Chronic allograft nephropathy

A T U L D E S A I

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CHRONIC ALLOGRAFT NEPHROPATHY

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 10 year survival

DECEASED 91% 58%

LIVING 90% 77%

LATE GRAFT DYSFUNCTION

Graft dysfunction > 3 months of transplant

Cause :

TRUE GRAFT DYSFUNCTION

50 %

DEATH WITH FUNCTIONING GRAFT• Cardiovascular event• Infections• Malignancies

CHRONIC ALLOGRAFT DYSFUNCTION

• Recurrent disease• Denovo disease• CNI toxicity• Infections• CHRONIC ALLOGRAFT NEPHROPATHY

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 aIF & TA only

TYPE bIF & TA + glomerular &

vascular changes

Sclerosing / fibrosing typeCommon 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 months90 % protocol biopsies at 1 year

Nankivell BJ, Borrows RJ, Fung CL, et al. The natural history of chronic

allograft nephropathy. N Engl J Med. 2003;349:2326-2333.

120 pts with type 1 DMAll but 1 with SPKFollowed for 10 yrs

Biopsy done 961

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 prednisolone-Azathioprine 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 fibrointimalhyperplasia; 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- γ), leading to interstitial and vascular fibrosis (by transforming growth factor [TGF]-β1).


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.


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 telomereAs the cell repeatedly divides, the telomeres progressively shorten, leading to arrest in the G1 phase of the cell cycle and a senescent phenotype.


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.


Cortical ischemia

Internal Architectural Degradation:

PROGRESSION OFHISTOLOGICAL 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 studies—starting 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, elctrolyteabnormalities 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 VirusNephropathy

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.

Classically nodular & peripheral

To rule out: DM, HTN, donor arteriolar hyalinosis, ischemic injury, dyslipidemia

Progrssive hyalinosis is a best diagnostic marker of CNI nephrotoxicity

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 individual18% of glomeruli in CAN29% in CNI toxicity


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 acid–Schiff 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.


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 splittingare defined by electron microscopy and probably indicatepast or recent endothelial cell injury with subsequent repair.

GRADING : • Mild : 2-4 laminations• Moderate : 5-6 laminations• Severe: > 7 laminations imply rejection

• Obstructive uropathy• Analgesic nephropathy• Radiation nephritis• IC Gnitis• DM• HTN• 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:

SUGGESTIVE:

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

• 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.


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.


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 calcineurininhibitor–induced hyalinosis and

Small muscular arteries for assessment of immune-mediated 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


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.


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


Drivers of injury are time dependent, and therapy ideally should be initiated before or during periods of ongoinginjury.

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 calcineurininhibitor therapy to suppress early rejection, followed by minimal levels to limit nephrotoxicity or infective complications, including BK nephropathy.


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

Health & Medicine

Chronic allograft nephropathy