Inflammation In Renal Transplant Recipients Research Articles

WCN23-0548 Association of urinary mitochondrial DNA with COVID-19 related acute kidney injury, mitochondrial stress, and inflammation in renal transplant recipients

WCN23-0548 Association of urinary mitochondrial DNA with COVID-19 related acute kidney injury, mitochondrial stress, and inflammation in renal transplant recipients

401.3: Microvascular Inflammation in Renal Transplant Recipients Without Antibody Mediated Rejection

Purpose: Microvascular inflammation (MVI) defined by glomerulitis (g) and peritubular capillaritis (ptc) is a hallmark of ABMR in renal transplantation. The prevalence and significance of MVI in patients without ABMR is less understood. Methods: Here, we analyzed MVI in the 1st post-transplant year, its relationship to DSA, and its clinical significance in a large cohort of patients without ABMR. Along with any for-cause biopsy (fcBx), patients underwent 2 protocol biopsies (pBx, 3 & 12mos). Bx were categorized as early (0-4mos) or late (5-12mos). Serum was screened for DSA at 0, 1, 3, 6, 9 & 12mos post-transplant. Results: MVI Prevalence: 956/1187 patients transplanted between 2013-18 underwent 1950 Bx (67% protocol, 33% for-cause). Of these Bx, 64 had either ABMR or GN and were excluded. MVI was noted in 23% (g+ptc score 1-1.5 in 13% & ≥2 in 10%) of the remaining 1887 Bx with greater prevalence in fcBx (fcBx 14% vs. pBx 7%) and late Bx (late Bx 29% vs. early Bx 17%). Of note, the MVI prevalence and its severity increased with increasing grades of tubulointerstitial inflammation (TII) (Fig 1A). Of note, 65% of patients with allograft infections (pyelonephritis & BKVN) had MVI. MVI & DSA: DSA was detected concurrently in 12% of all the 1887 Bx without ABMR. Although, MVI was associated with concurrent DSA detection in these Bx (OR 1.8, 95% CI 1.3-2.5, p<0.,001), ~60% of the biopsies never had DSA (concurrent/historic or future). Furthermore, in biopsies stratified by the grade of TCMR, there was no significant difference in concurrent DSA detection between patients with and without MVI (Fig.1B). Outcomes: MVI in patients without ABMR was associated with decreased 7yr-graft survival (Fig 1C, p<0.001). Importantly, the combination of MVI and TII was associated with worse graft survival when compared to either no inflammation or TII alone (Fig1C, p<0.001). Further, in a select sub-group of patients with allograft infection, MVI was associated with a trend towards decreased graft survival compared to no MVI (76% vs. 88%). Finally, MVI was associated with poor graft survival independent of potential confounders including DSA (HR 2.5, 95% CI 1.6-3.4, p<0.001). Conclusion: MVI is common even in the absence of ABMR or DSA and is a marker for the severity of allograft inflammation and subsequent poor clinical outcomes.

Platelet-to-Lymphocyte Ratio as a Potential Indicator of Infection-Associated Emergency Visits of Renal Transplant Recipients.

Infection-associated emergency department use in renal transplant recipients has been increasing as solid-organ transplant has become a more common treatment method for chronic kidney failure. Platelet-to-lymphocyte ratio has been demonstrated to be significantly elevated in nosocomial infections in patients treated at intensive care units and is positively correlated with duration of hospital stay. In this study, we aimed to determine whether the platelet-to-lymphocyte ratio could be used as an indicator of infection in renal transplant patients presenting to emergency departments. This case-control retrospective study included data from between May 2015 and February 2018. We used the patient information management system to review patient medical records and laboratory test results of study participants. Our study included 156 adults in the patient group (recipients with infection) and 170 adults in the control group (recipients without infection). We observed significant differences between patient and control groups in terms of the number of days of hospital stay; leukocyte, neutrophil, and lymphocyte counts; the platelet-to-lymphocyte ratio; and C-reactive protein levels. We plotted receiver operating characteristic curves to determine the sensitivity and specificity of the platelet-to-lymphocyte ratio along with C-reactive protein. The areas under the curve were 0.892 for C-reactive protein and 0.707 for the platelet-to-lymphocyte ratio. For systemic inflammation, platelet-to-lymphocyte ratio can be used in conjunction with other biomarkers as an indicator of inflammation in renal transplant recipients who present with infection-associated causes to emergency departments.

Contribution of diminished kidney transplant GFR to increased circulating chemokine ligand 27 level

BackgroundInflammatory chemokine ligands (CCLs) play an important role in cardiovascular disease and allograft injury. CCLs may independently associate with diminished estimated glomerular filtration rate (eGFR) in stable renal transplant recipients (RTR).MethodsPlasma levels of 19 CCLs (1, 2, 3, 4, 5, 8, 11, 13, 15, 17, 21, 24, 26, 27, CXCL5, 8, 10, 12 and 13) were measured in a cohort of 101 RTR. The cohort was divided according to CKD-EPI equation into three groups; group 1: eGFR ≥ 60 ml/min, group 2: eGFR 30–59.9 ml/min and group 3 eGFR ≤ 29.9 ml/min. ANOVA, Krusklwallis, Mann- Whitney Spearman correlation and regression analysis tests were used to determine association between reduced eGFR and inflammatory CCLs plasma levels measured by multiplex techniques. 20 healthy subjects with eGFR above 90 ml/min were included as control. Significance was sat at < 0.05.ResultsLevels of CCLs 1, 4, 15, 27, CXCL8 and CXCL10 were significantly different among the four studied groups. Multivariate regression analysis (MVA) between eGFR and all CCLs demonstrated that CCL27 was the only ligand to remain significantly associated with diminished eGFR {P = 0.021 and r = − 0.35,(P = 0.001)}. In a second MVA between CCL 27 and patient’s demographics and laboratory variables, diminished eGFR, and elevated PTH, out of the twenty one available variables remained significantly associated with elevated CCL27levels.ConclusionDiminished eGFR in stable RTR is associated with elevated plasma levels of CCL27. This association may explain, at least in part, the independent contribution of reduced eGFR to enhanced inflammation in RTR.

A Pilot Trial to Examine the Changes in Carotid Arterial Inflammation in Renal Transplant Recipients as Assessed by 18F-Fluorodeoxyglucose (18F-FDG) Positron Emission Tomography Computed Tomography (PET/CT).

BackgroundInflammatory activity of the artery can be assessed by measuring 18F-fluorodeoxyglucose (18F-FDG) uptake with positron emission tomography computed tomography (PET/CT). Improvement in vascular function after renal transplantation has been reported, but no studies have used 18F-FDG PET/CT to examine the changes in vascular inflammation. This study investigated the changes in the inflammatory activity in the carotid artery after renal transplantation in patients with chronic kidney disease (CKD).Material/Methods18F-FDG PET/CT was performed before and at 4 months after transplantation. We quantified 18F-FDG uptake as the target-to-background ratio (TBR) in the carotid artery in 10 CKD patients. TBR was evaluated in the whole carotid artery (WH) and most-diseased segment (MDS), and the mean and maximum values were analyzed. The concentrations of inflammatory cytokines, including tumor necrosis factor-alpha, interleukin-6, plasminogen activator inhibitor-1, and endothelin-1, were measured.ResultsEight patients showed a decrease in mean or maximum TBR. The average mean or maximum TBRs in the WH and MDS of the right and left arteries were all reduced after transplantation. The average mean TBR for the right WH decreased significantly (% reduction [95% CI]) by −5.74% [−15.37, −0.02] (p=0.047). TBRs did not correlate significantly with cytokine concentrations. The changes in cytokine concentrations after transplantation varied.Conclusions18F-FDG uptake by the WH and MDS tended to reduce after renal transplantation. Therefore, renal transplantation may confer an anti-inflammatory effect on carotid atherosclerosis in patients with CKD; however, this effect is not large enough to be demonstrated in this study with small sample size.

Astaxanthin has no effect on arterial stiffness, oxidative stress, or inflammation in renal transplant recipients: a randomized controlled trial (the XANTHIN trial)

There is evidence that renal transplant recipients have accelerated atherosclerosis that is manifest by increased cardiovascular morbidity and mortality. The high incidence of atherosclerosis is, in part, related to increased arterial stiffness, vascular dysfunction, elevated oxidative stress, and inflammation associated with immunosuppressive therapy. The carotenoid astaxanthin has shown potent antioxidant and anti-inflammatory properties. The aim was to investigate the effects of oral astaxanthin on arterial stiffness, oxidative stress, and inflammation in renal transplant recipients. This trial used a randomized, placebo-controlled, double-blind design in which 61 patients received either 12 mg astaxanthin/d or an identical placebo orally for 1 y. Primary outcomes were 1) arterial stiffness measured by aortic pulse wave velocity (PWV), 2) oxidative stress assessed by total plasma F2-isoprostanes, and 3) inflammation assessed by plasma pentraxin-3. Secondary outcomes included vascular function, carotid artery intima-media thickness, augmentation index, central blood pressure, subendocardial viability ratio, and additional measures of oxidative stress and inflammation. Patients underwent assessments at baseline and at 6 and 12 mo. Fifty-eight participants completed the study. There were no significant between-group differences in the changes in any of the primary outcome measures (PWV changed by +9.5% and +6.0%, F2-isoprostanes changed by -3.0% and -9.7%, and pentraxin-3 changed by +50.6% and -11.0% in the placebo and astaxanthin groups, respectively). There were no significant between-group differences in secondary outcome measures. Larger-than-expected variability decreased the power of the study and increased the possibility of a type 2 statistical error. Astaxanthin (12 mg/d for 12 mo) had no effect on arterial stiffness, oxidative stress, or inflammation in renal transplant recipients. This trial was registered at the Australian New Zealand Clinical Trials Registry (http://www.anzctr.org.au/) as ACTRN12608000159358.

The perils of immunosuppression minimization: lessons from protocol biopsies of renal allografts.

To emphasize the pathogenicity of subclinical cellular inflammation in renal transplant recipients, and its relation to poor graft outcomes and the development of de-novo donor-specific antibody (DSA). Protocol biopsies have identified the gene signatures of innate and adaptive immunity in patients with minimal inflammation that correlate with the subsequent development of graft interstitial fibrosis, transplant glomerulopathy and antibody-mediated rejection. The risks of immunosuppression minimization, especially in HLA mismatched donor-recipient pairs, are highlighted. The major cause of renal allograft loss is immunological and a contributor to this is the minimization of immunosuppression. The prevention of premature graft loss requires better matching of class II HLA antigens, the targets of de-novo DSA, and monitoring for subclinical inflammation rejection with protocol biopsies or urine chemokines.

Effects of a Diet Rich in N-3 Polyunsaturated Fatty Acids on Systemic Inflammation in Renal Transplant Recipients

Objective: n-3 Polyunsaturated fatty acids (PUFAs) supplementation reduces systemic inflammation and improves renal and cardiovascular prognosis in kidney transplant recipients. However, patient compliance is poor because bad-tasting fish oils are used as an n-3 PUFA source. Therefore, we explored whether the beneficial effects of n-3 can be obtained by administering a diet based on n-3-rich foods. Methods: Sixty kidney transplant recipients were assigned to 2 different groups: the CON group (n = 28), which continued with their usual diet, and the DIET group (n = 32), which followed an n-3-rich diet for 6 months. Twenty-six patients in the DIET group and 24 in the CON group completed the study. End points of the study were changes in n-3 PUFAs intake, n-6:n-3 PUFAs ratio, systemic inflammation markers, and renal function during the 6 months of the dietary treatment. Results: Three and 6 months after the beginning of the study, n-3 PUFA intake was significantly higher and the n-6:n-3 PUFA ratio was markedly lower than baseline in the DIET group. Plasma total cholesterol, triglycerides, C-reactive protein, and interleukin (IL)-6 decreased as well. IL-6 mRNA levels in peripheral blood mononuclear cells were also lower than at the beginning of the study. Proteinuria and microalbuminuria were reduced by 50% with respect to the baseline, whereas glomerular filtration rate (GFR) was unchanged. No change in the aforementioned parameters was observed in the CON group throughout the study. Conclusion: In long-term kidney transplant recipients a naturally n-3 PUFA-rich dietary plan causes an increase in n-3 PUFA intake, decreases systemic inflammation and proteinuria, and improves plasma lipid pattern.

Periodontal inflammation in renal transplant recipients receiving Everolimus or Tacrolimus – preliminary results

To compare oral health status between renal transplant recipients (RTRs) receiving tacrolimus (Tac) or everolimus (ERL) as immunosuppressive therapy. This study is a cross-sectional study. Thirty-six RTRs receiving Tac and 22 RTRs receiving ERL were included in the study. Age, gender, time since transplant and pharmacological data were recorded for both groups. Oral health status was assessed through the evaluation of teeth, periodontal parameters as well as saliva flow rate and pH. RTRs receiving ERL were older than those receiving Tac. No differences were found between groups concerning oral hygiene habits, oral symptoms, smoking habits, unstimulated and stimulated saliva flow rate and pH, clinical attachment level or the number of decayed, missing and filled teeth. However, RTRs receiving ERL presented lower visible plaque index and lower values for bleeding on probing when compared to RTRs receiving Tac. In addition, RTRs receiving ERL presented a gingival index varying from normal to moderate inflammation whereas RTRs receiving Tac presented a gingival index varying from mild to severe inflammation. RTRs receiving ERL have lower periodontal inflammation when compared to RTRs receiving Tac.

Anaemia in Renal Transplant Recipients: Is There a Role for Hepcidin?

Introduction and aims: Anaemia following renal transplantation is common and multi-factorial, with a prevalence of 20 to 57%. Hepcidin is a peptide hormone produced by hepatocytes in response to iron loading and inflammation. Renal dysfunction is associated with increased hepcidin levels, possibly contributing to the development of anaemia by dysregulation of iron homeostasis. Hepcidin has been investigated with great interest in patients with non-transplant chronic kidney disease, including the dialysis population. However, it has received relatively little attention in renal transplant population. The aims of this study were to evaluate the associations between hepcidin and renal function, iron status and inflammation in renal transplant recipients. Methods: In this cross-sectional study, patients who were at least 1 year post renal transplant were recruited. Haemoglobin (Hb), C-Reactive Protein (CRP), Albumin (Alb), Ferritin (Ferr) and Transferrin Saturation (TSAT) were assessed using standard laboratory methods. Estimated Glomerular Filtration Rate (eGFR) was estimated using MDRD formula. Serum hepcidin-25 levels were determined by mass spectrometry using stable isotope labelled synthetic hepcidin-25 as an internal standard. Results: Sixty-four patients were enrolled. Gender: 55% male and 45% female. Mean age: 51 years (22-77). Ethnicity: Caucasian 81%, Asian 10%, African/Caribbean: 9%. Types of kidney donation: 69% deceased donor and 31% living donor. Mean time post transplantation: 8 years (1-22). Mean eGFR = 44.10 ± 16.81 mL/min. Mean Hb = 12.71 ± 1.44 g/dL. Hepcidin correlated significantly with Hb (r = -0.24, p < 0.05) and eGFR (r = -0.36, p < 0.005). The significant correlation between hepcidin and Hb disappeared when adjusted for eGFR (r = -0.17, p = 0.19). Hepcidin did not correlate with CRP (r = 0.09, p = 0.47), Alb (r = -0.05, p = 0.72), Ferr (r = 0.37, p = 0.32) and TSAT (r = 0.03, p = 0.84). Conclusions: Hepcidin may be of limited utility as an anaemia biomarker in this relatively uninflamed and iron replete population. Nevertheless, the possibility remains that the link between anaemia and reduced eGFR may be mediated by hepcidin, which may potentially give rise to specific therapeutic strategies in this population.

Subclinical Inflammation in Renal Transplant Recipients: Impact of Cyclosporine Microemulsion Versus Tacrolimus

Background Renal insufficiency and renal transplant (RT) provoke a microinflammatory state that leads to increased atherosclerosis. It is not fully known whether calcineurin inhibitors (CNIs) play a role in the inflammation observed in these patients or whether any differences exist between CNIs. Objectives The study aimed to establish differences in the inflammatory state of two groups treated with cyclosporine microemulsion (CyA) or tacrolimus (TC). Patients and methods This prospective study included 81 RT patients divided into two groups according to the CNI: CyA group, n = 35 versus TC group, n = 46. The markers of inflammation (MIF) were determined preRT and at 3 and 12 months’ postRT: C-reactive protein (CRP), serum amyloid protein A (SAA), interleukin-6 (IL-6), soluble interleukin-2 receptor (sIL-2R), tumor necrosis factor-alpha (TNF-α), and pregnancy-associated plasma protein A (PAPP-A). Samples were collected in stable patients in the absence of rejection, active infection, or inflammatory processes. Results No significant differences existed between the markers of inflammation in the two treatment groups prior to transplantation. At 3 months’ posttransplant, patients treated with CyA showed significantly higher levels of IL-6 ( P = .05), SAA ( P = .03), and sIL-2R ( P = .008) compared with patients treated with TC. These differences were maintained for IL-6 ( P = .03) and sIL-2R ( P = .027) at 12 months’ posttransplant. A multivariate analysis at 3 months showed that only age [OR 10.1; CI (95% 2.6–38.4); P = .001], SAA [OR 4.8; IC (95% 1.4–16.5); P = .015], and sIL-2R [OR 4.9; IC (95% 1.5–16.2); P = .009] were independent predictors of the CNI used. At 12 months, age [OR 3.7; IC (95% 0.9–14.2] and sIL-2R [OR 6.04; IC (95% 1.5–23); P = .006] continued to be independent predictors. Conclusions Patients treated with CyA displayed significantly higher levels of inflammatory markers (IL-6, SAA, sIL-2R) at 3 and 12 months’ posttransplantation, independent of age, gender, time on dialysis, diabetes mellitus (preRT and de novo postRT), and renal function measured by serum creatinine.

Serum C-Reactive Protein Surge in Renal Transplant Recipients: Link With Allograft Survival

The restoration of kidney function by transplantation improves the common finding of chronic inflammation in patients with end-stage renal disease (ESRD). The C-reactive protein (CRP) level is a reliable marker of inflammation in renal transplant recipients. We analyzed the predictive value of posttransplant CRP surges on renal allograft survival among 141 ESRD patients who underwent renal transplantation between May 1999 and September 2001 at our institution. Twenty-seven cadaveric and 114 living donors were also studied. The subjects’ demographic, clinical, and laboratory data were recorded. The renal transplant recipients were divided into three groups defined by the type of serum CRP surge: a normal, intermittently high, or consistently high serum CRP concentration. Renal allograft survival rates were 90.0% among recipients with normal serum CRP concentrations, 72.6% among those with intermittently high concentrations, and 11.1% in those with consistently high concentrations. A Cox regression analysis of factors that affect allograft survival showed that acute rejection, advanced recipient age, and consistently high serum CRP concentrations were associated with a high risk of renal allograft loss. Intermittent elevations in the serum CRP level were not associated with an increased risk of allograft loss, according to the Cox regression model. We concluded that consistently high serum CRP concentrations in renal allograft recipients showed a high negative predictive value for renal allograft survival. In recipients who exhibited ongoing inflammatory process in the 5-year posttransplant period, additional efforts are necessary to manage inflammation and therefore prolong renal allograft survival.

Glycated haemoglobin levels are related to chronic subclinical inflammation in renal transplant recipients without pre-existing or new onset diabetes

C-reactive protein (CRP), a marker of chronic subclinical inflammation (CSI), is related to cardiovascular mortality in the general and renal transplant populations. In the general population, high CRP levels are associated with pre-diabetic glucose homeostasis alterations which may contribute to the proatherogenic effect of CSI. We studied 134 consecutive renal transplant recipients without pre-existing or new onset diabetes. CRP, oral glucose tolerance test, insulin sensitivity and HbA1c were measured. Among CRP tertiles, fasting glucose and glucose after 120 min were not different. However, HbA1c was higher (4.9+/-0.6; 5.2+/-0.5; 5.4+/-0.5; P=0.005] and insulin sensitivity lower (McAuley index: 7.2+/-2; 6.8+/-2; 6.2+/-1.3; P=0.042) in the third CRP tertile. In addition, HDL-cholesterol was lower and triglycerides and body mass index (BMI) higher in the third tertile. Consequently, metabolic syndrome was more prevalent in the upper CRP tertiles [11 (25%); 19 (43%); 22 (50%); P=0.01). In multivariate analyses, HbA1c was related to higher CRP levels (standardized beta coefficient=0.21, P=0.013), independently of BMI (standardized beta coefficient=0.24, P=0.005) and triglycerides (standardized beta coefficient=0.18; P=0.03). Subclinical glucose homeostasis alterations are related to chronic inflammation in renal transplant recipients without pre-existing or new onset diabetes and may contribute to their high cardiovascular mortality.

A Clinical Study of Gingival Inflammation in Renal Transplant Recipients Taking Immunosuppressive Drugs

The relationship between the gingival inflammation and plaque scores of patients who had received kidney transplants and were taking immunosuppressive drugs to combat rejection pheomena was compared with data from a control group. Equivalent plaque scores were associated with less gingival inflammation in the patients taking the immunosuppressive drugs. While there was no signficant difference between the plaque scores of the two groups the control group displayed signficantly more gingival inflammation. The implications of these results with respect to possible etiological mechanisms operating in periodontal disease are discussed.