Failed renal allograft is one of the most common causes of ESKD, reaching about 25-30 % of ptns on KTx waiting list
Failed renal allograft is one of the most common causes of ESKD, reaching about % of ptns on KTx waiting list. Also, > % 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 1st 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:
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.
Several risk factors, allo-Ag dependent and independent, appear to be contributing in the pathogenesis of chronic allograft dysfunction.
Allo-Ag-dependent risk factors
Allo-Ag-independent factors: allo-Ag-independent mechanisms may include:
Characteristic Histological findings: CAN is characterized by the finding of IF/TA. The pathologic alterations may be also affecting the BV & glomeruli.
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:
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 1st 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 1st 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.
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:
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:
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.
Similar histological findings: CAN must be DD histologically from disorders causing universal IF and/or a MPGN pattern on renal biopsy:
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 1st 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 1st 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., ng/mL for Tac and 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):
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.