tacrolimus and Primary-Graft-Dysfunction

Chronic, progressive, and irreversible loss of a transplanted kidney function, previously named chronic allograft nephropathy, is the leading cause of chronic allograft failure among kidney transplant recipients. Chronic allograft dysfunction (CAD) is a multifactorial process associated with progressive interstitial fibrosis and tubular atrophy. Current Data confirms that an additive series of time-dependent immunological factors such as acute and chronic antibody- and/or cell-mediated rejection and nonimmunological factors are involved in development of interstitial fibrosis and tubular atrophy as the fundamental parts of CAD. The use of calcineurin inhibitors has produced a major impact on achieving successful organ transplantation; however, although this assumption has been doubted recently, calcineurin inhibitors are deemed to be associated with nephrotoxicity and subsequent interstitial fibrosis, tubular atrophy, and kidney dysfunction. The early fibrotic changes are due to implantation stress, T-cell-mediated rejection, and infection; however, usually they do not lead to progressive fibrosis and allograft dysfunction per se. In the setting of CAD, many factors occurring lately after 1 year, such as chronic antibody-mediated rejection, recurrent or de novo glomerulonephritis, and nonadherent adequately address the existence of ongoing injuries and progression to fibrosis. Identification of patients who are at risk, close clinical monitoring, and optimization and individualization of their maintenance immunosuppressive regimen are among the means that could help us to improve the long-term outcome of kidney transplantation.

Topics: Calcineurin Inhibitors; Chronic Disease; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Mycophenolic Acid; Postoperative Complications; Primary Graft Dysfunction; Tacrolimus; Transplantation, Homologous

Diarrhea in kidney transplant recipients influences outcome of transplantation. Data from India in this regard are sparse and do not address the differential outcome of infective and non-infective diarrhea. We studied the demographic data, laboratory findings, treatment response, disease duration, and outcome of diarrhea in kidney transplant recipients, and the differential outcome between infective and non-infective diarrhea, if any.. All kidney transplant recipients who were referred to the Division of Gastroenterology with diarrhea between June 2015 and February 2017 were prospectively included. Demographic, clinical and laboratory data, graft function, treatment administered, and outcome were noted, and the patients were followed up for 3 months.. Forty-seven patients (median age 45 years, range 16-78; 34 men) with 64 episodes of diarrhea were studied. Thirty-three (51.5%) episodes were attributed to infections. Eleven (17%) were immunosuppressant-induced (mycophenolate 8, tacrolimus 2, cyclosporine 1). Twenty (31%) were due to other causes (antibiotics 6, laxatives 3, irritable bowel syndrome 3, sepsis 8). Fifty-three episodes (82%) had graft dysfunction during the diarrheal episodes. Mean increase in serum creatinine was 45% in the infectious diarrhea group and 95% in the non-infectious diarrhea group (p < 0.05). Median time to resolution of diarrhea was 3 days. With improvement in diarrhea, return to pre-diarrhea creatinine levels occurred in 87% of episodes at 3 months.. One-half of episodes of diarrhea in kidney transplant recipients were non-infectious in origin. Seventeen percent were attributed to immunosuppressants, requiring dose modification. More than 80% were associated with worsening of graft function. Recovery of graft function to baseline was seen in a majority of cases with the resolution of diarrhea.

Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Diarrhea; Female; Humans; Immunosuppressive Agents; Irritable Bowel Syndrome; Kidney Transplantation; Laxatives; Male; Middle Aged; Primary Graft Dysfunction; Prognosis; Prospective Studies; Retrospective Studies; Tacrolimus; Treatment Outcome; Young Adult

Chronic allograft dysfunction (CAD), defined as the replacement of functional renal tissue by extracellular matrix proteins, remains the first cause of graft loss. The aim of our study was to explore the potential role of the cannabinoid receptor 1 (CB1) during CAD. We retrospectively quantified CB1 expression and correlated it with renal fibrosis in 26 kidney-transplanted patients who underwent serial routine kidney biopsies. Whereas CB1 expression was low in normal kidney grafts, it was highly expressed during CAD, especially in tubular cells. CB1 expression significantly increased early on after transplantation, from day 0 (D0) to month 3 post-transplant (M3) (22.5% ± 15.4% vs 33.4% ± 13.8%, P < .01), and it remained stable thereafter. CB1 expression correlated with renal fibrosis at M3 (P = .04). In an in vitro model of tacrolimus-mediated fibrogenesis by tubular cells, we found that tacrolimus treatment significantly induced mRNA and protein expression of CB1 concomitantly to col3a1 and col4a3 up regulation. Administration of rimonabant, a CB1 antagonist, blunted collagen synthesis by tubular cells (P < .05). Overall, our study strongly suggests an involvement of the cannabinoid system in the progression of fibrosis during CAD and indicates the therapeutic potential of CB1 antagonists in this pathology.

Topics: Animals; Cells, Cultured; Chronic Disease; Female; Fibrosis; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Mice; Mice, Inbred C57BL; Middle Aged; Primary Graft Dysfunction; Receptor, Cannabinoid, CB1; Retrospective Studies; Tacrolimus

Pregnancy after solid organ transplantation is becoming more common, with the largest recorded numbers in renal and liver transplant recipients. Intestinal transplantation is relatively new compared to other solid organs, and reports of successful pregnancy are far less frequent. All pregnancies reported to date in intestinal transplant recipients have been in women with stable graft function. The case reported here involves the first reported successful term pregnancy in an intestine-pancreas transplant recipient with chronic graft dysfunction and dependence on both transplant immunosuppression and parenteral nutrition (PN) at the time of conception. Pregnancy was unplanned and unexpected in the setting of chronic illness and menstrual irregularities, discovered incidentally on abdominal ultrasound at approximately 18 weeks' gestation. Rapamune was held, tacrolimus continued, and PN adjusted to maintain consistent weight gain. A healthy female infant was delivered vaginally at term. Medical complications during pregnancy included anemia and need for tunneled catheter replacements. Ascites and edema were improved from baseline, with recurrence of large volume ascites shortly after delivery. Successful pregnancy is possible in the setting of transplant immunosuppression, chronic intestinal graft dysfunction, and long-term PN requirement, but close monitoring is required to ensure the health of mother and child.

Topics: Adult; Female; Gastrointestinal Stromal Tumors; Humans; Immunocompromised Host; Immunosuppressive Agents; Infant; Intestines; Pancreas Transplantation; Parenteral Nutrition; Pregnancy; Pregnancy Outcome; Pregnancy, High-Risk; Primary Graft Dysfunction; Sirolimus; Tacrolimus; Transplant Recipients

Macrophages are involved in the development and progression of kidney fibrosis. The aim of this study was to analyse the phenotype of circulating monocytes and their ability to predict kidney allograft dysfunction in living kidney transplant recipients. Whole blood samples from 25 kidney recipients and 17 donors were collected at five time-points. Monocyte phenotype was analysed by flow cytometry, and interleukin (IL)-10 and soluble CD163 by enzyme-linked immunosorbent assay. One week after transplantation, surface CD163 and IL-10 levels increased significantly from baseline [2·99 ± 1·38 mean fluorescence intensity (MFI) to 5·18 ± 2·42 MFI for CD163; 4·5 ± 1·46 pg/ml to 6·7 ± 2·5 pg/ml for IL-10]. This CD163 increase correlated with 4-month creatinine levels (r = 0·4394, P = 0·04). However, soluble CD163 decreased significantly from baseline at 1 week (797·11 ± 340·45 ng/ml to 576·50 ± 293·60 ng/ml). CD14(+) CD16(-) monocytes increased at 4 months and correlated positively with creatinine levels at 12 and 24 months (r = 0·6348, P = 0·002 and r = 0·467, P = 0·028, respectively) and negatively with Modification of Diet in Renal Disease (MDRD) at 12 months (r = 0·6056, P = 0·003). At 4 months, IL-10 decreased significantly (P = 0·008) and correlated positively with creatinine at 2 years (r = 0·68, P = 0·010) and with CD14(+) CD16(-) monocytes at 4 months (r = 0·732, P = 0·004). At 24 h, levels of human leucocyte antigen D-related declined from 12·12 ± 5·99 to 5·21 ± 3·84 and CD86 expression decreased from 2·76 ± 1·08 to 1·87 ± 0·95. Both markers recovered progressively until 12 months, when they decreased again. These results indicate that monitoring monocytes could be a promising new prognostic tool of graft dysfunction in renal transplant patients.

Topics: Allografts; Antigens, CD; Antigens, Differentiation, Myelomonocytic; B7-2 Antigen; Creatinine; Female; Fibrosis; HLA-DR Antigens; Humans; Immunosuppressive Agents; Inflammation; Interleukin-10; Kidney; Kidney Transplantation; Lipopolysaccharide Receptors; Macrophages; Male; Middle Aged; Monocytes; Mycophenolic Acid; Phenotype; Prednisone; Primary Graft Dysfunction; Prospective Studies; Receptors, Cell Surface; Receptors, IgG; Spain; Tacrolimus

In January 2007, our centre changed from a cyclosporin (CyA)/azathioprine (Aza)/ prednisolone (Pred) primary immunosuppression regimen (with basiliximab induction and mycophenolate mofetil [MMF] for those at immunologically high risk) to a tacrolimus (Tac) (low dose)/MMF/Pred regimen with basiliximab induction, following presentation of Symphony trial results. This analysis assesses the impact of this change on 5-year outcomes. Three hundred consecutive renal-only transplants were identified: 140 from the 2005-06 era and 160 from the 2007-08 era. The proportions of living donor (37.5 vs. 22.9%; p = 0.04) and donors after circulatory death (11.9 vs. 5.0%; p = 0.03) were higher in the 2007-08 cohort. Five-year actuarial patient survival was higher in the 2007-08 cohort (96.8 vs. 87.1%; p = 0.003), with a trend toward higher 5-year transplant survival (84.7 vs. 76.3%; p = 0.08). Estimated glomerular filtration rate (eGFR) was higher than in the 2005-06 era at 1 (53.5 vs. 44.5 ml/min/1.73m2; p = 0.0006) and 3 years (50.9 vs. 43.4 ml/min/1.73m2; p = 0.02), with a trend toward higher eGFR at 5 years (41.8 vs. 49.6 ml/min/1.73m2; p = 0.09). Differences were consistent when living donor and deceased donor transplants were analysed separately. In a "real world" population, a change from a CyA-based to a Tac (low-dose)/MMF/Pred primary immunosuppression regimen has been associated with better 5-year outcomes.

Topics: Adult; Cyclosporine; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kaplan-Meier Estimate; Kidney Transplantation; Male; Middle Aged; Primary Graft Dysfunction; Scotland; Tacrolimus; Treatment Outcome

Interleukin 18 (IL-18) is a potent proinflammatory cytokine, which promotes the secretions of TNF-α, IL-1β, IL-2 and IFN-γ. All those inflammatory cytokines can influence the CYP450 and MDR dependent drug disposition. On the other side, those cytokines can induce hepatic allograft dysfunction. We investigated the effects of serum IL-18 and IL-18 gene promoter polymorphisms on tacrolimus pharmacokinetics and hepatic allograft dysfunction in liver transplant recipients. A total of 155 liver transplant recipients were enrolled into this study (34 females and 121 males). The mean follow-up was 52 months (range 16-96 months).The total liver transplant recipients were divided into hepatic allograft dysfunction (N=14) and no hepatic allograft dysfunction (N=141). We studied two single-nucleotide polymorphisms in the promoter region of IL-18 gene at the position G-137C (rs187238) and A-607C (rs1946518) by HRM analysis (high-resolution melting curve analysis). Tacrolimus dosage, tacrolimus blood concentration, serum levels of IL-18 and IFN-γ were also investigated. We found the recipients with higher IL-18 and IFN-γ serum levels had lower tacrolimus concentration/dose (C/D) ratios (P<0.05). In the mean time, after transplantation hepatic allograft dysfunction was more likely to happen to those recipients. However, there was no significant difference in the frequencies of A-607C and G-137C allelic distribution in recipients' tacrolimus concentration/dose (C/D) ratios. This study identifies IL-18 reduced tacrolimus concentration/dose (C/D) ratio through up regulation of P-glycoprotein (P-gp).

Topics: Female; Humans; Immunosuppressive Agents; Interleukin-18; Liver Transplantation; Male; Polymorphism, Single Nucleotide; Primary Graft Dysfunction; Promoter Regions, Genetic; Tacrolimus