (controls) showed evidence of thrombosis in ptcs. Presence
of microthrombi in peritubular capillaries strongly correlated with only 3
parameters: the presence of fibrin in glomeruli (p<0.0001), the diagnosis of TMA
(p<0.0001); and the diagnosis of CNI tox (p = 0.045).
Conclusion: Ptc thrombosis is a lesion that has been overlooked in renal
transplant pathology, despite the fact that it is not a rare finding: We
demonstrated the presence of Ptc thrombosis in one third of our allograft
biopsies. Our results show that Ptc thrombosis has a strong association with
endothelial cell injury in both peritubular capillaries and glomeruli. Diagnoses of
TMA, proven by electron microscopy, and CNI tox, also have significant
association with Ptc thrombosis. We suggest that Ptc thrombosis is a sign of
endothelial cell injury in the microvasculature and should be considered as an
important lesion for the detection of TMA, possibly related to CNI tox. To our
surprise, Ptc thrombosis did not show any association with ABMR which also
affects both glomerular and peritubular capillary endothelium and causes TMA.