Kidney and Liver Transplant - Update and Issues
Case 2 -
Hyperacute and Acute Renal Transplant Rejection
Arthur H. Cohen, Juan Lechago and Cynthia C. Nast
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Hyperacute renal transplant rejection in an antibody-mediated process,
which typically occurs within the first hour post-engraftment, during which time the kidney grossly
becomes flaccid, cyanotic and swollen while urine output ceases or never begins
there is accumulation of neutrophils in glomerular and peritubular capillaries, arterioles and small
arteries. The capillaries and arterioles subsequently develop erythrocyte and fibrin thrombi while the
interstitium is edematous and may become hemorrhagic. Tubules undergo coagulative necrosis; there is no
inflammation in the interstitium or in the walls of tubules. Immunofluorescence microscopy may disclose
IgM, C3 and less often IgG in addition to fibrin within the affected glomeruli and arterioles, but these
immune reactants are not always observed. The differential diagnosis includes thrombosis of major
arteries and renal vein thrombosis, but widespread intravascular neutrophils and thrombosis of
capillaries and arterioles are distinctive features of hyperacute rejection.
The majority of cases of hyperacute rejection are caused by presensitization to alloantigens on the
surface of graft endothelial cells from blood transfusions, pregnancy and prior transplants
Circulating antibody binds to the alloantigens, fixes complement, and activates platelets and the
clotting system resulting in widespread intragraft microthrombosis. A smaller number of hyperacute
rejection episodes may be secondary to antibody-dependent cell mediated cytotoxicity against graft
endothelium . If only a small number of circulating antibodies are initially present, it may take 8
to 48 hours to produce enough antibody to cause graft damage and loss clinically resulting in a delayed
hyperacute rejection. This form of rejection is now quite rare due to the excellent pretransplant
screening available. Once it has occurred however, the graft must be explanted.
Acute renal transplant rejection occurs in two distinct forms: cell
mediated and antibody (humoral) mediated. The cell-mediated variety is far more frequent impacting
approximately one-third of all renal transplants, and can be further separated into tubulo-interstitial
and vascular types. Acute cell mediated tubulo-interstitial rejection
comprises 45-70% of all acute rejection episodes in renal allografts. When a kidney is undergoing this
form of rejection it becomes swollen and pale with a congested medulla. Microscopically the interstitium
is edematous with a mononuclear inflammatory infiltrate composed of lymphocytes and variable numbers of
monocytes. The lymphocytes are primarily activated T cells, both CD4 and CD8. The earliest infiltrates
occur at the cortico-medullary junction, then spread throughout the cortex and occasionally into the
superficial medulla; as with most renal biopsies unscarred cortex is required for diagnosis. Lymphocytes
extend into the tubules between the epithelial cells, a process termed tubulitis and a hallmark of rejection. Tubulitis is found in all parts of the
nephron and often begins in the distal tubules
. There is variable tubular cell necrosis and
tubules may rupture with interstitial extra-tubular Tamm-Horsfall protein. Up to 30% of involved grafts
will have some interstitial eosinophils and 25% may have few scattered neutrophils; more than just a few
neutrophils raises the possibility of infection or a form of humoral rejection described below. A very
small number of biopsies will show large numbers of polyclonal plasma cells without viral infection,
termed plasma cell rich acute rejection
; when this occurs it often is later in the course of
transplantation and carries a guarded prognosis. In tubulo-interstitial rejection glomerular and
peritubular capillaries are unremarkable or have few lymphocytes and monocytes in the lumina. The
differential diagnosis includes drug-induced acute interstitial nephritis and viral infections; special
stains and, as with all renal biopsies, close clinical correlation may be required for an accurate
Acute cell mediated vascular rejection is found in 30-55% of grafts with
rejection. It is characterized by T cells and monocytes extending under the endothelium of arteries
(interlobular and arcuate) and/or arterioles into the vascular intima. This process has been termed
endarteritis, endothelialitis and intimal arteritis, and is diagnostic for acute rejection . All the
changes of cell mediated tubulo-interstitial rejection may be seen with vascular rejection, although the
latter infrequently occurs as an isolated finding. Associated changes of acute tubular necrosis have
been linked to a more guarded prognosis [10a]. A considerable number of lymphocytes may be in the lumina
of peritubular and glomerular capillaries, and focal interstitial hemorrhage is a common accompaniment.
In a small number of patients with rejection (2-4%) the primary abnormality is acute
transplant glomerulopathy in which there are numerous capillary luminal monocytes with endothelial
cell swelling, subendothelial lucent zones observed ultrastructurally and occasional mesangiolysis. This
may be a form of glomerular vascular rejection, although is still controversial , and glomerular
monocytes may predict a worse prognosis .
Cell mediated rejection occurs when T cells react to donor alloantigens which are expressed in the
context of MHC. Tubular cells may be a target due to their ability to produce and express adhesion
molecules and chemokines, as well as their capacity to process and present antigen to T cells.
Alternatively, endothelium is a primary target as it also can present antigen to T cells, and tubular
epithelium may be at risk only due to its proximity to peritubular capillary endothelium. The immunology
and immunopathology of transplant rejection is quite complex, and reviews are available for those who
desire further details
. Clinically, patients present with a rapid rise in the serum
creatinine level over several days. In the current immunosuppression era, the classic findings of graft
tenderness and fever are seldom observed making renal biopsy a more necessary and oft-used tool for the
transplant nephrologist. Tubulo-interstitial rejection is usually treated with pulse steroid therapy
whereas vascular rejection is more refractory to therapy often necessitating OKT3 or other more
aggressive treatment if there is not severe background chronic renal damage.
Pathogenesis of Cell Mediated Rejection
|Donor alloantigen presentation/ MHC|
|T cell recognition and activation|
|T cell proliferation|
|Further leukocyte recruitment |
| Graft parenchymal damage|
Acute antibody-mediated (humoral) rejection in its classic form is far less
frequent than cell mediated vascular rejection . The classic arterial humoral rejection is
characterized by fibrinoid necrosis in the walls of arteries with myocyte necrosis, cellular debris and
disruption of the internal elastic lamina, with or without a neutrophil infiltrate . Lymphocytes and
monocytes may extend into the walls of arteries and arterial lumina may be thrombosed. Neutrophils
infiltrate the lumina of glomerular and peritubular capillaries, often with resulting thrombosis. The
interstitium often displays hemorrhage and tubular cells are necrotic; in severe cases there are foci of
infarction. Cell mediated tubulo-interstitial rejection may or may not accompany the humoral
rejection. Immunofluorescence microscopy discloses fibrin, C3 and often IgG or IgM in the arterial
More recently, a more subtle form of microvascular peritubular capillary acute
antibody-mediated rejection has been identified, which generally lacks the typical arterial
fibrinoid necrosis of humoral rejection. The most prominent feature in these biopsies is diffuse
peritubular capillary staining for the C4d fragment of complement best identified using indirect
immunofluorescence on frozen tissue
. Renal specimens from these patients show a variety of
mrophologic features including variable numbers of peritubular and glomerular capillary luminal
neutrophils with or without scattered neutrophilic tubulitis; occasionally the
biopsy only shows acute tubular necrosis
. C4d staining of peritubular
capillaries may be the only feature of acute rejection, although cell mediated acute tubulo-interstitial
rejection co-exists with C4d staining in 24-43% of biopsies showing this form of rejection. Up to 45% of
specimens showing endarteritis have peritubular capillary C4d staining . Antibody-mediated C4d+
acute rejection may accompany chronic rejection, indicating an ongoing or active rejection process likely
inducing or exacerbating the chronic injury . C4d positive rejection is found in up to one-third of
renal allograft biopsies in the first few months post-engraftment and to the same degree in all renal
. The long-term prognosis in C4d+ acute rejection appears to be worse than
for cell mediated rejection, but not as dismal as for classic humoral rejection with arterial fibrinoid
Humoral rejection is mediated by antibodies, although it may co-exist with cell mediated rejection.
Alloantibodies to MHC class I and class II antigens have been identified in patients with classic humoral
rejection and various donor specific antibodies including those against MHC class I have been found in
patient with C4d+ biopsies and acute rejection
. Anti-endothelial antibodies occasionally
can be identified by in vitro testing; the spectrum of alloantigens capable of inducing humoral rejection
is likely quite broad [28 ]. However, due to improved pretransplant testing and improved
immunosuppression, overall graft loss to classic humoral rejection remains rather low in the 5-7% range.
C4d+ acute rejection may be more prevalent, and its impact on overall graft survival remains to be
Pathology of Acute Rejection
| Rejection || Glomeruli || Tubules || Interstitium || PTCs* || Arteries|
|Hyperacute ||PMNs, Thrombi ||Necrosis ||Edema, Hemorrhage ||PMNs, thrombi ||Thrombi - small arteries|
|Cell-mediated tubulo-interstitial ||Normal ||Tubulitis ||Lymphocytes, Edema ||Normal ||Normal|
|Cell-mediated vascular ||±Monocytes ||±Tubulitis ||±Lymphocytes, Edema ||Lymphocytes ||Lymphocytes, in intima|
|Humoral arterial ||PMNs, Thrombi, ±Monocytes ||Necrosis ||Hemorrhage, Infarction ||PMNs, Thrombi ||PMNs, Fibrinoid necrosis|
|Humoral microvascular (C4d +) ||PMNs ||±PMNs ||Normal or Edema ||PMNs,C4d + ||Normal|
* Peritubular capillaries
Pathology of Acute Tubulo-interstitial Rejection and C-I Toxicity
| || Glomeruli || Tubules || Interstitium ||Arterioles || Arteries|
|Acute C-Itoxicity ||Normal ||Flattened, vacuoles, necrosis, lumina ||Mild edema ||Myocyte necrosis, Nodular hyalinization ||Normal|
|Acute cell mediatedrejection ||±Monocytes ||Tubulitis ||Lymphocytes,edema ||Normal or Lymphocytes in intima ||Normal or Lymphocytes in intima|
|Humoral (C4d+) microvascular acute rejection ||PMNs ||±PMNs ||Normal or Edema ||Normal ||Normal|
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