Risk Of Chronic Allograft Dysfunction Research Articles

Impact of statin treatment and exposure on the risk of chronic allograft dysfunction in Chinese lung transplant recipients

PurposeChronic lung allograft dysfunction (CLAD) was a common complication following lung transplantation that contributed to long-term morbidity and mortality. Statin therapy had been suggested to attenuate recipient inflammation and immune response, potentially reducing the risk and severity of CLAD. This study aimed to evaluate the impact of statin use and in vivo exposure on the incidence of CLAD in lung transplant recipients (LTRs), as well as their effects on immune cells and inflammatory factors. MethodsA retrospective cohort study was conducted on patients who underwent lung transplantation between January 2017 and December 2020. The incidence of CLAD, as per the 2019 ISHLT criteria, was assessed as the clinical outcome. The plasma concentrations of statin were measured using a validated UPLC-MS/MS method, while inflammation marker levels were determined using ELISA kits. ResultsThe statin group exhibited a significantly lower rate of CLAD (P = 0.002). Patients receiving statin therapy showed lower CD4+ T-cell counts, total T-lymphocyte counts, and IL-6 levels (P = 0.017, P = 0.048, and P = 0.038, respectively). Among the CLAD groups, the atorvastatin level (2.51 ± 1.31 ng/ml) was significantly lower than that in the non-CLAD group (OR = 1.438, 95%CI (1.007–2.053), P = 0.046). ConclusionStatin therapy significantly reduced the incidence of CLAD, as well as immune cell counts and inflammatory cytokine levels in LTRs. Although the statin exposure was significantly lower in CLAD patients, it was not associated with the incidence of CLAD.

Early posttransplant reductions in club cell secretory protein associate with future risk for chronic allograft dysfunction in lung recipients: results from a multicenter study

Chronic lung allograft dysfunction (CLAD) increases morbidity and mortality for lung transplant recipients. Club cell secretory protein (CCSP), produced by airway club cells, is reduced in the bronchoalveolar lavage fluid (BALF) of lung recipients with CLAD. We sought to understand the relationship between BALF CCSP and early posttransplant allograft injury and determine if early posttransplant BALF CCSP reductions indicate later CLAD risk. We quantified CCSP and total protein in 1606 BALF samples collected over the first posttransplant year from 392 adult lung recipients at 5 centers. Generalized estimating equation models were used to examine the correlation of allograft histology or infection events with protein-normalized BALF CCSP. We performed multivariable Cox regression to determine the association between a time-dependent binary indicator of normalized BALF CCSP level below the median in the first posttransplant year and development of probable CLAD. Normalized BALF CCSP concentrations were 19% to 48% lower among samples corresponding to histological allograft injury as compared with healthy samples. Patients who experienced any occurrence of a normalized BALF CCSP level below the median over the first posttransplant year had a significant increase in probable CLAD risk independent of other factors previously linked to CLAD (adjusted hazard ratio 1.95; p=0.035). We discovered a threshold for reduced BALF CCSP to discriminate future CLAD risk; supporting the utility of BALF CCSP as a tool for early posttransplant risk stratification. Additionally, our finding that low CCSP associates with future CLAD underscores a role for club cell injury in CLAD pathobiology.

SAT-325 ASSOCIATION OF CYP3A5 POLYMORPHISM WITH TACROLIMUS LEVELS AND GRAFT OUTCOMES IN INDIAN KIDNEY TRANSPLANT RECIPIENTS

Tacrolimus which is the sheet anchor of post-transplant immunosuppression has a narrow therapeutic index. It is imperative to achieve therapeutic tacrolimus levels for optimum graft survival as sub-optimal levels can predispose to graft rejections and toxic levels pose a risk of nephrotoxicity. The inter-individual variations in the pharmacokinetics of tacrolimus can be in part attributed to polymorphism in Cytochrome P450 (CYP) enzymes. The expressor [CYP3A5*1/*1] status leads to faster metabolism of tacrolimus than that in non- expressors [CYP3A5*3/*3]. Although it is well known that these differences in genotype affect tacrolimus levels, but their effect on long term graft outcome is equivocal. It is not proven that knowing the genotype pre-transplant and adjusting the induction dose accordingly improves graft outcomes. We aim to evaluate the association of CYP3A5 genotypes on tacrolimus trough levels and graft outcomes in adult and pediatric kidney transplant recipients. In this single-center study, consecutive kidney transplant recipients, both pediatric and adults, on tacrolimus therapy for atleast 3 months were enrolled. Genotyping was done using PCR-RFLP for CYP3A5 *1/*1, [expressors] *1/*3,[intermediate expressors] *3/*3 [non -expressors] polymorphisms., and patients were divided into these 3 groups. These groups were analyzed with retrospectively available data for differences in dose-adjusted tacrolimus levels at 1,3,12 months and graft outcomes - acute biopsy-proven rejection, chronic rejection, chronic allograft dysfunction, new-onset proteinuria, eGFR at 1,3,12 months and at last followup available, and graft loss. All groups received 0.1mg/kg/day dose of tacrolimus on day 0 of transplant and then the levels were modified according to subsequent trough tacrolimus levels. Out of 142 patients, 26% were females. Median age 48yrs, 11/142 had age <18 yrs. 16% were expressors[CYP3A5 *1/*1], 40.6% were intermediate[CYP3A5*1/*3], 43.4% were non-expressors[CYP3A5*3/*3]. Dose adjusted tacrolimus trough levels were significantly higher in non-expressors at 1 month [p=0.001], 3 months [p=0.015], 12 months [p=0.018]. Acute biopsy proven rejections were more in expressors [31.4%vs 22.6% p =0.042]. Also, chronic rejections were more in expressors [21%vs 6.53% p = 0.044] Non-expressors had higher incidence of chronic allograft dysfunction [48.4% vs 25.2% p=0.0004]. After being started with 0.1mg/kg/day of tacrolimus, expressors requied more dose escalations to reach therapeutic targets - median 3[0-6] vs 0[0-3] p =0.04. Non-expressors required more dose reductions to achieve targets - median 7[4-13] vs 2.5[0-16] p=0.02. The prevalence of non-expressors [CYP3A5 *3/*3] was 43.4% in Indian transplant recipients. When started at 0.1mg/kg/day dose, expressors had higher rates of subtherapeutic levels requiring more dose-escalation, while non-expressors required dose reductions due to supratherapeutic levels. Graft rejections both acute and chronic were more common in the expressors while non-expressors were at a higher risk of chronic allograft dysfunction. Our data support the use of pretransplant CYP3A5 genotyping to facilitate the individualization of tacrolimus dosing. Genotype guided dosing from the day of transplantation can improve graft outcomes by reducing nephrotoxicity [due to high doses] and rejections [due to suboptimal doses].

Association between TGFB1 genetic polymorphisms and chronic allograft dysfunction: a systematic review and meta-analysis

BackgroundEpidemiological studies have investigated the role of transforming growth factor-β1 (TGF-β1) in chronic allograft dysfunction (CAD) following kidney transplantation. TGFB1 gene polymorphisms (SNP rs1800470 and rs1800471) may be associated with the risk of CAD. In this meta-analysis, the relationship between these two variations and the risk of CAD was explored.Materials and MethodsMEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), Embase, the Chinese CNKI and WANFANG databases were searched. Data were extracted and pooled results were estimated from odds ratios (ORs) with 95% confidential intervals (95% CIs). Quality assessments were performed, and publication bias of all eligible studies examined.ResultsEight studies with 1038 subjects were included in our analysis. According to the effects on TGF-β1 secretion, haplotypes were categorized as “HIGH”, “INTERMEDIATE” and “LOW”. The combined results showed a statistically significant difference of TGFB1 haplotypes between the CAD recipients and control subjects when “HIGH” with “INTERMEDIATE” and “LOW” (“HIGH” vs. “INTERMEDIATE” + “LOW”: OR: 3.56, 95% CIs: 2.20, 5.78, P < 0.001) were compared. No significant association was found between the TGFB1 codon 10 or codon 25 and the CAD risk in all five genetic models.ConclusionsOur meta-analysis has found the haplotype of TGFB1 codon 10/25 T/T G/G and T/C G/G genotypes, associated with increased production of TGF-β1, was linked with CAD risk following kidney transplantation. Moreover, no significant difference was found between TGFB1 codon 10 or codon 25 and the development of CAD.

Acute cellular rejection elicits distinct microRNA signatures in airway epithelium of lung transplant patients.

Acute cellular rejection (ACR) is a common complication in lung transplantation and associated with increased risk of chronic allograft dysfunction. MicroRNAs are critical controllers of cellular transcription whose expression can be altered in disease states. The purpose of this pilot study was to evaluate whether microRNA profiling of epithelial cells obtained from airway brushings can distinguish lung transplant patients with ACR from those without rejection. We studied 21 subjects (10 with ACR, 11 without ACR) and assessed the expression of over 700 microRNAs in their airway epithelium. We identified 117 differentially expressed microRNAs that robustly segregated the two groups, and were uniformly downregulated in patients with ACR. Leveraging experimentally verified microRNA targets, we systematically mapped pathways and processes regulated by ACR-induced microRNAs and noted enrichment of programs involved in development, proliferation, migration, and repair. Collectively, our study suggests that ACR is associated with a distinct epithelial microRNA signature that can provide insight into the pathogenesis of acute rejection and potentially serve as a sensitive, minimally invasive biomarker tool for diagnostic and prognostic stratification of lung transplant patients.

(839) - Viral Pneumonia Accelerates Graft Death and CLAD in Lung Transplant Recipients

Community acquired respiratory virus (CARV) infections occur frequently after lung transplantation. We hypothesized that severe infection would increase the risk of chronic allograft dysfunction and graft death, while asymptomatic carriage would not.

Pharmacogenetics and drug-induced nephrotoxicity in renal transplant recipients.

Introduction: The advent of calcineurin inhibitors (CNIs), as the leading immunosuppressive agents, not only has revolutionized the transplant medicine but also made it a better therapeutic intervention that guarantees the graft outcome and improves the survival rate of patients. However, genetic polymorphism(s) in the CNIs metabolic substrates genes (CYP3A4, CYP3A5) and their transporter such as P-glycoprotein (P-gp) can influence the CNIs metabolism and elicit some possible systemic and intra-renal exposures to drugs and/or metabolites with differential risk of nephrotoxicity, jeopardizing the transplantation. Methods: In the current study, we review the recent literatures to evaluate the effects of genetic polymorphisms of the genes involved in development of chronic calcineurin nephrotoxicity and progression of chronic allograft dysfunction (CAD) providing an extensive overview on their clinical impacts. Results: Identifying the inherited genetic basis for the inter-individual differences in terms of drug responses and determining the risk of calcineurin-mediated nephrotoxicity and CAD allow optimized personalized administration of these agents whith minimal adverse effects. Conclusion: Pharmacogenetics characteristics of CYP isoforms (CYP3A) and efflux transporters (P-gp and MRP), involved in metabolism and extracellular transportation of the immunosuppressive CNIs, can be of pivotal information in the pharmacotherapy of the renal-transplant recipients. Such information can be used for the successes clinical interventions to attain an improved drug administration strategy with reduced rates of rejection and toxicity.

The Rate of Decline of Glomerular Filtration Rate Is a Predictor of Long-term Graft Outcome After Kidney Transplantation

BackgroundTo improve the long-term outcome of kidney transplantation (KT), it is important to identify and take active steps to reduce the number or severity of novel risk factors. We investigated whether changes in estimated glomerular filtration rate over the first year after KT (ΔeGFR12-3) was associated with long-term renal allograft function and survival. MethodsFour hundred twenty-eight allograft recipients transplanted between 1990 and 2001 underwent ΔeGFR12-3 calculation using the equation: ΔeGFR12-3 = ([eGFR at 12 months post-KT − eGFR at 3 months post-KT]/[eGFR at 3 months post-KT]) × 100%. Recipients were divided into 3 groups according to their ΔeGFR12-3: group I (n = 150), ΔeGFR12-3 ≥ 10%; group II (n = 151), 10 > ΔeGFR12-3 ≥ −10%; and group III (n = 127), ΔeGFR12-3 < −10%. Multiple linear regression analysis was used to adjust for confounding variables that may affect long-term renal allograft function, and Kaplan-Meier analysis, to compare allograft survival. ResultsAt a mean follow-up of 120 ± 58 months, we observed 112 renal allograft losses. The ΔeGFR over 10 years post-KT (ΔeGFR120-3) was significantly associated with the serum uric acid levels at 3 months post-transplantation and ΔeGFR12-3. Group III showed poor renal allograft survival; group I, 194 ± 8 months; group II, 197 ± 7 month and; group III, 163 ± 4 months; (log-rank test, P < .05). A Cox proportional hazard model revealed ΔeGFR12-3 to be independently associated with future renal allograft loss (hazard ratio, 0.981; 95% confidence interval, 0.974–0.992). ConclusionOur results suggested that ΔeGFR12-3 may be an independent predictor of kidney allograft survival. Routine application of eGFR is strongly recommended to identify patients at risk for chronic allograft dysfunction.

Do Intraoperative Hemodynamic Factors of the Recipient Influence Renal Graft Function?

PurposeTo assess the importance of intraoperative management of recipient hemodynamics for immediate versus delayed graft function. MethodsThe retrospective study of 1966 consecutive renal transplants performed in our department between June 1980 and December 2009 analyzed several perioperative hemodynamic factors: central venous pressure (CVP), mean arterial pressure (MAP) as well as volumes of fluids, fresh frozen plasma (FFP), albumin, and whole blood transfusions. We examined their influence on renal graft function parameters: immediate diuresis, serum creatinine levels, acute rejection, chronic transplant dysfunction, and graft survival. ResultsMean CVP was 9.23 ± 2.65 mm Hg and its variations showed no impact on graft function. We verified a twofold greater risk of chronic allograft dysfunction among patients with CVP ≥ 11 mm Hg (P < .001). Mean MAP was 93.74 ± 13.6 mm Hg; graft survivals among subjects with MAP ≥ 93 mm Hg were greater than those of patients with MAP < 93 mm Hg (P = .04). On average, 2303.6 ± 957.4 mL of saline solutions were infused during surgery. Patients who received whole blood transfusions (48%) showed a greater incidence of acute rejection episodes (ARE) (P = .049) and chronic graft dysfunction (P < .001). Patients who received FFP (55.7%), showed a higher incidence of ARE (P < .001). Only 4.6% of patients (n = 91) received human albumin with a lower incidence of ARE (P = .045) and chronic graft dysfunction (P = .024). Logistic binary regression analysis revealed that plasma administration was an independent risk factor for ARE (P < .001) and chronic dysfunction (P = .028). Volume administration (≥2500 mL) was also an independent risk factor for chronic allograft dysfunction (P = .016). Using Cox regression, we verified volume administration ≥ 2500 mL to be the only independent risk factor for graft failure (P < .001). ConclusionMAP ≥ 93 mm Hg and perioperative fluid administration <2500 mL were associated with greater graft survival. Albumin infusion seemed to be a protective factor, while CVP ≥ 11 mm Hg, whole blood, and FFP transfusions were associated with higher rates of ARE and chronic graft dysfunction.

Plasminogen Activator Inhibitor-1 in Chronic Kidney Disease

In 1984, Loskutoff et al. ([1][1]) purified plasminogen activator inhibitor-1 (PAI-1) from conditioned media of cultured endothelial cells. This 50-kd glycoprotein is the primary physiologic inhibitor of the serine proteases tissue-type and urokinase-type plasminogen activators (tPA and uPA,

Assessment of the Risk of Chronic Allograft Dysfunction after Renal Transplantation in a Randomized Cyclosporine Withdrawal Trial

We report the two-year follow-up of a trial comparing the three-month postgraft discontinuation of either cyclosporine (CsA) or mycophenolate mofetil (MMF) from a triple-drug regimen after de novo renal transplantation. One hundred and eight patients were enrolled in this study and randomized to be withdrawn from CsA (MMF group, n=54) or MMF (CsA group, n=54). Despite an increased risk of acute rejection and a lower, but nonsignificant, two-year graft survival, CsA withdrawal induced a sustained improvement of the renal function. At one year, the chronic allograft damage index was similar in both the MMF and CsA groups. However, CsA elimination resulted in a higher incidence of C4d deposits, irrespective of the occurrence of a prior acute rejection. While this finding could suggest a risk of chronic rejection in the MMF group, the outcome did not appear to be related to the C4d status. Moreover, logistic regression analysis showed that only two factors, acute rejection and the one-year glomerular filtration rate level, were predictive of a significant decline of the renal function at two years. These results point out the need to secure the minimization of the calcineurin inhibitors after renal transplantation, in order to reduce the risk of acute rejection in these patients, because this strategy allows the improvement of the one-year renal function which is predictive of a chronic allograft dysfunction.

Two-Hour Postdose Concentration: A Reliable Marker for Cyclosporine Exposure in Adolescents With Stable Renal Transplants

In pediatric renal transplant recipients, most patients receive maintenance treatment with cyclosporine (CsA) and mycophenolate mofetil (MMF). Until now, the 2-hour postdose CsA target level for combined maintenance treatment with MMF has not been defined. This prospective pilot study evaluated the pharmacokinetics of CsA under the influence of MMF to determine a reliable single CsA concentration time that correlates with the area under the curve (AUC 0–6h) estimates for adolescents who were additionally treated with MMF during the late posttransplant period. The study included 13 adolescents (mean posttransplantation time, 3.5 ± 2.55 years) with stable renal transplant function (S-Crea 121 ± 40 μmol/L). CsA pharmacokinetic absorption profiles over a 6-hour dose interval ( n = 26) were evaluated for the optimal single peak concentration using the CsA concentrations predose (C 0) and at 1, 2, 3, 4, and 6 hours postdose (C 1–6). Whereas C 2 (mean 743.2 ± 221.8 ng/mL) was the single point with the closest correlation to AUC 0–6h ( r 2 = 0.86; P < .001), C 0 (mean 120.5 ± 35.2 ng/mL) showed the weakest correlation ( r 2 = 0.61, P = .002). C 2 appears to be an accurate predictor of CsA exposure in adolescent kidney transplant recipients under maintenance immunosuppression in combination with MMF. Average values achieved with current dosing practices cluster around the target C 2 ranges recommended for adults. The data provide a foundation for initiation of prospective clinical trials to assess the long-term risk for chronic allograft dysfunction among pediatric stable renal transplant patients in combination protocols.

ANGIOTENSINOGEN AND PLASMINOGEN ACTIVATOR INHIBITOR‐1 GENE POLYMORPHISM IN RELATION TO CHRONIC ALLOGRAFT DYSFUNCTION

Chronic allograft dysfunction (CAD) is the most common cause of allograft failure in the long‐term, and current immunologic strategies have little effect on this condition. The renin‐angiotensin system (RAS) plays important roles in hypertension and progression of chronic renal disease. It is thought that plasminogen activator inhibitor‐1 (PAI‐1) functions in the RAS, in addition to involvement in thrombotic risk and fibrosis. This study investigated possible links between angiotensinogen (AGT) genotypes (M235T/MM, MT, TT) and PAI‐1 genotypes (4G4G, 4G5G, 5G5G) and CAD assessments of both types of polymorphism were performed in 82 renal allograft recipients (47 males and 35 females; mean age 34.87±11.22 years). One hundred healthy subjects (54 males and 46 females; mean age 35.54±10.26 years) were also investigated for AGT polymorphism, and 80 healthy subjects (45 males and 35 females; mean age 36.54±12.41) for PAI‐1 polymorphism. Genotypes were determined using polymerase chain reaction sequence‐specific primers, and polymerase chain reaction followed by restriction fragment length polymorphism analysis.Kidney recipients with CAD had significantly lower frequencies of the MM genotype and the M allele than those without CAD. (P&lt;0.05 and P&lt;0.001, respectively) Presence of the MT genotype was significantly associated with CAD, and this genotype introduced a 3.5‐fold risk of CAD compared with the MM genotype (P&lt;0.05; 95% confidence interval: 1.21–10.20). The transplant recipients with CAD also had significantly lower frequencies of the 5G/5G genotype and the 5G allele than those without CAD (P&lt;0.001 and P&lt;0.05, respectively). Presence of the 4G allele introduced a 1.94‐fold risk of CAD compared with the 5G allele (95% confidence interval: 1.05–3.66). Determination of AGT M235T and PAI‐1 genotypes before transplantation may help identify patients who are at risk for chronic renal transplant dysfunction.

Corticosteroid Withdrawal after Renal Transplantation in the Cyclosporin Era

In an effort to eliminate the well-known adverse effects of long term corticosteroid therapy, a number of transplant centres have attempted to withdraw corticosteroids at various times following renal transplantation. Reported benefits of corticosteroid withdrawal in patients maintained on cyclosporin-based immunosuppressive regimens have included accelerated growth in children, improvements in hypertension, reductions in total cholesterol levels and improved glycaemic control for diabetic patients. However, results from single centres, and from meta-analyses of randomised prospective trials, suggest that corticosteroid-free immunosuppression is associated with an increased risk of acute allograft rejection when compared with treatment with corticosteroid-based regimens. In addition, some long term follow-up studies suggest that withdrawal of corticosteroids may increase the risk of chronic allograft dysfunction. In the cyclosporin era, the risks of corticosteroid withdrawal outweigh the benefits in a substantial minority of patients. A number of new immunosuppressants may prove to be more corticosteroid-sparing than cyclosporin, and promise to increase the safety of corticosteroid-free immunosuppression for renal transplant recipients.