Vascular Pathology: From Vasculitis to Vasculopathy to Vascular Rejection
Section C -
Transplant Vascular Diseases
Volker Nickeleit, M.D.
J. Charles Jennette, M.D.
Many different disease processes can affect the arteries, arterioles and capillaries in solid organ
transplants. Vascular changes are clinically significant since they determine long-term graft function
and survival. Cardiac allograft vasculopathy is associated with considerable mortality. Some arterial
and arteriolar lesions are transplant specific, such as rejection episodes. Others are found in native
organs as well as in transplants, such as hypertension induced injury or calcineurin inhibitor induced
toxicity. Occasionally, in particular in heart allografts, different insults to the arterial tree occur
simultaneously or are superimposed on one another (e.g. pre-existing hypertension induced donor
arteriosclerosis with superimposed subsequent vascular rejection). Thus, the pathologist evaluating
transplant specimens faces a challenging task. We will focus here primarily on arterial lesions
encountered in kidney transplants since they are best characterized and most relevant for the practicing
pathologist. The pathophysiologic chain of events leading to vasculopathies in cardiac, pancreas and
renal allografts are very similar, however, cardiac transplant vasculopathies typically remain
histologically undeteceted due to the superficial nature of the subendocardial surveillance biopsies.
They often only become apparent at time of autopsy (see study case 11). For reasons only incompletely
understood transplant vasculopathies observed in liver and lung allografts are less common and seem to be
clinically less significant than those observed in kidney, heart or pancreas transplants.
Although the complication rate of transplant biopsies in the hands of an experienced clinician is
extremely low, a graft biopsy remains an invasive procedure associated with some risk and discomfort.
Thus, once a biopsy is indicated, the biopsy sample should be large enough to provide sufficient
information, in particular of the arterial tree in cases of a kidney or pancreas transplant biopsy.
Unnecessary re-biopsies or inadequate diagnostic yields should be avoided. Ideally, renal transplant
biopsies should consist of two tissue cores obtained with a 14 or 15 gauge needle in order to adequately
sample arteries, i.e. to obtain approximately 3 to 4 medium sized arterial cross sections (branches of
arcuate arteries or interlobular caliber vessels). If the sample is too small and arteries are not
properly sampled, then the diagnosis and therapy may be inadequate. This is the reason why we generally
discourage the use of fine needle aspiration or 18 gauge needles in the setting of kidney transplant
biopsies. Small tissue segments may be frozen for additional studies, i.e. the detection of the
complement degradation product C4d along (peritubular or myocardial) capillaries or MHC-class II (HLA-DR)
in tubular epithelial cells by immunofluorescence microscopy.
I) Calcineurin inhibitor induced toxicity
Cyclosporine A and tacrolimus are immunosuppressive drugs which both act via calcineurin inhibition
and suppression of interleukin-2. Both drugs are nephrotoxic and the observed side effects are very
similar. Since cyclosporine was introduced first and nephrotoxicity was already noticed by Calne and
colleagues in 1978, the side effects induced by calcineurin inhibitors are commonly referred to as
"cyclosporine type". Calcineurin inhibitor induced histologic changes are primarily seen in native and
For the classification of cyclosporine and tacrolimus induced nephrotoxicity we use the following
terminology: 1) functional, and 2) structural toxicity. 'Pure' functional toxicity is found without
morphological changes. It is due to vasospasms. Structural toxicity is characterized by morhological
alterations and is almost always associated with kidney dysfunction. Structural and/or functional
nephrotoxicity have been reported in patients with kidney, liver, heart, and bone marrow transplants, as
well as in patients with autoimmune diseases treated with calcineurin inhibitors. Cyclosporine and
tacrolimus nephrotoxicity is dose-dependent, however, it shows great inter-individual variations. Toxic
side effects may be noted in some 'sensitive' patients in therapeutic dose ranges or if additional risk
factors, e.g. ischemia, are present.
Of note: the observed morphological changes in the vasculature induced by calcineurin
inhibitors bear close similarities to those described above under "thrombotic microangiopathies".
2) Clinical findings
Almost all patients treated with cyclosporine or tacrolimus present with deterioration of renal
function, i.e. a rise in the serum creatinine. Occasionally, serum creatinine levels can double and
patients may even present with 'acute renal failure'. Dysfunction is due to vasospasms of arterioles, a
decrease in the glomerular filtration rate and renal plasma flow. Arterial hypertension is common;
hyperkalemia, mild metabolic acidosis, hypomagnesemia, and hyperuricemia are rare. The most serious
toxic side effect is a fully developed thrombotic microangiopathy with clinical signs of the 'hemolytic
uremic syndrome' (HUS). HUS can develop at any time after the initiation of therapy, most often,
however, it is seen during the early time course.
Calcineurin inhibitor induced microangiopathies are found in the peripheral vascular tree, most
characteristically in afferent arterioles. The arteriolar lesions can extend in severe cases downstream
into the glomerulus and upstream into small arteries with up to 2 layers of smooth muscle cells (close to
the branching points between interlobular arteries and pre-arterioles). Larger arteries with more than 2
layers of medial cells, i.e. arcuate type arteries and their branches, are typically spared. The
earliest morphological changes noted by light microscopy are vacuolization/ballooning of smooth muscle
cells (due to dilatation of the endoplasmic reticulum), and occasional single cell necrosis of
endothelial cells and/or medial smooth muscle cells. Such changes are common, vastly reversible on dose
reduction, and generally do not carry any prognostic significance. The fully developed calcineurin
inhibitor induced arteriolopathies reveal nodular, PAS positive, protein (hyaline) deposits deep in the
arteriolar wall replacing individual necrotic myocytes. Often, these protein deposits are arranged in a
necklace like pattern along the outer/adventitial aspect of the vessels. If myocyte and endothelial cell
necrosis progress, hyaline deposits can extend transmurally into the subendothelial compartment. In most
severe cases arteriolar walls are circumferentially devoid of medial smooth muscle cells and show
transmural hyaline deposits instead. Rarely, a calcineurin inhibitor induced arteriolopathy presents
with mucoid (TMA-like) thickening of the intimal layer. Severe thrombotic microangiopathies with fibrin
and platelet thrombi are uncommon events, seen in less than 1% of patients.
Mild and moderate forms of calcineurin inhibitor induced arteriolopathies with intramural hyaline
nodules may undergo remodeling, i.e. "healing", once the administration of cyclosporine or tacrolimus is
stopped. This phenomenon has been observed in repeat biopsies. Medial protein deposits can vanish and
the medial layer of affected arterioles may show thickening with irregularly (re)arranged smooth muscle
cells and an increase in extracellular matrix. Important: arteriolar lumens remain patent. In
contrast, severe arteriolopathies with circumferential and transmural hyaline deposits lead to arteriolar
scarring/occlusion and nephron loss.
The morphology of calcineurin inhibitor induced arteriolopathies is typical for toxic side effects but
not pathgnomonic. Findings have to be interpreted in the appropriate clinical context. The differential
diagnosis includes: 1) "thrombotic microangiopathies/HUS", e.g. recurrent disease or de-novo disease
induced by agents other than calcineurin inhibitors, 2) diabetic arteriolosclerosis, and 3) hypertension
induced arteriolosclerosis with hyalinosis. HUS or "nodular" diabetic arteriolosclerosis have to be
excluded based on clinical information since the histologic examination does not allow for the proper
identification. Hypertension induced arteriolosclerosis typically shows subendothelial hyaline deposits
overlying an intact, although occasionally atrophic, medial smooth muscle layer. Nodular hyaline
deposits in the media are generally absent in the setting of "benign nehrosclerosis"; they only become
prominent in patients suffering from marked hypertension with "malignant nephrosclerosis".
Associated findings : Calcineurin inhibitor induced glomerulopathies
often accompany severe forms of arteriolopathies (in our experience approximately 60% of cases with
circumferential and transmural hyaline deposits). The glomerular lesions can be interpreted as the
extension of arteriolar endothelial cell injury into the glomerulus. The more severe the arteriolopathy,
the more often glomerular changes are noted. Glomerular injury induced by calcineurin inhibitors usually
shows a focal and segmental distribution pattern. In some cases, only a single glomerulus might be
affected. Glomeruli can show signs of a thrombotic microangiopathy with intracapillary thrombus
formation, generally extending from afferent arterioles into the glomerular capillaries. These changes
are rare (seen in less than 1% of patients). More frequent are structural abnormalities of the glomeruli
with double contouration of the peripheral basement membranes and segmental mesangiolysis. The
glomerular changes are identical to (remote) forms of thrombotic microangiopathies seen in native
Striped interstitial fibrosis and tubular atrophy are often found in cases of calcineurin inhibitor
induced arteriolopathies. These changes represent 'non-specific', secondary phenomena caused by nephron
loss; they are not pathgnomonic for calcineurin inhibitor toxicity.
Toxic changes in tubules, i.e. isometric vacuolization of the cytoplasm of proximal tubular cells, can
accompany toxic arteriolopathies. Toxic tubular changes are fully reversible on dose reduction.
Immunohistology: The protein deposits along arterioles contain IgM
and/or complement factors (C3, C1q, C5b-9, C4d). Glomeruli do not show diagnostically relevant deposits.
In up to 20% of affected kidneys scant fibrin accumulation may be found along the vasculature. This
immunohistochemical staining profile is considered to be non-diagnostic. It can also be observed in
cases of hypertension induced arteriolosclerosis or thrombotic microangiopathies. Calcineurin inhibitor
induced toxicity is not associated with diagnostically significant C4d deposits along peri-tubular
capillaries. If C4d is noted then a second diagnosis of concurrent acute rejection should be
Functional calcineurin inhibitor induced toxicity is fully reversible on dose reduction; it is of no
prognostic significance. Mild and moderate forms of structural toxicity with 'cyclosporine type
arteriolopathies' do not affect long-term kidney function; generally the dose of calcineurin inhibitors
is lowered. Severe structural toxicity with circumferential and transmural hyaline deposits, vascular
occlusion or overt signs of 'thrombotic microangiopathies' with fibrin thrombi are serious complications
requiring therapeutic intervention, such as a change to calcineurin inhibitor free immunosuppressive drug
regimens. Long-term kidney function may be impaired due to advanced nephron loss and proteinuria may
develop due to secondary focal and segmental glomerulosclerosis.
II) Rejection / Vascular Rejection - Introduction
Acute rejection episodes involving a solid organ transplant, such as liver, kidney, pancreas or heart,
can involve the interstitial compartment and/or blood vessels. In the setting of heart, pancreas and
renal allografts, rejection episodes affecting arteries, i.e. vascular rejection episodes, are of
particular therapeutic and prognostic importance.
Rejection can be classified in different ways. Frequently, transplant physicians prefer a simplistic
approach based on the time-span post transplantation. Thus, the term "hyperacute" or "accelerated acute"
rejection implies a very early event within hours or days after transplantation, "acute" rejection is
seen within days or weeks, and "chronic" rejection is a late event occurring months or years after
grafting. The gold standard for the characterization of rejection episodes, however, is not the clinical
presentation but rather the detection of typical histological changes in a graft biopsy. Integration of
the different viewpoints - clinical versus histological - is problematic and sometimes even confusing
since morphological alterations cannot always be easily translated into the timeframe of "hyperacute,
acute and chronic". For example, histological changes characteristic for so-called "acute rejection" may
be encountered many years after transplantation in non-compliant patients. On the other hand,
morphological features typical for "chronic rejection" may already be seen a few weeks post grafting.
Frequently, "acute rejection" concurs with "chronic rejection". A rejection episode may be of cellular,
humoral or mixed etiology. Consequently, rejection (including "vascular rejection") is best classified
based on morphological findings. In this context, "vascular rejection" is used as a general, descriptive
term comprising various arterial and capillary changes occurring during rejection episodes. The term
"vascular rejection" does not characterize a specific etiology or morphologic phenotype. Since the basic
principles of "vascular rejection" are very similar in different organ systems (in particular in heart,
pancreas and kidney grafts), we will discuss for didactic purposes the various morphological phenotypes
of vascular rejection seen in renal allografts. Banff '97 and CCTT (coordinate clinical trial in
transplantation) classification categories of rejection will be highlighted.
1) Adjunct Immunohistochemical Markers of Rejection: the Complement Degradation Product C4d
The understanding and classification of rejection has undergone substantial changes in recent years.
For the first time, additional immunohistochemical markers are incorporated into the diagnostic decision
making process – similar to the practice long established for the work-up of malignant neoplasms. The
immunohistochemical detection of C4d in transplant biopsies – pioneered by H. Feucht from Munich more
than 10 years ago - has fundamentally changed our understanding, since we now have a marker for "humoral
rejection". This marker is widely used during the work-up of renal and to a lesser extent also of heart
C4d is the split product of the activated complement factor C4, a component of the classical
complement cascade that is typically activated subsequent to the binding of antibodies to their receptors
and activation of the complement factor C1. C4d transiently binds covalently to cell surfaces and
extracellular matrix proteins, such as basement membrane components, at the site of C4 activation. C4d
can easily be detected by immunohistochemistry both in fresh frozen and formalin fixed tissue samples.
Its detection in transplant biopsies is generally considered to be an indirect sign, a "foot print", of
an active antibody mediated alloresponse (immunoglobulins and activated complement factors are generally
not detected by immunohistochemistry, likely due to rapid shedding or internilization of the molecules).
C4d is often found in cases of "vascular rejection". For pathologists, the detection of C4d is an
important tool not only to accurately diagnose an antibody mediated allo-response ("C4d positive") but
also to exclude other differential diagnoses closely mimicking rejection, such as thrombotic
microangiopathies, surgical complications associated with thrombus formation or severe
ischemia/reperfusion injury ("C4d negative"). Nowadays, the search for C4d is considered "standard of
care" for the adequate evaluation and diagnostic work-up of kidney transplant biopsies. The results of
C4d staining are part of the classification of renal allograft rejection according to the updated Banff
'97 classification scheme.
C4d in renal allografts: Of diagnostic relevance is the focal or
diffuse, strong accumulation of C4d along peritubular capillaries in the renal cortex and/or medulla.
(In heart allograft biopsies, C4d is found along intramyocardial capillaries). Only non-fibrotic and non
necrotic parenchymal regions should be evaluated. The minimal threshold level to call a biopsy
'positive' is the strong, circumferential detection of C4d in 10 or more capillaries surrounding adjacent
tubules. (Minimal threshold levels in cardiac biopsies are undetermined). C4d deposits in other
locations (e.g. along the endothelium of arteries, in glomeruli, arterioles with hyalinosis or along
atrophic tubules) are regarded to be non-diagnostic. It is important to remember that the accumulation
of C4d marks an independent humoral allo-response. Consequently, C4d deposits can be detected in
combination with various histologic changes. The association between C4d and morphological signs of
acute "cellular" rejection defined by the CCTT criteria is statistically significant. C4d is found in
24% - 43% of tubulo-interstitial rejection episodes, in 45% of biopsies with transplant endarteritis, in
50% of severe vascular rejection episodes with fibrinoid vascular wall necrosis or thrombosis, and in 50%
- 60% of cases with glomerular rejection (i.e. transplant glomerulitis or –glomerulopathy). Sometimes,
the presence of markedly dilated peritubular capillaries filled with mononuclear cell elements or
abundant polymorphonuclear leukocytes may be a morphological indicator of C4d positivity/humoral
rejection. "Acute pure humoral rejection", also termed "C4d positive capillary transplant vasculopathy",
a newly defined entity characterized by strong C4d positivity in early, severely dysfunctioning grafts
lacking any signs of cellular rejection, is a rare event seen in our experience in less than 10% of all
C4d positive biopsies (see below).
Clinical observations and prognosis: During the post transplantation
period, C4d is detected in 30% of all diagnostic graft biopsies (35% of all biopsied patients). It is
typically detected early after transplantation (median: 38 days post grafting). Occasionally, C4d can
also be found years after grafting (in our experience, as late as 15 years). C4d is a dynamic marker
since it can accumulate and disappear within days (approximately 4 – 8 days).
At present, the clinical significance of C4d deposits in renal allografts is only incompletely
understood. As a general rule, C4d positivity in the setting of cellular rejection or significant
allograft dysfunction indicates serious rejection episodes requiring aggressive treatment. Often,
long-term prognosis is poor. C4d was found to be the strongest independent predictor of poor graft
outcome. In contrast, C4d can also occasionally be detected in stable renal grafts with normal
histology. This latter observation is of undetermined clinical significance. It does not indicate the
immediate necessity for aggressive therapeutic intervention.
C4d deposits in heart allografts: Only relatively little is known about
C4d deposits in heart allografts. It seems that C4d is not only detected in the setting of "rejection",
but also in surveillance biopsies of stable grafts (see USCAP 2005, abstract 258, AM Safley et al). If
histologic signs of "pure humoral rejection" are detected, i.e. swelling of endothelial cells, dilatation
of capillaries and intravascular accumulation of monocytes, then the detection of C4d can help to
establish a specific diagnosis of "acute pure humoral rejection" or "C4d positive capillary transplant
vasculopathy". Whether C4d positivity is associated with the development of cardiac allograft
vasculopathy is currently unknown.
Appendix - Detection of C4d: The complement degradation product C4d can
easily be detected in fresh frozen tissue samples by immunofluorescence microscopy. We use a mouse
monoclonal antibody which is commercially available from Quidel (San Diego, CA; dilution 1:50, 30 min
incubation at room temperature followed by incubation with a secondary goat anti-mouse affinity purified
and FITC labeled anti IgG antibody (Jackson ImmunoResearch Laboratories, PA), dilution 1:40, 30 minutes
at room temperature - as previously published).
C4d can also be detected in formalin fixed and paraffin embedded tissue sections employing
a rabbit polyclonal antibody (Biomedica Gruppe, Vienna, Austria). We use the steam antigen retrieval
technique (30 minutes), followed by a 30 minute incubation with the primary antibody at 37 degrees
Celsius (dilution 1:50) and subsequent avidin/biotin histochemical staining procedures as previously
published. This antibody cross reacts with cynomolgus monkeys.
2) Vascular Rejection: Morphological Variants
A) Transplant Vasculopathy with Massive Intravascular Coagulation/thrombosis and Vascular Immunoglobulin Deposition
Synonyms: Hyperacute, peracute rejection, Banff '97 class I rejection,
not classified according to the CCTT scheme.
Definition: Vascular immunoglobulin deposition, endothelial cell damage
and occlusive thrombi in large and small arteries and capillaries.
Macroscopic Findings: Following the restoration of blood flow during
surgery, the kidney graft develops a reddish mottled aspect, increases in size and rapidly turns
reddish-blue. Nephrectomy specimens are usually markedly swollen, hemorrhagic and infarcted.
Histology: The histology is characterized by fibrin thrombus formation in
large arteries (i.e. renal artery and branches) and small arteries (i.e. interlobar, arterioles) as well
as glomerular capillaries. Fibrin thrombi in large arteries can show a polymorphonuclear leukocyte
reaction along the endothelial cell surface, a "non-specific" change which should not be misinterpreted
as a pathgnomonic sign for an antibody mediated rejection phenomenon. Despite intravascular thrombosis,
vascular walls often remain viable, even in areas of infarction. If renal allografts survive for days,
early transplant biopsies reveal thrombus formation in only few vessels. This focality is due to the
unaltered fibrinolytic activity of the host organism resulting in thrombolysis in the transplant.
Thrombus formation causes acute ischemic type injury of tubular epithelial cells (so-called acute tubular
necrosis, ATN) or in more severe cases infarction. In the interstitial compartment foci of hemorrhage
and polymorphonuclear leukocytes are conspicuous. Polymorphonuclear leukocytes are found either as a
demarcation phenomenon between viable and infarcted areas (as for example typically seen in myocardial
infarcts), or adjacent to tubules with severe ATN. If polymorphonuclear leukocytes are primarily found
in dilated peritubular capillaries in viable regions of the renal parenchyma, they may be used as an
indicator for an antibody mediated rejection episode (see below). Significant lympho-histiotiocytic
infiltrates, i.e. signs of cellular rejection, are generally lacking, although they can become more
conspicuous if grafts survive for a few weeks. Ultimately, massive thrombosis leads to extensive
infarction and graft loss.
Immunohistology: During the early phases of rejection linear deposits of
IgG and IgM together with complement factors are present along the vascular endothelium of arteries,
glomeruli, and peritubular capillaries. In nephrectomy specimens with complete necrosis, immunoglobulin
deposits may be scant or even lacking. Transplant vasculopathies with massive intravascular coagulation
are generally C4d positive, although experience is very limited due to the rare occurrence of these
events (less than 0.2% of all rejection episodes).
Etiology: Preformed circulating recipient antibodies bind to the
endothelium of arteries and capillaries in the graft and lead to rapid and massive coagulopathy and
thrombosis in all caliber arteries and capillaries. Transplant vasculopathy with massive intravascular
coagulation is the "prototype" for an antibody mediated rejection phenomenon.
Outcome: In general ominous. Plasmapheresis may be tried in protracted
Comment: Rejection episodes with widespread thrombi are very rare
events (less than 0.2 %) that typically occur immediately post transplantation (rarely a few weeks after
B) Necrotizing Transplant Vasculopathy
Synonym: Accelerated acute rejection; category IV (type III) or
category II (type III) acute rejection (Banff '97 update); type III acute rejection (CCTT)
Definition: Transmural "fibrinoid" arterial wall necrosis affecting
all caliber arteries (most often interlobar, arcuate, interlobular caliber vessels).
Macroscopic Findings: The kidneys are grossly enlarged and show
hemorrhagic and anemic infarcts side by side ("mottled appearance"). In the most severe forms, the
nephrectomy specimens have a dark red and swollen appearance, closely resembling cases of transplant
vasculopathy with massive intravascular coagulation and immunoglobulin deposition.
Histology: Arterial lesions are patchy in nature, generally only
involving some of the examined arterial cross sections. Affected vessels exhibit segmental, less often,
circumferential fibrinoid necrosis which can be transmural (from the intimal to the adventitial layer) or
medial (involving only the inner part of the media with destruction of the internal elastic lamina). The
intimal surface is usually (but not always!) devoid of endothelial cells and covered with fibrin/platelet
aggregates. However, occlusive fibrin thrombi – resembling cases of transplant vasculopathy with massive
intravascular thrombosis - are generally not detected. In many cases, fibrinoid arterial necrosis is
associated with intimal and transmural mononuclear cell infiltrates (i.e. lymphocytes and histiocytes).
Severe arterial injury results in patchy interstitial hemorrhage or even focal infarction. If the
rejection episode responds to treatment, necrotic arterial walls can form microaneurysms and show
remodeling phenomena with infiltration of myofibroblasts, deposition of collagen and scar formation.
Elastic tissue stains characteristically reveal segmental destruction and loss of the lamina elastica
Associated findings : The glomeruli can show different abnormalities,
ranging from focal and segmental to diffuse and global: i) non-specific ischemic glomerular collapse,
ii) massive glomerular capillary dilatation with blood stasis, iii) fibrin thrombi, or iv) transplant
Immunohistology: Typically fibrin can be found in necrotic vessel walls
and in the interstitium. Specific IgG or IgM deposits along the endothelium of arteries or capillaries
are generally lacking. In our experience approximately 50% of cases with necrotizing transplant
vasculopathy are C4d positive.
Etiology: The specific etiology of fibrinoid arterial wall necrosis is
undetermined. Antibodies (de-novo ?) likely cause injury in C4d positive cases. Arteries may also show
signs of a cell mediated injury with intramural lymphocytic and histiocytic infiltrates.
Outcome: Generally poor; most grafts are lost within weeks post biopsy.
Comment: Necrotizing transplant vasculopathy is typically seen within the
first weeks after grafting. It is an uncommon form of rejection (seen in approximately 1% to 4% of all
rejection episodes occurring within the first weeks post grafting). According to the updated Banff '97
classification scheme, C4d positive cases are classified as "category II (type III)" and C4d negative
cases as category IV (type III) acute rejection. Necrotizing transplant vasculopathy can also be seen
many years after transplantation in non-functioning grafts/ patients off immunosuppression; it is then
typically accompanied by transplant endarteritis and sclerosing transplant vasculopathy.
C) Capillary Transplant Vasculopathy, C4d Positive
Synonym: Acute pure humoral rejection; category II (types I and II)
acute rejection (Banff '97 update); not classified according to CCTT.
Definition: Diffuse capillary injury with intracapillary accumulation
of polymorphonuclear leukocytes and mononuclear cell elements; occasionally capillary fibrin thrombi are
found; strong accumulation of C4d; detection of circulating donor specific antibodies in the plasma.
Macroscopic Findings: The kidneys are grossly enlarged, dark blue with
extensive hemorrhagic infarcts closely resembling cases of transplant vasculopathy with massive
intravascular coagulation and immunoglobulin deposition.
Histology: In typical cases focal or diffuse injury of peritubular
capillaries is noted. The capillaries are dilated and filled with polymorphonuclear leukocytes and/or
monocytes, as well as occasional fibrin thrombi. Capillary leakage results in foci of interstitial
hemorrhage and edema containing scattered inflammatory cells, i.e., lymphocytes, histiocytes and
polymorphonuclear leukocytes. The impaired capillary blood flow causes acute ischemic tubular injury,
i.e. ATN, and sometimes even frank necrosis. Signs of typical cellular rejection with conspicuous
tubulitis are lacking. Arteries are generally uninvolved.
(Similar changes have been described in early myocardial graft biopsies from dysfunctioning heart
transplants. Endomyocardial biopsies can show swollen endothelial cells, intracapillary macrophages, and
Associated findings : Often capillary injury not only involves
peritubular but also glomerular capiIlaries, which can contain mononuclear and polymorphonuclear
inflammatory cells (signs of transplant glomerulitis), and fibrin thrombi. In most severe cases
glomeruli reveal mesangiolysis and segmental tuft necrosis.
Immunohistology: The most characteristic finding, which led to the
recognition of this entity, is the strong and diffuse, linear accumulation of C4d along peritubular
capillaries. In addition – although it is not considered to be of additional diagnostic significance –
C3d is found. The detection of linear immunoglobulin deposits (IgG, IgM) along capillary walls is an
exceptionally rare event. In areas of hemorrhage and necrosis fibrin deposits are conspicuous.
Glomerular C4d deposits are considered to be of no diagnostic significance.
Etiology: C4d positive capillary transplant vasculopathy is caused by
circulating donor specific anti-class I or frequently anti-class II antibodies. In contrast to
transplant vasculopathy with massive intravascular thrombosis and vascular immunoglobulin deposition, the
donor specific antibodies are often formed de novo post transplantation. Little is known about specific
antigens on the capillary endothelium targeted by the antibodies.
Outcome: Graft survival varies. It is poor in cases with marked
thrombosis and necrosis and seems more favorable in grafts lacking capillary thrombi and interstitial
hemorrhage. However, clinical experience with this form of rejection is currently limited.
Comment: C4d positive capillary transplant vasculopathy, i.e.acute pure
humoral rejection, is a newly recognized entity and much remains to be learned in the future. These
antibody mediated rejection episodes are infrequent and account for far less than 5% of all rejection
episodes in our experience. Acute pure humoral rejection is typically diagnosed within the first weeks
post transplantation. Histological signs of cellular rejection, i.e. tubulitis and tubular MHC-class II
expression, are characteristically lacking. C4d positive capillary transplant vasculopathy is common in
kidney transplants originating from ABO incompatible donors. Therapeutic attempts are made with high
dose IVIG treatment and/or plasmapheresis or immunoabsorption.
In our opinion, C4d positive capillary transplant vasculopathy, i. e. acute pure humoral
rejection, has to be clearly separated from other histological changes associated with C4d deposits, in
particular, C4d positive cellular rejection episodes (tubulo-interstitial, transplant endarteritis).
From a pathophysiological point of view, such C4d positive rejection episodes do not qualify as "pure
humoral rejection" but rather reflect a mixed cellular and humoral etiology. However, this distinction
is not always made. Mixed humoral and cellular rejection episodes likely require specific, currently
undetermined anti-rejection therapy.
D) Transplant Endarteritis
Synonym: Infiltrative and proliferative transplant vasculopathy; acute
transplant vasculitis; endovasculitis; endothelialitis; category IV (type II) acute rejection (Banff '97
update); type II acute rejection (CCTT)
Definition: Infiltration of lymphocytes and macrophages through the
activated endothelial cell layer into the subendothelial compartment/intima of arteries. De novo intimal
collagen types I and III deposits are inconspicuous. The media and the internal elastica of the affected
arteries remain unaltered.
Macroscopic Findings: Nephrectomy specimens showing pure transplant
endarteritis are extremely rare. The kidneys are of normal size or slightly enlarged and may exhibit
small anemic infarcts.
Histology: Transplant endarteritis progresses through various stages.
Infiltrative stage: The earliest changes are detected along the endothelial cell layer. The endothelial
cells are activated with nuclear enlargement, cytoplasmic swelling and vacuolization. The most striking
form of 'activation' is an arcade-like detachment of the endothelial cell from the underlying basement
membrane. Per definition, mononuclear cell elements, i.e. lymphocytes and histiocytes, are present under
the activated endothelial cell layer. Endothelial cell necrosis is generally inconspicuous, although, it
can be occasionally noted in association with small intimal fibrin deposits. Occlusive thrombi, however,
are typically absent. During the course of transplant endarteritis, i.e. in days or few weeks, the
macrophages in the intima can transform into foam cells. Proliferative stage: The infiltrative stage
imperceptibly evolves into the proliferative stage characterized by spindle-shaped cell elements with
large nuclei (i.e. myofibroblasts), which progressively increase in number. Proliferation markers, such
as KI-67, reveal a high proliferative activity in the inflamed intima. While the number of
myofibroblasts increases over time, usually the number of lymphocytes and macrophages decreases. Foam
cells, however, typically persist. The accumulation of myofibroblasts is associated with the deposition
of "early" extracellular matrix proteins, in particular fibronectins and collagen type IV. Of note:
"scar" collagens I and III are absent (their deposition marks the transformation of transplant
endarteritis into sclerosing transplant vasculopathy, see below). During the infiltrative and
proliferative phases, endothelial cells characteristically remain enlarged and activated.
Infiltrative/proliferative transplant vasculopathy mostly involves the entire intimal circumference of
an artery, however, segmental changes can be found, often at arterial branching points. Since the
inflammatory process is limited to the intima, both the lamina elastica interna and the media remain
unchanged. Transplant endarteritis – like all vascular lesions seen in rejection - is a focal phenomenon
that can be superimposed on pre-existing lesions, such as arterionephrosclerosis originating from the
Associated findings : Transplant endarteritis may be accompanied by
transplant glomerulitis and/or by transplant glomerulopathy. Focal or diffuse tubulo-interstitial
rejection with tubulitis is common.
Immunohistology: Many cells infiltrating the arterial intima are CD68
positive monocytes / macrophages. In addition, T lymphocytes are detected among which CD8-cells are more
common than CD4-cells (about 2:1). Activated T-cells positive for IL-2R and TNF-R are rare. Even during
the early infiltrative stages of transplant endarteritis, scattered alpha-smooth muscle actin positive
myofibroblasts are detected, often in small clusters close to the internal elastic lamina.
Myofibroblasts are of utmost importance since they do not respond to conventional anti-rejection therapy
and serve as machineries for intimal scar formation. Currently, it is undetermined whether
myofibroblasts originate from the medial smooth muscle cell layer, from circulating progenitor cells or
alternatively from trans-differentiated histiocytes. The intimal inflammatory process typically lacks a
B-cell component (very rarely, individual CD-20 positive cells or plasma cells can be detected).
Activated endothelial cells and infiltrating mononuclear cells upregulate MHC-class II (HLA-DR) and
adhesion molecules such as ICAM or VCAM.
Approximately 40% to 50% of rejection episodes with transplant endarteritis are C4d positive, i.e.
show C4d along peritubular capillaries. In contrast, the accumulation of C4d along the endothelium of
arteries seems to be a non-specific phenomenon, also found in native kidneys.
Etiology: Transplant endarteritis is a cell mediated type of injury,
mainly driven by T-cells and macrophages. C4d positive cases seem to represent mixed "cellular" and
"humoral" rejection episodes that should be specifically diagnosed.
Outcome : Transplant endarteritis – in comparison to tubulo-interstitial
rejection – carries a less favorable longterm prognosis. The detrimental impact on transplant survival
becomes already apparent after one year of follow-up. Transplant endarteritis is often associated with
the subsequent development of sclerosing transplant vasculopathy (i.e. so-called chronic vascular
Comment: Transplant endarteritis is a common phenomenon, seen in
approximately 30% of rejection episodes occurring during the first year. We have diagnosed it as early
as 6 days and as late as 14 years post transplantation. Transplant endarteritis may often be
underdiagnosed due to small (inadequate) biopsy samples lacking arteries. The diagnosis of transplant
endarteritis carries great prognostic and therapeutic significance. Patients usually do not benefit from
conventional bolus steroid therapy, but rather require potent treatment with ATG or OKT3. Treatment is
most efficient during the early, infiltrative phase when myofibroblasts are absent. However, even
aggressive anti-rejection therapy often does not result in the complete histological clearance of the
intimal inflammatory process, which can persist as smoldering inflammation. In our experience, this
phenomenon is seen in 22% of cases. "Smoldering" intimal inflammation results in the persistent
stimulation of myofibroblasts and consequently in progressive intimal sclerosis, i.e. sclerosing
transplant vasculopathy. Thus, transplant endarteritis is a major risk factor for so-called "chronic
Approximately 40% to 50% of cases with transplant endarteritis are C4d positive. Some
studies showed that outcome of these rejection episodes is poor, potentially requiring currently
undetermined new treatment strategies.
(Transplant endarteritis also occurs in epicardial arteries of heart allografts, however, it remains
E) Sclerosing Transplant Vasculopathy
Synonym: Chronic vascular rejection; chronic transplant vasculopathy;
category V rejection (Banff '97 update); not classified according to CCTT.
Definition: Rejection induced arterial intimal thickening mainly due to
the de-novo deposition of collagens types I and III; absence of intimal elastosis.
Macroscopic Findings: Nephrectomy specimens with pure sclerosing
transplant vasculopathy are very rare; they are most often found at time of autopsy. The kidneys are
reduced in size, pale pink, granular and exhibit scars. Arteries at the hilum and in the peri-pelvic
adipose tissue are stenosed. (Coronary arteries and their branches often show diffuse hardening and
concentric thickening with stenoses; the hearts are frequently dilated and may show acute infarcts).
Histology: The lumen of arteries is narrowed by concentric or sometimes
eccentric intimal fibrosis, which is most pronounced at arterial branching points. The pattern of
intimal fibrosis in cases of sclerosing transplant vasculopathy displays some distinct, diagnostically
helpful features: 1) Most characteristic is the lack of elastic lamellae, i.e. an absence of marked
intimal elastosis. Typically the inner elastic lamina remains intact. (The elastica only gets disrupted
subsequent to inflammation and necrosis of the media) 2) The fibrotic intima contains scattered,
irregularly arranged myofibroblasts with enlarged "activated" nuclei. 3) The fibrotic intima may contain
scattered mononuclear inflammatory cell elements, i.e. histiocytes and lymphocytes. 4) Sometimes foam
cells are present. 5) During intimal remodeling, myofibroblasts may occasionally form a new rudimentary
media under the endothelial layer. Such a so-called neo-media formation is almost pathognomonic for
"chronic vascular rejection". (Neo-media formation appears to be more prominent in renal allografts) 6)
The endothelial cell nuclei are typically enlarged, hyperchromatic and slightly polymorphic. These
features help to establish a specific diagnosis of sclerosing transplant vasculopathy/chronic vascular
The differential diagnosis of sclerosing transplant vasculopathy includes arteriosclerosis induced by
hypertension or diabetes mellitus. Arteriosclerosis shows a hypocellular intima with only rare, small,
regularly arranged myofibroblasts embedded in a dense, fibrotic intima rich in elastic lamellae, i.e.,
fibro-elastosis. Neither the accumulation of foam cells nor neo-media formation is a feature of
Sclerosing transplant vasculopathy can be associated with other changes. Frequently, scattered
lymphocytes are found in the intima, likely a sign of an ongoing, smoldering rejection. A diagnosis of
concurrent transplant endarteritis should be rendered if clusters of lymphocytes and histiocytes are
noted under activated endothelial cells. Often, sclerosing transplant vasculopathy is superimposed on
pre-existing arteriosclerosis (donor organ disease). In these latter cases remote, dense fibro-elastosis
is detected along the inner aspect of the thickened intima and typical changes of chronic vascular
rejection are superimposed towards the endothelial surface.
Associated findings : Transplant glomerulopathy and transplant
glomerulitis are often found, i.e. signs of glomerular rejection (in our experience in approximately 40%
of cases). If sclerosing transplant vasculopathy is complicated by transplant endarteritis, the
interstitial compartment usually shows evidence of tubulo-interstitial rejection. Chronic vascular
rejection frequently results in arterial stenosis, ischemia, tubular atrophy and interstitial fibrosis,
which can, however, be surprisingly minimal in some instances.
Immunohistology: Immunohistology is unrevealing. In some cases
deposits of IgM, complement factor C3, C4d and C5b-9 are present in arterial walls (non-diagnostic). In
general, C4d is not detected along peritubular capillaries. If capillary C4d accumulation is noted (in
approximately 30% of cases) then this observation indicates an "active" rejection episode. C4d positive
cases of sclerosing transplant vasculopathy often show additional histologic evidence of active
rejection, such as transplant endarteritis and/or glomerulitis.
Etiology: Sclerosing transplant vasculopathy, i.e. chronic vascular
rejection, is the scarring stage of rejection episodes involving the arterial tree. It is most
frequently found subsequent to rejection episodes showing transplant endarteritis and can develop within
few weeks. Intimal inflammation including the influx of macrophages induces the proliferation of
myofibroblasts that synthesize extracellular matrix proteins, in particular scar collagens types I and
III. Matrix synthesis is promoted by various cytokines and growth factors including platelet derived
growth factor (PDGF), transforming growth factor beta (TGF-beta), basic fibrobast growth factor (bFGF)
and others. Thus, sclerosing transplant vasculopathy is an immune mediated type of injury, initially
driven by lymphocytes and macrophages. Likely, also circulating donor specific antibodies play a
currently undefined role in the pathogenesis, last not least based on the detection of C4d along
capillaries in some of the cases. Wether the intimal myofibroblasts are donor derived (from the medial
smooth muscle layer) and/or recipient derived (from circulating progenitoir cells) is currently
Outcome : Grafts with sclerosing transplant vasculopathy, in particular,
those with concentric changes or additional evidence of active rejection have an unfavorable prognosis.
Frequently, graft function is lost within months to few years.
Comment: Sclerosing transplant vasculopathy does not respond to
treatment ("intimal scar"). However, if signs of active rejection, such as transplant endarteritis or
C4d deposits, are additionally noted, therapeutic attempts can be made (anti-lymphocytic preparations,
high dose tacrolimus or mycophenolate-mofetil).
Cardiac allograft vasculopathy: Cardiac allograft vasculopathy is a major
cause for morbidity and mortality after heart transplantation. It shares most histologic features with
sclerosing renal transplant vasculopathy, however, due to the lack of histologic data much less is known
about the evolution of cardiac allograft vasculopathy in humans. There is clear evidence that
immunologic phenomena, i.e. rejection episodes, also promote myofibroblastic proliferation and scar
formation in arteries of the heart. This process can be further aggrevated by hypertension,
hyperlipidemia and diabetes mellitus. Since epicardial arteries are also prime targets for
non-immunologic injuries, namely atherosclerosis induced by hypertension, diabetes mellitus or
hyperlipidemia, "chronic vascular rejection" of the heart can be associated with typical atherosclerotic
plaques/atherosclerotic disease. (Although hypertension induced arterial intimal fibroelastosis is
common in intrarenal arteries, atherosclerotic plaque formation with calcification and accumulation of
lipids are typically absent.) Often cardiac allograft vasculopathy involves epicardial arteries in a
diffuse fashion, and it can sometimes even extend into small intramyocardial arterial branches. In
contrast, pure atherosclerotic disease of epicardial arteries is typically focal in nature and commonly
accentuated at vascular branching points.
Selected References (Section C)
Alexander RT, Lathrop S, Vollmer R et al. Graft vascular disease after cardiac transplantation and
its relationship to mean acute rejection score. Arch Pathol Lab Med 2005,
Ashraf S, Parrott NR, Dyer P, Roberts I, Johnson RW. Clinical response and temporal patterns of acute
cellular rejection: relationship to chronic transplant nephropathy. Transpl
Int 1998; 11 Suppl 1: S5-9
Billingham ME. Cardiac transplant atherosclerosis. Transplant Proceed
1987; 4 (suppl. 5 August): 19
Billingham ME. Chronic rejection in human allografts. In' Transplant vascular sclerosis', Orosz CG,
Sedmak DD, Ferguson RM eds, Springer Verlag/ RG Landes Company, Austin 1995
Busch GJ, Reynolds ES, Galvanek EG, Braun WE, Dammin GJ. Human renal allografts. The role of
vascular injury in early graft failure. Medicine 1971; 50: 29-83
Cary N. Heart transplantation. In 'Pathology and Immunology of Transplantation and Rejection', Thiru
S and Waldmann H, eds, Blackwell Science, Oxford, 2001
Colvin RB. Kidney. In: R.B. Colvin, A.K. Bhan, R.T. McCluskey (eds). Diagnostic Immunopathology
(ed. 2). New York : Raven Press 1995: pp 329-365
Colvin RB, Cohen AH, Saiontz C et al.: Evaluation of pathologic criteria for acute renal allograft
rejection: Reproducibility , sensitivity, and clinical correlation. J Am Soc
Nephrol 1997; 8: 1930-1941
Colvin RB: Renal transplant pathology. In: Jennette JC, Olson JC, Schwartz ML, Silva FG (eds).
Heptinstall's Pathology of the Kidney.( 5th ed), Lippincott-Raven, Philadelphia , USA ; 1998: pp
Croker BP, Ramos EL. Pathology of the renal allograft. In: Tisher CC, Brenner MB(eds.). Renal
Pathology (2nd ed) Vol. II. Lippincott JB Comp Philadelphia, USA; 1994: pp 1591-1640
Croker BP, Clapp WL, Abu Shamat AR, Kone BC, Peterson JC. Macrophages and chronic renal allograft
nephropathy. Kidney Int Suppl 1996; 57: S42-49
Dammin G. The kidney as a homograft and its host. U Mich Med Bull 1960; 26: 278
Forbes RCD, Zheng S-X, Gomersall M, Guttmann RD. Irreversible chronic vascular rejection occurs only
after development of advanced allograft vasculopathy: a comparitive study of a rat cardiac allograft
model using a retransplantation protocol. Transplantation 1997; 63:
Gaber LW, Moore LW, Gaber AO, Tesi RJ, Meyer J, Schroeder TJ. Correlation of histology to clinical
rejection reversal: a thymoglobulin multicenter trial report. Kidney Int
1999; 55: 2415-2422
Haas M, Kraus ES, Samaniego-Picota M, Racusen LC, Ni W, Eustace JA: Acute renal allograft rejection
with intimal arteritis: histologic predictors of response to therapy and graft surviaval. Kid Int 2002; 61: 1516-1526
Hall BM. Cells mediating allograft rejection. Transplantation 1991; 51:
Hosenpud JD, Shipley GD, Wagner CR. Cardiac allograft vasculopathy: current concepts, recent
developments, and future directions.
J Heart Lung Transplant 1992; 11: 9
Kiss D, Landmann J, Mihatsch MJ, Huser B, Brunner FP, Thiel G. Risks and benefits of graft biopsy in
renal transplantation under Cyclosporin-A. Clin Nephrol 1992; 38:
Matas AJ, Sibley R, Mauer M, Sutherland DE, Simmons RL, Najarian JS. A retrospective study of
biopsies performed during putative rejection episodes. Transplantation
1983; 22: 420-426
Mihatsch MJ, Nickeleit V, Gudat F. Morphologic criteria of chronic renal allograft rejection. Transplant Proc 1999; 31: 1295-1297
Milford EL, Hancock W., Carpenter CB. Immunopathogenetic mechanisms of allograft rejection. In:
Tisher CC, Brenner MB (eds.). Renal Pathology (2nd ed) Vol. II. Lippincott JB Comp Philadelphia , USA
; 1994: pp 1581-1590
Nickeleit V, Vamvakas EC, Pascual M et al.: The prognostic significance of specific arterial lesions
in acute renal allograft rejection. J Am Soc Nephrol 1998; 9: 1301-1308
Pascual N, Vallhonrat H, Cosimi AB, Tolkoff-Rubin N, Colvin RB, Delmonico FL, Ko DS, Schoenfeld DA,
Williams WW, Jr. The clinical usefulness of the renal allograft biopsy in the cyclosporin era: a
prospective study. Transplantation 1999: 67: 737-741
Paul LC. Chronic allograft nephropathy: An update. Kidney Int 1999;
Racusen LC., Solez K, Olsen S. Pathology of kidney transplantation. In: Solez K, Racusen LC,
Billingham, M.E. (eds). Solid Organ Transplant Rejection (2nd ed). Dekker
M. INC New York , Basel , Hong Kong 199: pp 207-241
Racusen LC, Solez K, Colvin RB, Bonsib SM, Castro MCR, Cavallo T, Croker BP, Demetris AJ, Drachenberg
CB, Fogo AB, Furness P, Gaber LW, Gibson IW, Glotz D, Goldberg JC, Grande J, Halloran PF, Hansen HE,
Hartley B, Hayry PJ, Hill CM, Hoffman EO, Hunsicker LG, Lindblad AS, Marcussen N, Mihatsch MJ, Morozumi
K, Nadasdy T, Nickerson P, Olsen TS, Papadimitriou JC, Randhawa PS, Rayner DC, Roberts I, Rose S, Rush D,
Salinas-Madrigal L, Salomom DR, Sund S, Taskinen E, Trpkov K, Yamaguchi Y. The Banff 97 working
classification of renal allograft pathology. Kidney Int 1999; 713-723
Racusen LC, Colvin RB, Solez K, Mihatsch MJ, Halloran PF, Campbell PM, Cecka MJ, Cosyns JP, Demetris
AJ, Fishbein MC, Fogo AB, Furness P, Gibson IW, Glotz D, Hayry PJ, Hunsickern L, Kashgarian M, Kerman R,
Magil AJ, Montgomery R, Morozumi K, Nickeleit V, Randhawa P, Regele H, Seron D, Seshan S, Sund S, Trpkov
K. Antibody-mediated rejection criteria – an addition to the Banff '97 classification of renal allograft
rejection. pathology. Am J Transplant 2003; 708-714
Schroeder TJ, Weiss MA, Smith RD, Stephens GW, First MR. The efficacy of OKT3 in vascular rejection.
Transplantation 1991; 51: 312-315
Vassalli G, Gallino A, Weis M, von Scheidt W, Kappenberger L, von Segesser LK, Goy JJ. Alloimmunity
and nonimmunologic risk factors in cardiac allograft vasculopathy. Europ Heart
J 2003; 24:1180-1188
Virmani R, Burke A, Farb A, Atkinson JB. Pathology of heart transplantation. In 'Cardiovascular
pathology', chapter 9, Major Problems in Pathology, vol. 40, WB Saunders Company, Philadelphia, London,
New York 2001
Waller J, Brook NR, Nicholson ML. Cardiac allograft vasculopathy: current concepts and treatment.
Transplant Int 2003; 16: 367-375
Yamani MH, Yousufuddin M, Starling RC, Tuzcu M, Ratliff NB, Cook DJ, Abdo A, Crowe T, Hobbs R, Rincon
G, Bott-Silverman C, McCarthy PM, Young JB. Does acute cellular rejection correlate with cardiac
allograft vasculopathy? J Heart Lung Transplant 2004; 23: 272-276
Zollinger HU, Mihatsch MJ. Renal pathology in biopsy. Berlin. Springer
Verlag; 1978: pp 564-608
Humoral Rejection and Antibodies - C4d
Beht TM, Feucht HE, Richter K, Reiter C, Spes CH, Pongratz D, Überfuhr, Meister B, Theisen K,
Angermann CE. Detection of humoral rejection in human cardiac allografts by assessing the capillary
deposition of complement fragment C4d in endomyocardial biopsies. J Heart Lung
Transplant 1999; 18: 904-912
Böhmig GA, Exner M, Habicht A, Schillinger M, Lang U, Kletzmayr J, Säemann MD, Hörl WH, Watschinger B,
Regele H: Capillary C4d deposition in kidney allografts: a specific marker of an alloantibody-dependent
graft injury. J Am Soc Nephrol 2002; 13: 1091-1099
Böhmig GA , Exner M, Watschinger B, Wenter C, Wahrmann M, Österreicher C, Säemann MD, Mersich N, Hörl
WH, Zlabinger GJ, Regele H: C4d deposits in renal allografts are associated with inferior graft outcome.
Transplant Proc 2001; 33: 1151-1152
Böhmig GA , Regele H, Saemann MD, Exner M, Druml W, Kovarik J, Hörl WH, Zlabinger GJ, Watschinger B:
Role of humoral immune reactions as targets for antirejection therapy in recipients of a spousal-donor
kidney graft. Am J Kidney Dis 2000; 35: 667-673
Collins AB , Schneeberger EE, Pascual MA, Saidman SL, Williams WW, Tolkoff-Rubin N, Cosimi AB , Colvin
RB: Complement activation in acute humoral renal allograft rejection: diagnostic significance of C4d
deposits in peritubular capillaries. J Am Soc Nephrol 1999; 10: 2208-2214
Crespo M, Pascual M, Tolkoff-Rubin N, Mauiyyedi S, Collins AB, Fitzpatrick D, Farrell ML, Williams WW,
Delmonico FL, Cosimi AB, Colvin RB, Saidman SL: Acute humoral rejection in renal allograft recipients:
incidence, serology and clinical characteristics. Transplantation 2001;
Feucht HE, Opelz G: The humoral immune response towards HLA class II determinants in renal
transplantation. Kidney Int 1996; 50: 1464-1475
Feucht HE, Felber E, Gokel MJ, Hillebrand G, Nattermann U, Brockmeyer C, Held E, Riethmuller G, Land
W, Albert E: Vascular deposition of complement-split products in kidney allografts with cell-mediated
rejection. Clin exp Immunol 1991; 86: 464-470
Feucht HE, Schneeberger H, Hillebrand G, Burkhardt K, Weiss M, Riethmuller G, Land W, Albert E:
Capillary deposition of C4d complement fragment and early renal graft loss. Kidney
Int 1993; 43: 1333-1338
Herzenberg AM, Gill JS, Djurdjev O, Magil AB : C4d deposition in acute rejection: an independent
long-term prognostic factor. J Am Soc Nephrol 2002; 13: 234-241
Lederer SR, Kluth-Pepper B, Schneeberger H, Albert E, Land W, Feucht HE: Impact of humoral
alloreactivity early after transplantation on the long-term survival of renal allografts. Kidney Int 2001; 59: 334-341
Magil AB , Tinckam K. Monocytes and peritubular capillary C4d deposition in acute renal allograft
rejection. Kid Int 2003; 63: 1888
Michaels PJ, Fishbein MC, Colvin RB. Humoral rejection of human organ transplants. Springer Semin Immunopathol 2003; 25:119-140
Nickeleit V, Zeiler M, Gudat F, Thiel G, Mihatsch MJ. Detection of the complement degradation product
C4d in renal allografts: diagnostic and therapeutic implications. J Am Soc
Nephrol 2002; 13: 242-251
Nickeleit V, Mihatsch MJ. Kidney transplants, antibodies and rejection: is C4d a magic marker? Nephrol Dial Transplant 2003; 18: 2232-2239, 2003
van der Woude FJ, Deckers JG, Mallat MJ, Yard BA, Schrama E, van Sasse JL, Daha MR: Tissue antigens
in tubulointerstitial and vascular rejection. Kidney Int Suppl 1995; 52:
Calcineurin Inhibitor Toxicity – Cyclosporine and Tacrolimus
Bergstrand A, Bohman SO, Farnsworth A, Gokel JM, Krause PH, Lang W, Mihatsch MJ, Oppedal B, Sll S,
Sibley RK, Thiru S, Verani R, Wallace AC, Zollinger HU, Ryffel B, Thiel G, Wonigeit K. Renal
histopathology in kidney transplant recipients immunosuppressed with cyclosporin A. Clin Nephrol 1985; 24: 107-119
Japanese FK506 Study Group:
Morphological characteristics of renal allografts showing renal dysfunction under FK 506 therapy: is
graft biopsy available to reveal the morphological findings corresponding with FK 506 nephropathy?
Transplant Proc 1993;25: 624-627
Japanese FK 506 Study Group:
Morphopathological findings of renal allografts under FK 506 therapy.
Transplant Proc 1994;26: 1933-1936
Mihatsch M J, Gudat F, Ryffel B, Thiel G. Cyclosporine nephropathy. In: Tisher CC, Brenner MB
(eds.). Renal Pathology (2nd ed) Vol. II. Lippincott JB Comp Philadelphia , USA ; 1994: pp 1641-1686
Mihatsch MJ, Thiel G, Spichtin HP, Oberholzer M, Brunner FP, Harder F, Olivieri V, Bremer R, Ryffel B,
Stöcklin E, Torhorst J, Gudat F, Zollinger HU, Lörtscher R. Morphological findings in kidney transplants
after treatment with cyclosporin. Transplant Proc 1983; 15: 2821-2835
Mihatsch MJ, Kyo M, Morozumi K, Yamaguchi Y, Nickeleit V, Ryffel B. The side-effects of ciclosporine-A
and tacrolimus. Clin Nephrol 1998; 49: 356-363
Thiru S, Maher ER, Hamilton DV, Evans DB, Calne RY. Tubular changes in renal transplant recipients on
cyclosporin. Transplant Proc 1983; 15: 2848-2851
Randhawa PS, Shapiro R, Jordan ML, Starzl TE, Demetris AJ:
The histopathological changes associated with allograft rejection and drug toxicity in renal
transplant recipients maintained on FK 506. Am J Surg Pathol 1993;17: