The Spectrum of Renal Allograft Failure

Abstract

Background: Causes of "true" late kidney allograft failure remain unclear as study selection bias and limited follow-up risk incomplete representation of the spectrum.

Methods: We evaluated all unselected graft failures from 2008-2014 (n = 171; 0-36 years post-transplantation) by contemporary classification of indication biopsies "proximate" to failure, DSA assessment, clinical and biochemical data.

Results: The spectrum of graft failure changed markedly depending on the timing of allograft failure. Failures within the first year were most commonly attributed to technical failure, acute rejection (with T-cell mediated rejection [TCMR] dominating antibody-mediated rejection [ABMR]). Failures beyond a year were increasingly dominated by ABMR and 'interstitial fibrosis with tubular atrophy' without rejection, infection or recurrent disease ("IFTA"). Cases of IFTA associated with inflammation in non-scarred areas (compared with no inflammation or inflammation solely within scarred regions) were more commonly associated with episodes of prior rejection, late rejection and nonadherence, pointing to an alloimmune aetiology. Nonadherence and late rejection were common in ABMR and TCMR, particularly Acute Active ABMR. Acute Active ABMR and nonadherence were associated with younger age, faster functional decline, and less hyalinosis on biopsy. Chronic and Chronic Active ABMR were more commonly associated with Class II DSA. C1q-binding DSA, detected in 33% of ABMR episodes, were associated with shorter time to graft failure. Most non-biopsied patients were DSA-negative (16/21; 76.1%). Finally, twelve losses to recurrent disease were seen (16%).

Conclusion: This data from an unselected population identifies IFTA alongside ABMR as a very important cause of true late graft failure, with nonadherence-associated TCMR as a phenomenon in some patients. It highlights clinical and immunological characteristics of ABMR subgroups, and should inform clinical practice and individualised patient care.

Fig 1. Causes of graft failure by period following transplantation.

Fig 2. Relationship between proteinuria (early morning “spot” albumin:creatinine ration; UACR) and percentage glomerulosclerosis in patients with IFTA on indication biopsy proximate to graft failure (n = 25).

Fig 3. Characteristics of patients displaying TCMR on indication biopsy.

Microcirculation injury evident in 4 patients. None displayed circulating donor-specific HLA antibodies or C4d staining and therefore did not fulfil current criteria for ABMR. In addition to interstitial infiltrates these patients displayed the following: glomerulitis n = 1; chronic transplant glomerulopathy n = 1; chronic transplant glomerulopathy with nonadherence n = 1; glomerulitis and chronic transplant glomerulopathy with nonadherence n = 1.

Fig 4

Breakdown of causes of graft failure beyond 5 years (4a), 10 years (4b) and 15 years (4c) post-transplantation, with each figure representing the graft failure distribution between the time point mentioned and the time of graft failure. Note therefore that graft failures comprising each summary figure will overlap, but the temporal relationships can be discerned by presenting the data in this way.