CAN

Failed renal allograft is one of the most common causes of ESKD, reaching about 25-30 % of ptns on KTx waiting list

 

CAN

 

 Abbreviations: (Read twice please and leave comment please)

  

o   Ac Rj: acute rejection

o   ACEi: angiotensin-converting enzyme inhibitor

o   Ag: antigen

o   AMR: active antibody-mediated rejection

o   APO: Acute pulmonary edema

o   ARB: angiotensin II receptor blocker

o   Aza: azathioprine

o   BKPyV: BK polyomavirus

o   BM: basement membrane

o   BP: blood pressure

o   BV: Blood vessels

o   CAN: Chronic allograft nephropathy

o   CNIs: calcineurin inhibitors

o   CT: connective tissue

o   CyA: cyclosporine

o   DD: Differential diagnosis

o   DGF: Delayed graft function

o   Dgx: diagnosis

o   DSAs: donor-specific antibodies

o   EM: electron microscopy

o   ESKD: end-stage kidney disease

o   Evrol: Everolimus

o   GBM: glomerular basement membrane

o   GFR: glomerular filtration rate

o   GN: glomerulonephritis

o   GSc: glomerulosclerosis

o   HCV: hepatitis C virus

o   HT: hypertension

o   IF/TA: interstitial fibrosis/tubular atrophy

o   IF: immunofluorescence

o   IF: interstitial fibrosis

o   IgA Np: immunoglobulin A nephropathy

o   im/m: immunosuppression/immunosuppressive

o   KPT: kidney-pancreas transplant

o   KTR: kidney transplant recipients

o   KTx: kidney transplant/transplantation

o   LM: light microscopy

o   Methyprd: Methylprednisolone

o   MMF: Mycophenolate mofetil

o   MPGN: membranoproliferative glomerulonephritis

o   mTORi: mTOR inhibitors

o   Np: Nephropathy

o   PCR: polymerase chain reaction

o   Pr/Cr: protein-to-creatinine

o   Pred: Prednisone

o   RAS: renal artery stenosis

o   RCT: randomized controlled trials

o   SCr: Serum creatinine concentration

o   SKP: simultaneous kidney-pancreas Tx

o   SRL: Sirolimus

o   Tac: Tacrolimus

o   TCMR: T cell-mediated rejection

o   TG: transplant glomerulopathy

o   TMA: thrombotic microangiopathy

o   TR: transplant recipients

o   Ttt: treatment

o   Tx Np: transplant nephropathy

o   Tx: transplant centers

o   Tx: transplantation

o   US: ultrasound

o   UTI: urinary tract infections

 

 

Failed renal allograft is one of the most common causes of ESKD, reaching about 25-30 % of ptns on KTx waiting list. Also, > 20 % of KTx in the US performed to ptns who have lost one of more kidney grafts. The most common cause of allograft failure after the 1^st y is not well understood clinicopathologically and called (CAN; or IF/TA). CAN is a histopathological entity, rather than a specific disorder referring to the criteria of chronic IF & TA within graft tissues. It has been named before chronic rejection, Tx Np, chronic graft dysfunction, TG, or chronic graft injury. I will review the pathogenetic nature, pathology, Dgx, and control of CAN:

TERMINOLOGY

CAN: is a histopathologic term, rather than a specified disorder referring to chronic IF & TA within allograft tissues. This term was early introduced in 1991 by the Banff system replacing the popular/misleading name "chronic rejection". The idea was to correct the mis concept that all late scarring process of graft tissues was induced by alloimmune Rj. However, the term CAN subsequently applied in Tx literature has promoted the mis concept that CAN was a specified disease entity, rather than pathological term for non-specific allograft tissue scarring. Moreover, application of CAN as a generic term for all causes of chronic graft dysfunction with fibrosis was considered to limit the attempts recognizing the background etiology of the histological alterations, some of them could be correctable.

Consequent revision in Banff 2005 system replaced CAN with IF/TA, without evidence of any specific etiology". This was done to differentiate specific diagnostic entities (e.g., chronic AMR, chronic active TCMR, CNI toxicity, & BKPyV-associated Np) from a non-specific fibrotic subtype of CAN. However, the newer term IF/TA is no more or less disease specified than CAN.  

Chronic allograft dysfunction: is defined as a clinical entity characterized by a slow (over weeks/mo), progressive decline of allograft function, commonly associated with HT & worsened proteinuria. It may be induced by several causes, including CAN, recurrent/de novo GN, BKPyV-associated Np, late/recurrent Ac Rj, RAS, and sometimes, ureteric obstruction.

 

RISK FACTORS FOR CHRONIC ALLOGRAFT INJURY

Several risk factors, allo-Ag dependent and independent, appear to be contributing in the pathogenesis of chronic allograft dysfunction.

Allo-Ag-dependent risk factors

o   Acute Rj: is a robust risk factor for developing CAN. Incidence of CAN is <1 % in ptns lacking any episodes of Ac Rj. In contrary, incidence of CAN is greater with history of Ac Rj: 20 % for living-related & 36 % for deceased kidneys, if Ac Rj seen within 60 ds post-Tx, and 43 % for living-related & 60 % for deceased kidneys, if seen > 60 d. post-Tx. Risk of CAN is greater with multiple attacks of Ac Rj, late Rj attacks (>6 mo post-Tx), and high severity of the Ac Rj attacks.

o   im/m regimens: Robust im/m may help prevent acute, subclinical, and/or chronic immunologic Rj, supplying certain protection against CAN evolution. However, some im/m agents, especially CNIs, may contribute to long-term graft dysfunction that’s hardly to DD from CAN.  

Allo-Ag-independent factors:  allo-Ag-independent mechanisms may include:

o   HT

o   DGF

o   Hyperlipidemia

o   Glomerular hyperfiltration & hypertrophy

o   Superadded recurrent/de novo GN.

PATHOLOGY

Characteristic Histological findings:  CAN is characterized by the finding of IF/TA. The pathologic alterations may be also affecting the BV & glomeruli.

o   Interstitium: variable degrees of patchy fibrosis & focal cellular infiltrates with lymphocytes/plasma cells + variable degree of tubular atrophy & tubular drop-out. These non-specific changes are also seen in many disorders, e.g., CNI toxicity. CAN severity can be graded according to severity of IF and the intensity of atrophy & tubular loss.

o   BV: Vascular walls are thickened by the accumulated subintimal loose & then organized CT, mononuclear cell infiltration, proliferated myofibroblasts, and disrupted & duplicated internal elastic lamina. The endothelial inflammation/ injury may be one of the earlier events > progressive intimal thickening with narrowed vascular lumen simulating those of the TMA.  

o   Glomeruli: thickened glomerular capillary wall with occasional double-contour simulating MPGN but dense deposits are lacking. The glomerulus may be enlarged with lobular pattern; segmental or, may show global sclerosis. E/M: mesangial cell interposition + accumulated subendothelial electron-lucent material. Immune complex deposition is not seen.

Natural history of CAN: considering the natural history of CAN was given by a report of 120 kidney-pancreas TR undergoing sequential protocol biopsy (s) along 10-y post-Tx. According to the post-Tx timing, 2 types of histological injuries, early & late, could be determined:

o   Early damage, observed over one y post-Tx, due to immunologic factors, e.g., severe Ac Rj, continued early subclinical Rj, and ischemic injury.

o   After one y, progressive high-grade arteriolar hyalinosis, narrowed vessel, GSc, and tubulointerstitial injury that could be attributed to CNI toxicity. Of note, chronic immune Rj was uncommonly seen with continued follow-up.

After 10 ys follow up, intense allograft Np was found in 60 % of TR, with GSc seen in almost 40 % of glomeruli suggesting that several ttt plans for CAN, based partially on the timing post-Tx (preventing Rj in the 1^st y, in stable ptns, limited CNI exposure in next y.), may be efficacious. However, next reports of adult TR of solitary KTx (1998-2004) were suggesting intense histological changes are not commonly seen in the 1^st 5 y.s after Tx. Variabile severity of histological changes given by these 2 reports may be reflecting the variability in the rate of Ac Rj with SKP Tx performed in early im/m era with high levels of CyA-based im/m compared with more recent solitary KTx, or reflecting sequalae of frequent dehydration/recurrent UTI related to bladder-drained pancreas in KPT.

DIAGNOSTIC ASSESSMENT

Suspecting CAN:  suspected in any KTR presenting with chronic graft dysfunction (i.e., slow, progressive decline in graft function, with HT & worsened proteinuria).

Chronic allograft dysfunction: In KTR presenting with chronic graft dysfunction, the target of diagnostic assessment is to recognize the potential cause(s) of progressive allograft dysfunction. A suggested approach is the following:

o   Renal US + Doppler renal artery, for graft sizing/echogenicity & exclude RAS.  

o   Evaluate proteinuria via spot urine Pr/Cr ratio. If >1 g/d, > allograft biopsy.

o   Evaluate the finding and strength/titers of DSAs.  

o   Recognize the presence of BKPyV via blood viral loading.  

There’s great variability among Tx to obtain tissue material for histological studies. It’s the author’s opinion that graft histology is beneficial to confirm the Dgx and to exclude other variables, e.g., Ac Rj or recurrent GN. Moreover, the percutaneous kidney graft biopsy is providing prognostic view assisting ptns counseling.

Evaluation of IF/TA:  CAN intensity can be classified quantitatively according to the magnitude of IF and tubular loss/atrophy (IF/TA) in graft biopsy:

o   Grade I: Mild IF (i.e., involving 6-25 % of the cortical zone) and mild TA (i.e., up to 25 % of cortical tubules)

o   G. II: Moderate IF (i.e., involving 25-50 % of cortical tubules) and moderate TA (i.e., involving 26-50 % of cortical tubules)

o   G. III: Severe IF (i.e., involving >50 % of the cortical area) and TA (i.e., involving >50 % of the cortical tubules)

DD: Differential Dgx of CAN may involve several factors inducing progressive graft dysfunction and/or showing similar histological findings.  

Progressive graft dysfunction: beside CAN, crucial causes of chronic graft dysfunction may include chronic AMR, diabetic kidney (recurrent or de novo), recurrent/de novo GN, BKPyV-associated Np, late Ac Rj, & RAS.

1)    Chronic AMR: Chronic AMR, one of the most common causes of chronic allograft failure, may show slowly progressive graft dysfunction like CAN. It can be DD from CAN histologically by the finding of C4d staining in the peritubular capillaries that’s lacking in CAN. Positive DSAs may also supporting the Dgx of chronic AMR and excludes the Dgx of CAN.  

2)    Diabetic kidney disease: Recurrent or de novo diabetic kidney may induce progressive graft dysfunction among diabetic TR. It can be DD from CAN by the finding of specific histologic findings e.g., diffuse or nodular expanded mesangial, (termed "Kimmelstiel-Wilson nodules") & GSc.

3)    Recurrent/de novo GN: can induce progressive graft dysfunction with long-term graft loss. Prior history of biopsy-proved glomerular disease in the native kidneys with findings on graft biopsy may help DD recurrent glomerular disease from CAN. De novo GN, most commonly caused by IgA Np or an immune complex GN, is also Dgx via graft biopsy. IF & EM testing of the graft biopsy should be included if such Dgx is considered.

4)    BKPyV-associated Np: Typically presenting with subacute progressive graft dysfunction. Dgx is considered by the finding of viral particles in blood (or urine) via PCR. Dgx is established by particular findings on graft biopsy, especially those with immunohistochemical and/or ultrastructural testing via E/M.  

5)    Late or recurrent Ac Rj: commonly seen due to non-adherence to im/m regimen or under-im/m due to early weaning of im/m by physicians.

6)    RAS: ACEi/ARB provided to a TR with Tx RAS can induce reversible drop in GFR. So, rising SCr in this setting is highly suggestive, but not diagnostic, of graft RAS. Persistently higher HT, flash APO, and an acute rise in BP are other commonly seen with RAS. Dgx is based on imaging results.  

Similar histological findings: CAN must be DD histologically from disorders causing universal IF and/or a MPGN pattern on renal biopsy:

1)    IF: The finding of severe IF due to CAN must be DD from other causes of fibrosis, especially the typical "striped fibrosis" of CNIs toxicity (e.g., CyA or Tac). Here, characteristic glomerulopathy or the finding of peritubular capillary BM splitting & lamination is mostly consistent with CAN. On contrary, newly developed hyaline arteriolar lesions is related to CyA nephrotoxicity. However, CAN is not always linked to these criteria, and the arteriolar lesions suggestive of CyA toxicity may not be recent. It’s therefore commonly difficult or impossible to DD between these two entities, according to microscopic finding alone. Some TR also have alterations of both disorders.  

2)    MPGN: The MPGN pattern of TG must be DD from other glomerular disorders, particularly MPGN that’s related to HCV infection or to recurrent/de novo disease. These disorders may appear similar on LM. Distinctive Dgx can be made via E/M that’s typically shows thickening & duplication of GBM without immune deposits in TG; by comparison, there’re prominent subendothelial immune deposits in HCV-related MPGN. HCV positivity alone is not enough to conclude the distinction, as it may be found concomitantly with CAN.  

 

 

LM of TG shows MPGN pattern: capillary wall thickening + double-contour owng to mesangial interposition (arrow).

 

PREVENTION & ttt

The prevention/ttt of CAN still the most common 2 problems challenging Tx nephrologists. Several CAN prevention/management plans, based partially on timing post-Tx, could be of benefit. In the 1^st y, efforts should be directed at preventing Rj, and in the following years among stable ptns, efforts should be focused on limiting the exposure to CNIs. However, there’s no definitive therapy available for stabilized CAN, and all TR will inevitably proceed to ESKD.

Prevention of Rj: Given the role of Ac Rj attacks in CAN evolution, preventive measures aiming at preventing Rj episodes, particularly in the 1^st y post-Tx, should help preventing chronic graft dysfunction. Triple maintenance im/m therapy, in a regimen of CNI (Tac is mostly utilized in the US, despite CyA sometimes used), Pred, and an antimetabolite. Despite the increasing risk of CAN related to CNI, we may consider that im/m benefits outweigh its adverse impacts. Added preventive measures may include optimized HLA matching, limiting ischemic injury (that enhance proinflammatory cytokines), and to avoid sensitization.

Modification of im/m: Several im/m attitudes and changes in protocols have been assessment to decline the risk of enhancing CAN development. These include regimens with/without CNIs, addition/substituting mTORi (e.g., SRL or Evrol), substituting MMF for Aza. However, amended im/m agents have greatly been ineffective in correcting the prognosis for ptns with settled CAN.

Reduction of CNI exposure: In ptns with settled CAN on CNIs therapy, some evidence suggesting that decreasing such therapy may be efficacious in impeding progressive allograft dysfunction. TR with settled CAN on triple im/m with CNI, Pred, & antimetabolite, minimizing CNI (lowered-than-standard dosing) rather than holding (gradual removal of CNI) or conversion (switch from CNI to an alternate im/m agent) of CNI therapy. Minimizing CNI via lowered trough levels (e.g., 3.5-5 ng/mL for Tac and 75-125 ng/mL for CyA). Holding CNI has been complicated with more Ac Rj and the evolution of DSAs and is NOT currently advised.

2016 meta-analysis: 88 RCT assessed the outcome of 4 different regimens to limit CNIs exposure, including minimizing (via lowered-than-standard CNI dosing), converting (switching from CNI to an alternate im/m member after Tx), holding (gradual CNI removal after Tx), and avoiding (avoided CNI from the time of Tx):

o   Minimizing CNIs, if combined with MMF, resulted in better graft function, less risk of biopsy-proven Ac Rj, & lowered rate of allograft loss. Whilst minimizing CNIs, if combined with mTORi, had no effect on Ac Rj or graft loss.

o   Conversion protocols had no impact on any endpoint; withdrawal plans may augment the risk of Ac Rj.

o   9 trials tested avoidance strategies via variable replacement im/m agents (i.e., belatacept, mTORi). Generally, avoidance plans did not offer any benefit.  

CyA vs Tac: Tac is the most commonly utilized CNI agent among KTR in the US, despite CyA is still sometimes used. Registry and limited trial data conclude similar long-term ptn & graft survival rates for ptns on Tac & CyA. In ptns with settled CAN on CyA, we do not routinely shift to Tac, as converting CyA to Tac has not been shown to impede CAN progression.

One trial, 150 KTR assigned to one of 3 maintenance im/m: Tac + SRL, Tac + MMF, or CyA + SRL. All ptns receiving induction therapy with daclizumab & maintained on Methyprd. Ptn & allograft survival were similar in all 3 g. at 3 ys. There was tendency to better graft function & fewer Ac Rj with Tac + MMF associated with significant decline in post-Tx DM & dyslipidemia. Similarly shown, better protection from chronic graft dysfunction with Tac-based protocol than with CyA-based one were reported in a protocol biopsy trial.

However, other reports have shown: converted CyA to Tac does not decline CAN progression. One trial: 106 CyA-ttt ptns with biopsy-proven CAN and impaired graft function were assigned to convert to Tac or continue on CyA. At 5 ys, graft survival was similar in both groups (73 & 81 % for the Tac and CyA g.s, resp).

MMF Use: Another strategy using MMF instead of Aza, to prevent or ttt of settled CAN receiving Aza on maintenance im/m. This substitution may help ameliorating progressive allograft dysfunction, e.g., One study: initial im/m of 121 ptns with biopsy-proved CAN were either CyA + Pred (59 ptns) or CyA + Pred + Aza (62 ptns). If being provided, Aza was held, and replaced by MMF (2 g./d.). Follow-up for 36 mo, alteration in the GFR slope was obviously better with MMF. Benefits also reported in minimizing CNI protocols in which MMF is combined with the CNI.  

Steroid withdrawal: holding Steroids to prevent CAN is not advised, as it has been complicated by higher risk of CAN. RCT: compares early Steroid withdrawal with low-dosing, long-term Steroids (Pred 5 mg/d) in KTR on recent maintenance im/m, both rates of biopsy-proven Ac Rj (18 vs 11 %) and CAN (10 vs 4 %) were greater in the Steroid withdrawal arm, despite CAN was not a definite endpoint.

Additional measures: Other supportive maneuvers to prevent CAN evolution may include tight control of BP & hyperlipidemia. BP control: it’s still unclear if ACEi/ARBs provide specific benefit by declining the intraglomerular pressure. We could be reluctant using these agents in KTR owing to the higher risk of hyper-K⁺ & diminished renal perfusion. Review: 21 RCT with 1549 ptns assessing the effects of ACEi/ARBs in KTR showed no enough data assessing the impacts on graft/ptns longevity; none of the trials particularly including ptns with CAN.

Retrospective studies have reported conflicting findings on allograft & ptn survival. Ptns with CAN, retrospective studies suggest a possible benefit with ACEi/ARBs in slowing the rate of drop in graft function. Despite reversing metabolic acidosis may slow the progression of CKD in non-Tx ptns, there have been no available studies reporting the KTR. Other maneuvers, may include antiplatelet agents, thromboxane antagonists, fish oil, and protein restriction, have not been proven to be efficacious in human reports and currently neglected.

FUTURE CONCEPTS: An emerging role for gene expression profiling of peripheral blood or in graft biopsy tissue to recognize ptns at higher risk of fibrosis & allograft loss and who may get benefits from therapeutic regimens to impede the progressive fibrosis.