CHRONIC ALLOGRAFT NEPHROPATHY

ATUL DESAI 1/8/12

INTRODUCTION
With current immunosupressives :
1 year graft survival improved : 90 % in deceased donors, 97% living donors Acute rejections reduced

No change in long term graft outcome. Late graft loss continues to be the Achilles heel of renal transplantation. 5 year survival DECEASED LIVING 91% 90% 10 year survival 58% 77%

LATE GRAFT DYSFUNCTION

Graft dysfunction > 3 months of transplant

Cause :
TRUE GRAFT DYSFUNCTION 50 % DEATH WITH FUNCTIONING GRAFT Cardiovascular event Infections Malignancies Recurrent disease Denovo disease CNI toxicity Infections CHRONIC ALLOGRAFT NEPHROPATHY

CHRONIC ALLOGRAFT DYSFUNCTION

CHRONIC ALLOGRAFT NEPHROPATHY

A clinico-pathologic syndrome characterized by slow

progressive decline in graft function, proteinuria, hypertension, and histopathologic features of interstitial fibrosis and tubular atrophy.

HISTOLOGY OF CAN
1) Tubular atrophy, interstitial fibrosis 2) Glomerular changes: glomerular capillary double contours, increased mesangial matrix = transplant glomerulopathy (DD : MPGN) 3) Vascular changes: fibro intimal hyperplasia in small muscular arteries. Mononuclear cell infiltration in intima. Neointimal formation. Internal elastic lamina disruption.

INTERSTITIAL FIBROSIS TUBULAR ATROPHY

TRANSPLANT GLOMERULOPATHY

VASCULAR CHANGES

SUBTYPES OF CAN

TYPE a IF & TA only

TYPE b IF & TA + glomerular & vascular changes

Sclerosing / fibrosing type Common lesion Nonspecific etiology

Immune mediated injury chronic rejection

GRADING CAN
1- TAIF 6-25% of cortical area

2- TAIF 26-50% of cortical area

3- TAIF > 50% of cortical area

PROBLEMS WITH NOMENCLATURE

Being inappropriately considered a specific disease

state rather than a term for nonspecific scarring. This belief inhibited the search for an accurate etiologic diagnosis Hence it has been eliminated from the Banff classification of renal allograft pathology

ALTERNATE NAME
BANFF 2007 UPDATE:
interstitial fibrosis/tubular atrophy with no evidence of specific etiology (IF/TA) Chronic active antibody mediated rejection Chronic active cell mediated rejection Changes thought not due to rejecton - either acute or chronic

EPIDEMIOLOGY
CAN is leading cause of death censored graft failure

late after transplantation.

Exact incidence and prevalence is difficult to

determine, as the onset is often insidious and not all patients undergo biopsy.
Studies with protocol biopsy :
50 % of protocol biopsy at 3 months 90 % protocol biopsies at 1 year 120 pts with type 1 DM All but 1 with SPK Followed for 10 yrs Biopsy done 961

Nankivell BJ, Borrows RJ, Fung CL, et al. The natural history of chronic allograft nephropathy. N Engl J Med. 2003;349:2326-2333.

PATHOPHYSIOLOGY
CAUSES (EVENTS & RISKS):
ALLOIMMUNE Acute rejection : late, multiple, severe Subclinical rejection MHC ag mismatch Preformed anti HLA abs Previous Tx Young recipient Deceased donor DGF CMV infection

Non immune Size mismatch Older donor age Extended criteria donor Proteinuria HTN Dyslipidemia Cigarette smoking BKV infection Pyelonephritis CNI toxicity Recurrent/ Denovo GN Deceased donor Donor brain death

THEORIES OF GRAFT DAMAGE

CHRONIC REJECTION INPUT- STRESS MODEL

CUMULATIVE DAMAGE HYPOTHESIS

THEORIES : CHRONIC REJECTION

Originally, allograft damage was thought simply to

represent alloimmune injury to the transplanted kidney and correspondingly designated as chronic rejection. This pattern of lymphocytic infiltration with characteristic vascular and glomerular changes was commonly described in the prednisoloneAzathioprine era

 Present era : this type of injury is seen in:

a) immunologically active or noncompliant recipients;

b) with excessive prescribed reductions of

immunosuppressive therapy (e.g., following the diagnosis of cancer or late infection); c) when chronic low-level alloimmune activity is histologically manifested by persistent cellular interstitial inflammation and fibrointimal hyperplasia; or with transplant glomerulopathy associated with circulating donor-specific antibody and tissue C4d.

THEORIES: INPUT-STRESS MODEL

Describes the interaction between the starting input of

the transplanted kidney (the overall quality or condition of the organ and early events including procurement, preservation, and reimplantation injury) with a series of subsequent immune and nonimmune stresses, including cellular infiltration; antibody-mediated alloimmunity; and other nonimmune (load) mechanisms, including hypertension, hyperfiltration, proteinuria, dyslipidemia, nephrotoxic drugs, and infection. These stressors have been postulated to drive cells from a normal state into a senescent phenotype, exhaust repair processes, and deplete the finite nephron supply, leading to graft failure.

THEORIES : CUMULATIVE DAMAGE

Based on sequential observational pathology.

Assumes that chronic allograft nephropathy is the

end result of a series of time-dependent immune and nonimmune insults inflicted on the transplanted kidney, resulting in permanent nephron damage.

MECHANISMS OF INJURY
CYTOKINE EXCESS THEORY: postulates CAN is

due to acute and repeated tissue injury inducing excessive cytokine production (e.g., interferon- ), leading to interstitial and vascular fibrosis (by transforming growth factor [TGF]-1).

MECHANISMS OF INJURY
HYPERFILTRATION THEORY : implies that when

individual nephrons are progressively lost, the metabolic load and tubular protein reabsorption from the ultrafiltrate falls onto a diminishing number of remaining nephrons. Hyperfiltration with glomerular hypertension can result in further tubular and glomerular damage. Hyperfiltration may have a deleterious effect only when substantial glomerular loss has occurred, such as in advanced chronic allograft nephropathy or when a small infant donor kidney is transplanted into a large adult.

MECHANISMS OF INJURY
Failure to Resolve Chronic Inflammation. Replicative Senescence : an aging process leading to

cellular exhaustion. Somatic cells after fixed number of division (Hayflick limit), stop cycling and become senescent.
Control of telomere As the cell repeatedly divides, the telomeres progressively shorten, leading to arrest in the G1 phase of the cell cycle and a senescent phenotype.

MECHANISMS OF INJURY
Replicative senescence theory explains why graft

from older donors have a poor outcome. Alternate explanations for poor outcomes from older donor kidneys include: a differential response to injury with age, an impaired ability to withstand stress (e.g., reduced antioxidants and capacity to neutralize ROS), and a limited ability to repair damage once incurred.

Why older age donor graft have poor outcome

preexisting structural abnormalities commonly

present in older kidneys amplify external insults, for example, older donor fibrointimal vascular narrowing may exacerbate downstream glomerular ischemia from superimposed calcineurin inhibitor induced arteriolar hyalinosis and vasoconstriction.

MECHANISMS OF INJURY
Cortical ischemia Internal Architectural Degradation:

PROGRESSION OF HISTOLOGICAL DAMAGE

The pathway of progression from donor kidney to

end-stage disease comprises a time-dependent series of pathological insults causing histological injury that is sequentially overlaid on earlier stages of damage. There are two broad phases of allograft damage observed by sequential biopsy studiesstarting with early tubulointerstitial injury followed by later microvascular and glomerular abnormalities and further progressive fibrosis and tubular atrophy.

Risk factors
Deceased donor: Donor brain death influences graft

outcome by nonspecific effects and by potentiation of graft immunogenicity and alloresponsiveness.

The transplanted organ is not inert but can be

immunologically altered by a cascade of proinflammatory mediators released by brain death, leading to cellular infiltration of the allograft with increased acute rejection episodes.

 The autonomic storm generated by brain death is

accompanied by chaotic blood pressure fluctuations initially with a hypertensive phase from brainstem herniation and massive circulating catecholamine release, followed by hypotension from hypothalamic-pituitary dysfunction, elctrolyte abnormalities CVS dysfunction.

SUBCLINICAL REJECTION
SCR is histologically defined acute rejection

characterized by tubulointerstitial mononuclear infiltration without concurrent functional deterioration (variably defined by a serum creatinine <10%, <20%, or < 25% of baseline values) It is diagnosed only on biopsy specimens taken per protocol

 The prevalence of SCR (acute rejection Banff grade

1a) in 3-month protocol biopsy specimens ranges from 3% to 31%, with borderline SCR ranging from 11% to 41%.
Allografts with SCR result in greater histological

damage on subsequent biopsy specimens, renal dysfunction, and impaired graft Rx SCR : prevents CAN

Tubulointerstitial Injury from BK Virus Nephropathy

BK virus is an endemic polyomavirus infection of

high prevalence, low morbidity, and long latency that may asymptomatically reactivate in immunocompetent individuals.
Acquireed in child hood Persists in renal cortex and medulla Transplanted with renal allograft Tx Asymptomatic reactivation: 10-68% pts on CNI Graft dysfunction: 1-10% Asymptomatic viremia by 3 months post Tx Clinical renal impairemment 3-12 months

BKVAN
Tubular injury, with cellular atypia, viral inclusions

Inflammatory response : monocytes, PMN,

plasmacytoid cells. IHC : SV40T shows viral inclusions EM: 35-38 nm intranuclear paracrystalline viral arrays Viral DNA PCR

CNI nephrotoxicity
Denovo or increasing arteriolar hyalinosis

Striped cortical fibrosis

Isometric tubular vacuolization Tubular microcalcification

Arteriolar hyalinosis
Seen in arterioles : < 3

smooth muscle in media, and incomplete or no intima Due to vacuolization and necrosis of Sm & endothelial cell, and there replacement by protein forming hyaline deposit. Progrssive hyalinosis Classically nodular & is a best diagnostic marker of CNI nephrotoxicity peripheral To rule out: DM, HTN, donor arteriolar hyalinosis, ischemic injury, dyslipidemia

Striped fibrosis
represents an area of

severe tubular damage subjectively defined by a dense striped cortical fibrosis and atrophic tubules demarcated against areas of normal adjacent cortex Pathognomonic

Glomerular changes seen in CAN

Transplant glomerulopathy Ischemic glomerulosclerosis, along with larger

glomeruli (hyperfiltrating)
Atubular glomeruli: glomeruli detached from

tubules.
Small glomeruli, contracted within enlarged glomerular cyst, and may be surrounded by periglomerular fibrosis. Bowmans space is filled by proteinaceous material 1-2 % glomeruli in normal individual 18% of glomeruli in CAN 29% in CNI toxicity

TRANSPLANT GLOMERULOPATHY
thickening or duplication

of the glomerular capillary basement membrane, double contour formation, and mesangial interposition

SCORING
Chronic glomerulopathy scores (designated as Banff

cg) are determined by the extent of peripheral capillary loop involvement of the most affected of nonsclerotic glomeruli, preferably using periodic acidSchiff stains. A score of cg0 is no glomerulopathy, cg1 is 10% to 25% of the most affected peripheral capillary loops, cg2 is 26% to 50%, and cg3 is greater than 50% of affected.

TRANSPLANT GLOMERULOPATHY
ASSOCIATED HISTO FINDINGS:
deposition of subendothelial flocculent or fibrillary material mesangial cellular proliferation with matrix expansion; multilamination, or multilayering, of the PTC basement membrane C4d deposition in glomerular capillaries or PTCs PTC basement membrane multilamination and splitting are defined by electron microscopy and probably indicate Obstructive uropathy past or recent endothelial cell injury with subsequent repair. Analgesic nephropathy Radiation nephritis GRADING : IC Gnitis Mild : 2-4 laminations DM Moderate : 5-6 laminations HTN Severe: > 7 laminations imply rejection Tx kidneys with other Glomerular disease

Chronic antibody mediated rejection

Diagnostic triad :

1. Morphological features of transplant glomerulopathy (Banff score cg1, with double contours on LM), supported by PTC basement membrane multilamination by electron microscopy, and possibly PTC loss
2. Diffuse C4d deposition in PTCs or in glomeruli (assessable only by paraffin sections), or in both 3. The presence of donor-specific antibody to donorHLA or endothelial antigens

Chronic antibody mediated rejection

SUPPORTIVE:
Mononuclear inflammatory cells within the PTCs, Transplant glomerulitis, chronic arteriopathy with fibrous intimal thickening a plasma cell interstitial infiltrate

SUGGESTIVE:
chronic capillary changes are associated with either C4d or donor-specific antibody

ASSESSMENT
usually presents as a decline in glomerular filtration

rate (GFR) or an increase in urine protein excretion.

Diagnosis is therefore delayed All pts with proteinuria and 40 % with nephrotic

range have IFTA on Bx

KIDNEY TX BIOPSY: principles

Transplant biopsy should be considered after clinical

exclusion of obvious causes of dysfunction, such as ureteric obstruction, acute calcineurin inhibitor nephrotoxicity, dehydration, transplant hypoperfusion, uncontrolled hypertension, and sepsis.

KIDNEY TX BIOPSY: principles

Biopsy should be done early before substantial

deterioration in transplant function because late histology with significant damage is often nonspecific, the damage is less responsive to therapy, and it is more difficult to define an etiological diagnosis.

KIDNEY TX BIOPSY: principles

Biopsy samples containing at least 10 glomeruli and 2

arteries are needed to fulfill the Banff adequacy criteria. Samples also should include arterioles (defined as fewer than 3 medial muscle layers and absent or incomplete internal elastic lamina) for assessment of calcineurin inhibitorinduced hyalinosis and Small muscular arteries for assessment of immunemediated fibrointimal hyperplasia (scored as Banff cv). 2 cores needed to identify patchy fibrosis of CNI toxicity Always examine glomeruli & vessels : as pathology in them give definite etiologic diagnosis

KIDNEY TX BIOPSY: principles

Implantation or postperfusion biopsy specimens are

important to distinguish preexisting donor pathology from newer changes and allow comparison of changes over time. If a temporal sequence of histology can be created from the implantation biopsy specimen with other interval biopsy specimens, contemporary histology can be compared with interval clinical events and therapy to aid the interpretation and the etiological assessment of graft dysfunction.

KIDNEY TX BIOPSY: principles

Adequate clinical information should be available to

the interpreting pathologist, including current transplant function; donor quality; previous events, such as delayed function, acute rejection, immunosuppression, and suspected noncompliance; and the cause of recipient end-stage renal failure. A collaborative clinicopathological diagnosis is the optimal way to interpret transplant histology

TREATMENT: principles
Chronic allograft nephropathy is the end result of

multiple pathophysiological pathways of injury . No single magic bullet is likely to be sufficient for its treatment. Rather several therapies and approaches would be needed to counteract the specific and varied etiological insults

TREATMENT: principles
Drivers of injury are time dependent, and therapy ideally

should be initiated before or during periods of ongoing injury. Experimental and clinical data suggest that treatments have different windows of benefit: Some may help early after transplantation only, and others may be detrimental if used late. Therapeutic flexibility of immunosuppression should be maintained. An example would be potent front-loaded calcineurin inhibitor therapy to suppress early rejection, followed by minimal levels to limit nephrotoxicity or infective complications, including BK nephropathy.

TREATMENT: principles
Prevention is better than cure.

Chronic allograft nephropathy and allograft fibrosis

reflect the later expression of prior pathogenic insults. Treatment options need to be exercised early to prevent permanent nephron destruction and to minimize early tubulointerstitial damage and nephron loss from ischemia and alloimmune insults.

TREATMENT

TREATMENT