================CHAPTER27================

Pathology of Kidney Allograft Dysfunction

Bela Ivanyi"

Abstract

he pathologic features, clinical correlations and differential diagnoses of the major causes of kidney allograft dysfunction are
reviewed. Rejection is an inflammatory process of the recipient
during which donor cells bearing alloantigens are destroyed; the rejection
process is classified traditionally as hyperacute, acute or chronic. Hyperacute
rejection is caused by high titers of preformed antibodies to donor
endothelial cell antigens that lead to thrombosis in the renal vasculature and
ischemic death of the graft. Acute cellular rejection is primarily mediated by
contact-dependent cellular cytotoxicity. The indicator lesions are interstitial
infiltrates composed predominantly of T-lymphocytes and tubuli tis, with or
without intimal arteritis. Acute humoral rejection is caused by donor-specific
HLA class I antibodies. The morphological features include complement 4d
positivity along the peri tubular capillaries, neutrophils in the peri tubular
and glomerular capillaries, micro thrombi in the rnicrovesscls and
transmural arteritis, with or without fibrinoid necrosis. Chronic rejection is
mediated by humoral and/or cellular alloimmune mechanisms and is
characterized morphologically by obliterative intimal fibrosis in the arteries,
double-contoured glomerular capillary loops and circumferentially
multiplied and split basement membrane in the peri tubular capillaries.
Chronic allograft nephropathy is the result of a series of alloimmune and
non-immune insults that cumulate and subsequently manifest in arterial
intimal fibroelastosis, focal-global glomerular sclerosis, interstitial fibrosis
and tubular atrophy. Calcineurin inhibitor toxicity may cause acute toxic
tubulopathy and/or acute vascular toxicity or chronic hyaline artcriolopathy,
Prolonged warm or cold ischemia prior to transplantation leads to
posttransplant acute tubular necrosis. The indicator lesions are diffuse
tubular damage (loss of brush border, focal epithelial necrosis, desquamation
of cells into the tubular lumen, etc.,) and interstitial edema.

Introduction
The gold standard for the assessment of structural abnormalities in the
transplanted kidney is the morphological examination of a core-needle
biopsy specimen. The biopsy is performed at the time of a graft dysfunction,
when the etiology cannot be explored by clinical or non-invasive means, or
at predetermined intervals, in order to recognize subclinical rejection, to
identify drug toxicity or to determine the efficacy of new
immunosuppressive drugs. The standard evaluation procedure (at least two
cores whenever possible) involves light microscopic staining on serial
sections (H&E, PAS, trichrome and methenamine silver) and
immunostaining for complement (C) 4d.!-3The biopsy is regarded as
adequate if 1 0 or more glomeruli with at least 2 arteries can be investigated
by light microscopy (LM). For optimum interpretative power of the
histologic changes, comparison with a time-zero biopsy is

strongly advised.' Some pathologists also perform elastin staining, apply the
full immunofluorescence (IF) panel (IgG, IgA, IgM, C3, Clq and fibrinogen)
and investigate the up regulation of tubular HLA- D R antigen,4.5 because
such stainings sometimes furnish additional diagnostic information. Tissue
sampling for electron microscopy (EM) is suggested if there is a clinical
suspicion of de novo or recurrent glomerular disease. The ultrastructural
examination of glomerular and peri tubular capillaries facilitates a more
definitive identification of glomerular and peri tubular capillary lesions of
chronic rejection, 6 but it is not routinely performed because of cost-benefit
concerns.
This survey discusses the pathologic features (summarized in Tables 1
and 2), clinical correlations and differential diagnoses of the major causes of
allograft dysfunction (for more details, see refs. 5 and 7). Chapter 38 in this
book is dedicated to the topic ofBK polyomavirus nephropathy.

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Transplant Rejection
Rejection is an inflammatory response of the recipient during which
donor cells bearing antigens recognized as foreign (allogenic) are destroyed.
The targeted antigens are the HLA class I and II antigens, the non HLA
minor alloantigens and the ABO blood group antigens. The class I antigens
are expressed by all renal parenchymal cells, but most intensely by the
vascular endothelial cells. The class II antigens are displayed by capillary
endothelial cells," mesangial cells, proximal tubular epithelial cells and
interstitial dendritic cells. Interferon-y, produced by activated Tlymphocytes, enhances HLA antigen expression and particularly the
expression of class II antigens in the tubules. Two types of alloantigen
presentation exist. In the direct pathway, the CD8+ and CD4+ Tlymphocytes of the recipient recognize the allogenic molecules on the
surface of the antigen-presenting cells in the graft. The CD8+ cells then
differentiate into cytotoxic T-lymphocytes and cause the contact-dependent
killing of the target cells. The CD4 + T-cells differentiate into Thl effector
cells, which produce cyrokincs that induce a local delayed hypersensitivity
reaction and stimulate B-lymphocytes and CD8+ T-lymphocytes. In the
indirect pathway, the T-lymphocytes of the recipient recognize alloantigens
after they are presented by the recipient's own antigen-presenting cells. T hI
effector cells are generated and these mediate tissue injury via a local
delayed hypersensitivity reaction and B-cell rcsponses.v'"
Traditionally, three forms of rejection are distinguished: hyperacute,
acute and chronic. Acute rejection is subclassified into cell-mediated and
antibody-mediated types. Acute cellular rejection is primarily initiated by
direct allorecognition and chronic rejection by indirect allorecognition. The
pathology of rejection has an intrinsic focal nature.

*Bela Ivanyi-Department of Pathology, Allomas u. 2, H-6720 Szeged, Hungary. Email: ivanyi@patho.szote.u-szeged.hu

Chronic Allograft Failure: Natural History, Pathogenesis, Diagnosis and Management, edited by Nasimul Ahsan. 2008 Landes Bioscience.

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223

Pathology of Kidney Allograft Dysfunction

Table 1. Lesions of acute rejection, acute calcineurin inhibitor (CN/) nephrotoxicity and posttransplant acute tubular necrosis
(ATN)
Acute Rejection

Acute CNI Toxicity*

ATN

Cellular

Acute afferent arteriolopathy

Dilation and flattening of tubules Loss

Interstitial infiltrates of activated

lymphocytes
Lymphocytic tubulitis; HLA-DR
expression of tubules Lymphocytic
intimal arteritis Transplant
glomerulitis

Endothelial swelling/vacuolization Necrosis and

early hyaline replacement of individual myocytes

of brush border

Humoral

Tubulopathy

Fibrinoid necrosis of small arteries and/or

afferent arterioles

Small, evenly distributed vacuoles mainly in the

proximal straight tubules

*Rare manifestation: thrombotic

microangiopathy

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Glomerular microthrombi
Neutrophils in peritubular capillaries
Ischemic tubular damage
Complement 4d localized along peritubular
capillaries

Individual necrosis and desquamation of

tubular epithelial cells
Enlarged regenerative nuclei
Interstitial edema

U)

Hyperacute Rejection
This is produced by high titers of preformed antibodies targeting
antigens on donor endothelial cells, such as blood group antigens or
HLA class I antigens. The antibodies initiate complement fixation,
platelet activation, the lysis of endothelial cells and activation of the
clotting system, with thrombosis, circulation blockage and ischemic
death of the grafted kidney. 11

Morphology
LM reveals swelling and lysis of the endothelial cells, denudation
of the basement membrane, margination of the neutrophils and
thrombi in the arteries, arterioles and glomeruli. The ncutrophils are
typically incorporated into the thrombi. The renal compartments
undergo ischemic injury. Within 1 day, cortical and medullary infarcts
develop. IF discloses strong staining for fibrin in the microvasculature
and often in the interstitium. IgM or IgG, C3

and C4d may be observed in the walls of the arteries and arterioles
and along the glomerular and peri tubular capillaries.

Clinical Correlation
Hyperacute rejection is extremely rare in consequence of the
regular screening for donor-specific antibodies prior to transplantation. However, certain cases fail to be identified for some reason 12 and
within minutes after the vascular anastornes have been established,
the implanted kidney becomes cyanotic, edematous and flaccid and
anuria develops. Hyperacute rejection is irreversible and the graft
must be removed.

Differential Diagnosis
Other conditions that can cause a primary graft failure are acute
tubular necrosis (ATN), perfusion injury and major arterial occlusion.
A common feature of all these is that IF reveals no immunoglobulin
deposits along the endothelial surfaces.

Table 2. Lesions of chronic rejection, chronic allograft nephropathy (CAN), chronic calcineurin inhibitor (CN/) nephrotoxicity and BK
polyoma virus nephropathy
Chronic Rejection

CAN

Chronic CNI Toxicity

Transplant arteriopathy New-

Intimal fibroelastosis in
the arteries

Hyaline

onset intimal fibrosis Foam

cells/mononuclears in the
intima

BK Polyoma Virus Nephropathy*

Double-contoured glomerular
capillaries
Transplant capillaropathy

At least 3 peritubular capillaries with

5 or more circumferential basement
membrane layers on electron
microscopy Complement 4d
positivity
Interstitial fibrosis and tubular
atrophy

Myocytes are replaced

by beaded hyaline deposits that bulge
into the adventitia

No change or subendothelial
hyalinosis in the arterioles

Nonspecific segmental or
global glomerular sclerosis

Cytopathic changes

Nonspecific segmental or
global glomerular sclerosis

Striped interstitial fibrosis and

tubular atrophy

Cytolytic changes

Interstitial fibrosis and tubular

atrophy

* Adjunct immunohistochemical or electron microsopic studies confirm the diagnosis.

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arteriolopathy

Absent elastosis
Transplant glomerulopathy

Enlarged tubular cells, karyomegaly,

nuclear inclusions
Lysis of tubular epithelial cells,
denudation of basement membrane

Interstitial inflammatory
infiltrates

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Chronic Allograft Failure: Natural History, Pathogenesis, Diagnosis and Management

Acute Cellular Rejection

This is mediated primarily by CD8+ cytotoxic 'T-lyrnphocytes and,
to a lesser extent, by local delayed hypersensitivity reaction induced by
CD4+ helper T'-lyrnphocytcs. Other effector mechanisms, such as
antibody-dependent cellular cytotoxicity or local humoral responses,
may also playa role in the evolution of alloimmune damage to the
kidney.

Morphology
The rejection process affects the interstitium, tubules, glomeruli and
arteries, in varying combinations and with varying degrees of involvement. Three patterns are distinguished: tubulointcrstitial, vascular and
glomerular.

Conventional Type ofTubulointerstitial Rejection

The majority of cases belong in this category and are characterized
by infiltration of the interstitium by mononuclear leukocytes,
accompanied by tubulitis (Fig. 1), peri tubular capillaritis and
interstitial edema. 1 The infiltrates consist mainly of CD8+ and CD4+
T-Iymphocytes and macrophages. Scattered B-Iymphocytes, plasma
cells, cosinophils, neutrophils and natural killer cells are minor
components of the infiltrate. Tubulitis (infiltration of the tubular
epithelium by lymphocytes) in non-atrophic tubules is a defining lesion
of acute tubulointerstitial rejection 1.13 and is usually accompanied by
acute tubular injury: epithelial cell lysis or apoptosis induced by
tubular wall-localized cytotoxic T-Iymphocytes, epithelial thinning and
detachment, enlarged regenerative nuclei and mitotic figures. The
features of peritubular capillaritis include endothelial cell hypertrophy,
accumulation and margination of lymphocytes and monocytes in the
capillary lumina, 13.14 migration of endothelium-adherent inflammatory
cells to the interstitium and, on occasion, lysis or apoptosis of
endothelial cells in the close vicinity of cytotoxic T-Iymphocytes. IF
reveals the up regulation of class II antigens on tubular epithelial cells.

Other Types ofTubulointerstitial Rejection

These occur infrequently and are characterized by interstitial infiltrates rich in B-Iymphocytesl5 or plasma cclls.l" 17 mild tubulitis and a
worse outcome.
Vascular Rejection is diagnosed if infiltration of the intima of the
arteries by T-Iymphocytes and macrophages (Fig. 2) is noted. IS The
lesion is termed intimal arteritis (synonyms: endothelialitis or
endarteritis) and may occur with or without intimal edema and fibrin
deposition. Vascular rejection involves the large arteries more
frequently than the interlobular arteries and arterioles.

Figure 2. Acute cellular vascular rejection. Lymphocytes localize in

the intima (asterisk) of the interlobular artery. Elastin staining.

In about 10% of the cases of acute cellular rejection, there is a

marked infiltration of the glomerular tufts by 'T-lyrnphocytes and
monocytes; this situation is denoted transplant glomerulitis.

Clinical Correlation
Acute cellular rejection is the most common cause of a graft dysfunction in the first 3 months after transplantation. However, it may
develop even yeats later. The cardinal sign is a sudden asymptomatic
increase (> 20%) in the serum creatinine level. With current immunosuppression regimens, symptoms such as pain, fever or oliguria ate
rate. Conventional tubulointerstitial rejection responds well to highdose intravenous corticosteroid therapy. In contrast, the B-cell-rich or
plasma cell-rich subtypes ate usually steroid-resistanc."'"!" Vascular
rejection can be reversed with anti-lymphocyte antibody preparations.
Refractory cases have a poor outcome. A rate complication of acute
cellular rejection is spontaneous rupture of the kidney allograft. 19

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Differential Diagnosis
Acute tubulointerstitial rejection must be differentiated from BK
polyoma virus nephropathy (rejection: lack of nuclear inclusion bodies
in the tubular epithelial cells), acute bacterial tubulointerstitial
nephritis (rejection: lymphocytic, but not neurroph il ic" rubulitis),
drug-induced acute interstitial nephritis (rejection: intense tubular
HLA-DR staining) and posttransplant lymphoproliferative disease
(rejection: predominance of T-Iymphocytes, not B-Iymphocytes).
Intimal arteritis is pathognomic of acute cellular rejection. Transplant
glomerulitis must be distinguished from recurrent or de novo
proliferative glomerulonephritis. In the latter conditions, IF demonstrates glomerular immune deposits.

Acute Antibody-Mediated Rejection

This form is mainly caused by donor-specific HLA class I
antibodies which induce complement-mediated cytotoxic injury to the
endothelial cells. Risk factors include a historically positive cross
match, an increased lymphocytotoxic panel-reactive antibody titer,
sensitization through previous renal transplantation, pregnancy or
blood transfusions. The complement split product C4d binds
covalently near the original antibody targets and resists rapid
elimination. The immunohistochemical identification of C4d along the
pcritubular capillaries has been demonstrated to be strongly correlated
with circulating donor-specific antibodies and acute humoral rejection
and has therefore been used as a marker of humoral rejection.21-23

Morphology
Figure 1. Acute cellular tubulointerstitial rejection. Lymphocytes
infiltrate the interstitium (IS) and tubules. The latter phenomenon is
termed tubulitis (asterisk). PAS staining.

LM reveals the accumulation and margination of the ncutrophils

and later monocytes in the peri tubular and glomerulat capillaries,
endothelial swelling/necrosis and micro thrombi in the glomerulat and
pcritubular capillaries and small arteries. Larger arteries may display

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225

Pathology of Kidney Allograft Dysfunction

to progressive nonspecific interstitial fibrosis and tubular atrophy.27.28

Since chronic rejection, CNI nephrotoxicity, hypertensive vascular disease
and chronic infection/reflux cannot always be distinguished in the biopsy
specimen, the Banff classification of kidney transplant pathology! has
coined the term chronic allograft nephropathy (CAN) to emphasize the
multifactorial nature of the chronic kidney allograft injury. At the moment,
there is no therapeutic consequence via which to distinguish chronic
rejection from CAN. The usual diagnostic label is either CAN, with or
without features of chronic rejection, or chronic rejection/CAN.

Morphology

Figure 3. Acute humoral rejection by immunofluorescence. Bright

linear staining of peritubular capillaries with complement 4d component. G-glomerulus.
transmural infiltrates oflymphocytes and ncurrophils, with or without
fibrinoid necrosis of the medial smooth muscle cells. There is little, if any,
mononuclear inflammatory infiltration of the interstitium or tubulitis.i" The
tubules exhibit degenerative changes or ATN. There may be focal interstitial
microhemorrhages and patchy cortical infarctions. IF reveals (Fig. 3) bright
linear staining of the cortical and medullary peri tubular capillaries with
C4d.25 In some cases, IgG or IgM and C3 can be observed together with
fibrin along the glomerular and peritubular capillaries and in arterial
fibrinoid necrosis. On EM, the peri tubular capillaries display severe
swelling of the endothelial cells, with rupture of the cell membrane
(cytolysis), an increased rate ofapoptosis, denudation of the basement
membrane and intra- and extracapillary fibrin dcposition.v l-or a definitive
diagnosis of acute antibody-mediated rejection, the serologic evidence of
circulating antibodies to donor HLA or other anti-donor endothelial antigens
is required.'

The interstitium displays a varying degree of fibrosis and the tubules in

the fibrotic areas are atrophic (Fig. 4). The marker lesions of chronic
rejection are transplant artcriopathy, transplant glomerulopathy and
transplant capillaropathy, present either alone or in combination (Table 2).
Transplant arteriopathy is diagnosed if the narrowing of medium-sized and
large arteries by new-onset intimal fibrosis is observed (Fig. 5). The lesion
may be associated with foam cells/ rnononuclcars in the intima, breaks in the
internal elastic lamina and the formation of nco-media. Elastosis is absent.
Transplant glomerulopathy is characterized by double-contoured capillary
loops

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Clinical Correlation
Acute antibody-mediated rejection is a relatively infrequent condition

(2-8%). It can arise at any time following transplantation, but most

commonly in the first few weeks. After an initial period of good graft
function, there is a sudden rise in the serum creatinine level, accompa nied
by a reduced urine output. Oligoanuria develops within days. The prognosis
is poor. If an early diagnosis is achieved, therapeutic efforts may reverse the
rejection process.

Differential Diagnosis

Figure 4. Chronic allograft nephropathy. At the asterisk, the interstitium displays fibrosis (blue) and the tubules lack segment-specific
features indicating atrophy. G-glomerulus. Trichrome staining.

Conditions that should be considered are thrombotic micro angiopathy

(TMA) secondary to calcincurin inhibitor (CN!) toxicity, anticardiolipin
syndrome, viral infection due to cytomegalovirus or parvovirus B 19 and
recurrent hemolytic-uremic syndrome. C4d-positive peri tubular capillaritis
supports the diagnosis of acute antibody-mediated rejection.

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Chronic Rejection and Chronic

Allograft Nephropathy
Chronic rejection involves ongoing, smoldering damage to the allograft,
mediated predominantly by humoral alloirnrnunc mechanisms. In addition
to the chronic alloimmune damage to the renal parenchyma, the nephrons
are depleted by a variety of alloantigen-independent factors, such as
advanced donor age, ischemic injury to the graft during the implantation
period, hypertension, CNI nephrotoxicity, infection, an increased ureteral
pressure, ctc., The alloimmune and non-immune mechanisms cumulate and,
in association with additional mechanisms of injury, such as internal
architectural disruption of the kidney, chronic cortical ischemia, persistent
chronic inflammation, replicative senescence, epithelial-to-mesenchymal
transition, ctc., lead

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Figure 5. Chronic rejection, transplant arteriopathy. The arcuate

artery is severely narrowed by intimal fibrosis (I F). Elastosis is
absent. Elastin staining.

226

Chronic Allograft Failure: Natural History, Pathogenesis, Diagnosis and Management

Differential Diagnosis
The main conditions to be differentiated are chronic CNI nephrotoxicity, de novo or recurrent glomerulonephritis and BK polyomavirus
nephropathy. Hyaline arteriolopathy indicates CNI nephrotoxicity.
Glomerulonephritis can be readily detected if the full immunohistochemical panel is used and embedding for EM is carried out. Nuclear
inclusion bodies in the tubular cells, tubular epithelial injury, a varying
degree of interstitial inflammation and tubular atrophy suggest polyomavirus nephropathy. Ancillary techniques, such as immunohistochemistry on paraffin sections with antibody to the SV 40 large T-antigen
or electron microscopy of infected tubular epithelial cells (virions 40
nm in diameter, often arranged in paracrystalloid arrays), confirm the
diagnosis of polyomavirus nephropathy.

The Banff Classification of Kidney

Transplant Pathology

Figure 6. Chronic rejection, transplant glomerulopathy. Doublecontoured capillary loops (arrowheads). Silver impregnation.

A scheme for the nomenclature and classification of renal allograft

pathology was created by a group of experts in Banff, Canada in 1991
to standardize renal allograft biopsy interpretation and reporting and
has subsequently been regularly updated. The diagnostic categories
include normal, antibody-mediated rejection, "suspicious" for acute
cellular rejection, acute/active cellular rejection, chronic/sclerosing
allograft nephropathy and other changes not considered to be due to
rejection. Vascular, glomerular, interstitial and tubular lesions of acute
rejection and CAN are defined and scored 0 to 3 +.1 The scoring codes
are designated u, g, i or t for acute vascular, glomerular, interstitial or
tubular changes and cu; cg, ci or ct for the corresponding chronic changes,
respectively. The degree of arteriolar hyaline thickening (ah) is also
defined and scored. The scores provide the basis for arbitrary grades of
mild, moderate and severe.

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Calcineurin Inhibitor (CNI) Toxicity

CNIs (cyclosporine and tacrolimus) can cause acute or chronic
nephrotoxicity; the lesions are identical. The pathogenetic pathways are
complex and beyond the scope of the present paper.

Acute Nephrotoxicity
This may appear as functional toxicity, a delayed recovery from
post-transplant ATN, toxic tubulopathy or vascular toxicity.s.7.3o

Toxic Tubulopathy
Figure 7. Chronic rejection, transplant capillaropathy. Electron
microscopy reveals the multiplied and split basement membrane of
the peritubular capillary profile (asterisk). L -I urncn, E-endothelial
layer.

(Fig. 6), with or without increase in the mesangial matrix, mesangial

hypercellularity and mesangial interposition. On EM, the glomerular
basement membrane is reduplicated or rnultiplcd and this accounts for
the phenomenon of doublecontours. Transplant capillaropathy is
identified ultrastructurally (Fig. 7): the capillaries display a serrated
contour and the basement membranes are circumferentially rnultiplcd
and split (5 or more layers in at least 3 profiles).29 Chronic rejection
may be accompanied by features of active cellular and/or humoral
rejection. CAN is diagnosed if the lesions of chronic rejection cannot
be verified (Table 2). Chronic rejection/CAN may coexist with CNI
nephrotoxicity or recurrent glomerulonephritis.

Clinical Correlation
Chronic rejection/CAN is the major cause of graft loss after 1 year.
It is manifested by an insidious, progressive decline in the glomerular
filtration rate, frequently accompanied by proteinuria (often in the
nephrotic range) and hypertension.

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Morphology

Isometric tubular vacuolization is observed focally, predominantly

affecting the proximal straight tubules (Table 1). The vacuoles are
small, clear and evenly distributed throughout the cytoplasm.
Ultrastructurally, they correspond to dilations of the endoplasmic
reticulum. Focal tubular calcification may also be seen.

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Clinical Correlation

The patients present with an acute allograft dysfunction, the

condition usually being associated with an elevated serum drug level.
Following lowering of the dose of the drug, toxic tubulopathy is
reversible.

Differential Diagnosis
The features of this tubulopathy are indistinguishable from those of
radiocontrast nephrotoxicity or osmotic nephrosis, conditions to be
considered while making the diagnosis.

Vascular Toxicity
CNIs may have a direct toxic effect on endothelial cells, with or
without platelet aggregation. Two types of toxicity have been
identified: acute arteriolopathy and TMA.

Pathology of Kidney Allograft Dysfunction

22
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Chronic Allograft Failure: Natural History, Pathogenesis, Diagnosis and Management

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2.
3.
4.
5.
6.
7.
8.
9.

10.
11.

12.
13.
14.

15.

The indicator lesion is hyaline artcriolopachy, which affects the

afferent arterioles and the distal portions of the small interlobular
arteries. The necrotized/ apoptotic smooth muscle cells are replaced by
beaded hyaline deposits, situated on the outer aspect of the media, that
bulge into the adventitia. The insudates are positive for IgM and C3
and the staining displays a pearl necklace pattern. In advanced cases,
the entire wall is replaced by the hyaline material (Fig. 8) and the
lumen is severely narrowed. The interstitium shows striped fibrosis and
corresponding tubular atrophy. The glomerular changes include
compensatory hypertrophy, mesangial matrix expansion, capillary
collapse and focal-segmental and/or focal-global sclerosis.

Clinical Correlation
Chronic CNI nephrotoxicity occurs several months after transplantation; the incidence increases with time. There is a slow, insidious rise
in the serum creatinine level. Some patients have an elevated serum
level of cyclosporine or tacrolimus. The kidney damage is irreversible.
The appropriate management is a dose reduction or discontinuation of
cyclosporine or tacrolimus, with the administration of an alternative
immunosuppressive agent.

227

16.

Desvaux D, Le Gouvello S, Pastural M et al. Acute renal allograft

rejections with major interstitial oedema and plasma cell-rich infiltrates:
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Figure 8. Chronic
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Pathologic
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The smooth
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404.

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Morphology
The features include dilation and flattening of the tubular profiles,
the loss of brush borders, individual necrosis of the tubular epithelial
cells, cytoplasmic basophilia and enlarged regenerative nuclei. The
desquamation of tubular epithelial cells into the tubular lumen may be
observed. The tubular changes are accompanied by interstitial edema
and sparse lymphocytic/mononuclear infiltrates, without tubulitis."

Clinical Correlation
The condition is a common complication of cadaveric renal transplantation. It manifests as oligoanuria in the immediate postoperative
period, which resolves spontaneously over days and sometimes weeks.
The recipients are maintained on dialysis until the urine output has
been restored and the renal function has been recovered. Because of
potential exaggeration of the ischemic tubular damage, CNIs are
introduced only when the allograft function has been established.

Differential Diagnosis
A renal biopsy is often necessary to differentiate from acute rejection. In ATN, tubular damage and interstitial edema are the leading
features; marked interstitial inflammation, tubuli tis or intimal arteritis
indicates rejection.

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