1. Chronic allograft nephropathy/ Interstitial fibrosis and tubular atrophy(IFTA)/CAN

2. Chronic allograft nephropathy/Interstitial fibrosis and tubular atrophy(IFTA)/CAN

• Both immunological and non immunological factors play a role in graft dysfunction and loss beyond the first 3 months.

• CAN is a histological term used to described the appearance found with progressively declining graft function.

• At 2 years post transplant ,70-90% of grafts will show features of CAN

Ref:Oxford hand book

3.

• • Chronic allograft dysfunction is a clinically defined condition:

• • • • characterized by

• • • • • declining renal function (as evidenced by a slow, progressive decrease in glomerular filtration rate)

• • • • • associated with de novo or aggravated hypertension and worsening proteinuria.

ref:Oxford hand book

4. Contributors of chronic graft failure:

• Alloantigen dependent:

• • Chronic rejection:

• • • Poor HLA matching

• • • Donor specific antibody

• • • Inadequate immunosuppression

• • • Medication non compliance

ref:Oxford hand book

5.

• Alloantigen independent:

• • CNI toxicity

• • • DGF

• • • Prolonged cold ischemia

• • • Reduced nephron number

• • • Increase donor age

• • • Increased BP

• • • Increase lipid

• • • CMV disease

• • • BK nephropathy

ref:Oxford hand book

6. Histology (as was originally agreed on by the Banff classification of 1997)

• Characteristic histological changes include

• • focal tubular atrophy ,

• • interstitial fibrosis and

• • arterial narrowing

• Rejection more likely -> under immunosuppresed

• • Cellular infiltratessubclinical rejection (i.e. unchanged creatinine )

• • Presence of chronic transplant glomerulopathy

• • C4d staining +/- donor specific antibodies

• CNI toxicity more likely (over exposure to CNI):

• • Nodular hyalinosis within arterial wall

• • Stripe fibrosis

ref:Oxford hand book

7. C4d

• In the clinical setting,C4d deposition (as a marker of anti-HLAantibodies) in the peritubular capillaries of the kidney have been correlated with both acute rejection

• and with slowly failing kidney allografts

• C4d staining may be a more sensitive and specific marker than the presence of circulating antibodies because antibodies may be removed

• from the circulation through adsorption to the graft.

• This is in contrast to C4d positivity in only 1 of 21 biopsy specimens that showed CNI toxicity.

• Acute rejection with positive C4d staining is more likely to result from (32%-44%) and also predict the subsequent onset of transplant glomerulopathy and chronic rejection compared with C4d-negative acute rejection (8%-14%).

8. Clinically:

• Usually deteriorating eGFR (months to year) accompanied by increased BP and proteinuria

• It is analogues to CKD in native kidney

ref:Oxford hand book

9.

• Clinically ,CAN presents in one of three ways:

• As a finding in patients undergoing biopsy for an acute increase in serum creatine or proteinuria

• As a finding in patients undergoing biopsy for gradually declining allograft function or proteinuria

• As a finding on a protocol biopsy obtained in patients with no clinical or laboratory abnormality

Ref:Hand book of kidney transplant(Gabriel)

10. Alloantigen dependent risk factors:

• An episode of acute rejection in the first 6 months after transplantation increases the risk for late graft loss by upto 50%.

• Acute rejection that occur late appear to be more predictive of CAN than those that occur during the first 3 months .

• Multiple acute rejections also appear to be more predictive of CAN.

• Deceased donor kidney transplant that have zero MHC mismatches have the best long term allograft survival.

• Detection of preformed antibodies at the time of transplantation and subsequent CAN.

Ref:Hand book of kidney transplant(Gabriel)

11. Alloantigen dependent risk factors..

• Absence of preformed antibodies has correlated with long term allograft survival .

• C4d stain in the evaluation renal transplant biopsy role of ongoing humoral injury in CAN

• 60% of patients with CAN show evidence of antibody mediated Injury

• Higher doses of immunosuppression prevented CAN.

• MMF reduces CAN(but CsA may causes nephrotoxicity )

• Patient who are noncompliant follow up visit ,non compliant with anti hypertensive drug increases risk of CAN

• Acute rejection that occur late (after the first 3 months) appear to be more predictive of CAN than those that occur during the 1 st 3 months.

Ref:Hand book of kidney transplant(Gabriel)

12. Alloantigen Dependent

• Cellular Immune Response

• Humoral Immune Response

• Acute Rejection Episodes

• Histocompatibility Match

• PRA

• Immunosuppression Adequacy

13.

14. Alloantigen independent risk factors:

• Patient with delayed or slow graft function have higher rate of late allograft failure.

• Reduced number of nephron causing CAN

• Expanded criteria donor kidneys are defined by their higher incidence of late graft loss.

• Inadequate no of nephron

• Small kidney into large recipient inadequate nephron dosing precipitated CAN

• CNI interstitial fibrosis

• Cig. Smoking graft vasculopathy CAN

• Higher level of homocystine CAN

• Increase incidence of CMV and other infection CAN

• Proteinuria also causes(causes interstial nephritis) CAN

Ref:Hand book of kidney transplant(Gabriel)

15. CMV infection

• CMV enhanced the expression of endothelial TGF-1 and platelet-derived growth factor proteins in renal allografts causing transplant

• vasculopathy and by up-regulating connective tissue growth factorinduced interstitial fibrosis.

16. Role of Calcineurin Inhibitors in CAN

• the intrinsic nephrotoxicity of these agents and their contribution to CAN has greatly diminished the enthusiasm for their long-term use

• Chronic allograft injury is a fibrogenic response secondary to both proliferative and infiltrative responses mediated by chemokines, cytokines, and growth factors.

• In a naive mouse cyclosporin nephrotoxicity model, administration of TGF-neutralizing antibody has been

• shown to ameliorate CsA-induced morphologic alterations and preserve renal function.

17. Features of CNI Toxicity

• Tubular isometric vacuolization

• Arteriolar medial/peripheral hyaline

• Striped pattern of tubular atrophy and interstitial fibrosis

* Ischemic collapse of glomeruli, Tubular dystrophic calcifications, juxtaglomerular apparatus hyperplasia

18. NATURAL HISTORY OF CAN

• CAN is an almost universal, progressive, time dependent finding.

• It is commonly a composite end point resulting from multiple insults of both donor and recipient origins such as

• ischemia-reperfusion injury, hyperfiltration injury secondary to inadequate renal mass,

• acute/ chronic rejection, recurrent or de novo glomerulonephritis,

• hypertension and metabolic injury such as diabetes and hypercholesterolemia,

• immunosuppression- related side effects including CNI toxicity, and secondary viral and bacterial infections.

• (Ref: Internet)

19.

• the FK 506 Kidney transplant study group which compared treatment with cyclosporine or tacrolimus, showed that 72.3% and 62% of biopsy specimens, respectively, showed CAN at 2 years.

20. longitudinal histologic evolution of CAN

• Ten-year follow-up data on recipients of simultaneous kidney-pancreas transplants

• Two thirds of the fibrosis present by 10 years already had appeared by 1 year,

• Between 1 and 10 years after transplantation, tubular atrophy and interstitial fibrosis progressed simultaneously, with dominant features of chronic CNI toxicity.

• Classic features of CNI toxicity such as striped interstitial

• fibrosis and arteriolar hyalinosis with or without calcification developed almost universally by 10 years.

21.

• Arteriolar hyalinosis appeared between 3 and 12 months after transplantation

• and was associated very strongly with CNI dose.

• By 10 years, 75% of the patients had arteriolar hyalinosis, and in most patients hyalinosis preceded the onset of hypertension.

22.

• Glomerulosclerosis, which represents the final and irreversible destruction of nephrons, was seen in 2 phases.

• Early glomerulo-sclerosis resulted from interstitial fibrosis with development of periglomerular fibrosis and atubular glomeruli.

• The later phase of glomerular destruction was secondary to high-grade arteriolar hyalinosis, resulting in ischemic glomeruli.

23. CAN is a leading cause for renal transplant graft failure 0 10 20 30 40 50 Death with functioning graft Acute rejection CAN Hyperacute rejection Vascular Technical problems Recurrent primary disease Non- compliance Other Death or graft failure (%) Campbell S et al . ANZdata Registry 2007

24. CAN / IFTA: a non-specific descriptive entity defined by pathology Arteriolar hyalinosis Interstitial fibrosis and tubular atrophy GBM double contours Arteriolosclerosis CAN, chronic allograft nephropathy; IFTA, interstitial fibrosis and tubular atrophy; GBM, glomerular basement membrane Fletcher JT et al. Pediatric Nephrol 2009;24:146571

25. Multiple factors contribute to early CAN / IFTA Allo-immunity CNI toxicity Interstitial fibrosis and tubular atrophy De novo DM Chronic obstruction Recurrent disease CAN, chronic allograft nephropathy; IFTA, interstitial fibrosis and tubular atrophy; CNI, calcineurin inhibitor; CMV, cytomegalovirus; I/R, ischaemia / reperfusion; DM, diabetes mellitus Hypertension Polyoma-virus CMV Donor factors I/R-injury

26. Choice of immunosuppressant can influence long-term outcomes ++ ++++ +++ ++ Prednisolone CNIs Everolimus / sirolimus MPA Cancer CVD CAN Prevention of AR Drug CNI, calcineurin inhibitor; MPA, mycophenolic acid; AR, acute rejection; CAN, chronic allograft nephropathy; CVD, cardiovascular disease Long-term outcomes Efficacy

27. Everolimus

• Everolimus: characteristics and mode of action

• Protection against acute rejection

• • Maintain efficacy

• • Reduce nephrotoxicity: CNI minimisation or elimination

• Protection against CMV / BKV infection

• Antiproliferative effects

• • Effect on CAN

• • Potential cardiovascular benefits

• Antitumour effects

• Management of adverse events

CNI, calcineurin inhibitor; CMV, cytomegalovirus; BKV, BK virus; CAN, chronic allograft nephropathy

28. Proliferation Signal Inhibitors: qualities to improve long-term outcomes PSI Protects against opportunistic CMV infection CNI minimisation or elimination prevents nephrotoxicity CNI, calcineurin inhibitor CMV, cytomegalovirus PSI, proliferation signal inhibitor Low incidence of acute rejection Inhibits vascular remodelling Potential cardiovascular benefits Prevention of graft fibrosis Antitumour effects Antiproliferative effects

29. Antiproliferative effects of everolimus ameliorate chronic allograft nephropathy Control (28 weeks)* Normal glomeruli, mild tubular dilation-atrophy and normal artery after 28 weeks Glomerulosclerosis, tubular atrophy, interstitial fibrosis and vasculopathy (insert) after 28 weeks *Preclinical data from transplanted Lewis rats receiving everolimus (0.5 mg/kg/day) or vehicle by daily gavage (control) Lutz J et al. Transplantation 2003;76:50815 Everolimus (1228 weeks)*

30. Measures for early detection of CAN Gold standard used in research protocols All renal transplant recipients Patients at a high risk Measured GFR Protocol biopsy Monitor every month during the first year post-transplant, then 3 monthly Recognise the clinical syndrome Histology + physiology Test new non-interventional tests Ultrasound biopsy Other causes Recurrent glomerulonephritis Renal artery stenosis Ureteric obstruction BK virus nephropathy CAN (tubular atrophy + interstitial fibrosis) OR CAN + CNI nephrotoxicity CAN + transplant vasculopathy CAN + sub-clinical rejection CAN + chronic antibody-mediated rejection (including CTG, DSAb, C4d) THERAPEUTIC INTERVENTION Test novel interventional strategies Absolute serum creatinine Change of serum creatinine (%) Estimated GFR Slope of change of calculated GFR Slope of 1/serum creatinine Other indications of renal change Proteinurie Deterioration of blood pressure JM Campistol et al Clin Transplant 2009;23:769

31. Suspicion of CAN/IFTA by Monitoring

• Absolute serum creatinine

• • > 1.8 mg/dL (or > 130 mol/L)

• Absolute GFR

• • < 50 ml/min

• Change of serum creatinine

• • Irreversible rise of 30% at 6 month post transplant

• • Increase of 0,3 mg/dL (or 20 mol/L) measured 3 x over 3 months

• • 15-20% rise over one year

• Change of GFR

• • 10% deterioration over 3 months

32. Most important things to be in the late post transplant period:

• Minimize immunosuppression whenever possible

• To prevent non compliance.

• Monitor renal function closely.

• Make an accurate pathological diagnosis of the cause of allograft dysfunction.

• Aggressively treat hyperlipaedemia .

• Aggressively treat hypertension.

• Encourage a healthy life style .

• Screen for cancer.

• Prevent infection.

• Protects the bones.

Ref:Hand book of kidney transplant(Gabriel)

33. Prevention and treatment:

• The optimal treatment remains unclear.

• Protocol biopsy suggests subclinical rejection to be frequent early finding and predict subsequent CAN.

• CNI toxicity should be remediable .

• MMF may have anti fibrotic effects independent of immunosuppression .Regimes using low/no CNI and MMF may offer advantages.

• Similarly for Sirolimus ,with CNI avoidance or early withdrawal

• Using MMF or Sirolimus may slow progression of CAN.

• control B.P. with ACE +/- ARB

• Treat hyperlipaedemia.

ref:Oxford hand book

34. Recurrent and de-novo focal and segmental glomerulosclerosis (FSGS) in renal allografts

35.

• Recurrence of original disease following transplantation affects :10-20% of patients and accounts for upto 8% of graft failures at 10 years .

• • Primary (idiopathic) FSGS

• • Secondary FSGS

• • • Familial/genetic (mutations)

• • • Virus-associated (HIV, parvovirus)

• • • Drug-induced

• • • Mediated by adaptive structural-functional responses, e.g.:

• • • - Chronic allograft nephropathy

• • • - Any advanced renal disease with reduction in functioning nephrons

36.

• FSGS can be classified according to the Columbia classification

• Five variants:

• • Tip lesion

• • Cellular variant

• • Collapsing variant

• • Perihilar variant

• • FSGS not otherwise specified

37. Tip lesion and cellular variant

• Tip lesion: located near the origin of the proximal convoluted tubule

• Cellular variant: endocapillary hypercellularity

38. Collapsing and perihilar variant

• Collapsing lesion: collapse of the glomerular tuft with epithelial cell hypertrophy and hyperplasia

• Perihilar variant: predominantly located at the vascular pole

39.

• Transplanted Alports patients may rarely developed de novo anti GBM antibodies and a RPGN as donor alpha 5 type IV collagen is recognized as non self.

• The commonest de novo form of GN post transplant is membranous nephropathy.

• Prim.FSGS recur within days of KT,- NS and graft dysfunction(from ATN) plasma exchange has been used (variable success)

40.