Arteriosclerosis in zero‐time biopsy is a risk factor for tacrolimus‐induced chronic nephrotoxicity

Abstract

ABSTRACT:Aim: Calcineurin inhibitors reduce the acute rejection rate and greatly improve renal allograft survival. However, they are associated with some adverse events, including nephrotoxicity, a risk factor for allograft failure. Chronic calcineurin inhibitor-induced nephrotoxicity causes irreversible damage to renal components, such as arteriolar hyaline thickening. The aim of this study is to investigate the risk factors for tacrolimus-induced chronic nephrotoxicity using zero-time biopsy specimens.Methods: Between January 2001 and December 2010, 483 patients who underwent living-related kidney transplantation and had also been placed on a tacrolimus-based regimen were enrolled in this study. There were 1859 specimens evaluated comprising 483 zero-time biopsy specimens and 1376 protocol and for-cause biopsy specimens. De novo arteriolar hyaline thickening due to tacrolimus-induced chronic nephrotoxicity was scored according to the Banff classification aah score. In this study, tacrolimus-induced nephrotoxicity was defined as a positive aah score. Results:Of the 483 patients, 108 patients (22.4%) had biopsy-proven tacrolimus-induced chronic nephrotoxicity. Multivariate analysis showed that interlobular arteriosclerosis proven by zero-time biopsy (OR: 2.23, 95%CI: 1.38-3.58, P < 0.01) and acute rejection episodes (OR: 1.58, 95%CI: 1.00-2.47, P = 0.04) were independent risk factors for tacrolimus-induced chronic nephrotoxicity. However, tacrolimus-induced chronic nephrotoxicity did not affect long-term graft survival.Conclusion: This is the first report showing that arteriosclerosis in zero-time biopsy specimens is a risk factor for histological tacrolimus-induced chronic nephrotoxicity.There is no doubt that calcineurin inhibitor (CNI) reduce the acute rejection rate and greatly improve short and long-term renal allograft survival. While CNI contributed to an improved clinical course after kidney transplantation, they carry the risk of adverse events including nephrotoxicity, neurotoxicity, glucose intolerance, liver dysfunction, hypertension, neoplasm, and infectious complications. Among them, CNI-induced chronic nephrotoxicity has been considered a significant risk factor for allograft survival and function. Arteriolar hyaline thickening is a typical histological feature of CNI long-term toxicity. [1][2][3][4][5][6] Previous studies have established that chronic CNI nephrotoxicity is a cause of allograft failure. 7 Even with appropriate trough level control, nephrotoxicity is inevitable as long as the patient is exposed to CNIs. However, the risk factors for CNI nephrotoxicity are not yet fully established. At our institution, zero-time renal allograft biopsy has been routinely performed in all cases. We have previously reported that zero-time biopsy data have a strong clinical impact on various aspects of kidney transplantation. 8 In this study, we seek to establish risk factors for CNI toxicity by analyzing our pre-transplant patient characteristics, including zero-time biopsy. METHODSThis retrospective s...

Presence of arteriolar hyalinosis in post‐reperfusion biopsies represents an additional risk to ischaemic injury in renal transplant

“…According to some authors, the presence of AH predisposes to development of arteriolopathy associated with calcineurin inhibitors, which can partly explain the association of AH with poor renal function at 12 months observed in this study. Both renal hypoperfusion and predisposition to nephrotoxicity of calcineurin inhibitors also can explain tubular dysfunction observed at 12 months in the group with AH in this study.…”

Association between periodontal disease and mortality in people with CKD: a meta-analysis of cohort studies

“…Of them, the study by Palmer was reported as a ERA-EDTA conference abstract [ 23 ]. Reasons for exclusion of sixteen studies were overlapped data ( n = 3) [ 28 – 30 ], studies were lack of data ( n = 5) [ 31 – 35 ], commentary study ( n = 1) [ 36 ], inappropriate study design (cross-sectional study, n = 4 [ 37 – 40 ]; intervention study, n = 1 [ 41 ]), inappropriate exposure (tooth loss) n = 2 [ 42 , 43 ]. Figure 1 illustrates our study selection process.…”

“…Adequate evidence revealed that this study, which was based on the ORAL-D cohort study, is the biggest source of heterogeneity among eight included studies. Strangely enough, full-text articles of corresponding data have not yet been published in authority journal, instead, only some related conference abstracts are found [ 23 , 28 ]. Therefore, it is inferred that the reason for such unstable results pooled from large cohorts lies in the existence of the study by Palmer [ 23 ].…”

Risk factors for calcineurin inhibitor nephrotoxicity after renal transplantation: a systematic review and meta-analysis

“… 23 Shimizu and coworkers affirmed the preexistence of moderate- to severe-grade interlobular zero-time arteriosclerosis in an allograft as a risk factor for the development of acute FK506-induced nephrotoxicity. 28 Zero-time arteriosclerosis, identified by biopsy as fibrous intimal thickening of arcuate and interlobular arteries, was associated with transforming growth factor-β (TGF-β) and other profibrogenic molecules, 40 and the fibrotic processes were exactly reckoned as the hallmarks of CNI-induced long-term nephrotoxicity. What was more, TGF-β was closely associated with angiotensin II, which might lead to an uncontrolled activation of the renin–angiotensin system (RAS).…”