Arteriovenous fistulas are frequently considered biologically quiescent after successful kidney transplantation, and their long-term management remains debated. We report the case of a 59-year-old kidney transplant recipient who presented with persistent bleeding and progressive enlargement of a long-standing, non-functioning brachiocephalic arteriovenous fistula. The patient was receiving tacrolimus, mycophenolate, and steroids, with stable graft function. Clinical evaluation initially suggested pseudoaneurysm or inflammatory changes. Due to recurrent bleeding, surgical resection was performed, and histopathological examination revealed a high-grade epithelioid angiosarcoma arising from the fistula wall. Staging studies demonstrated pulmonary metastases at the time of diagnosis. The diagnosis was established only after surgery, without prior biopsy, reflecting the nonspecific clinical presentation. Despite surgical management and oncologic assessment, the disease progressed rapidly, and the patient died shortly thereafter. Angiosarcoma arising from abandoned vascular access is an exceptionally rare but highly aggressive malignancy in transplant recipients. These findings underscore the importance of early evaluation of atypical vascular access lesions in transplant recipients, as delayed diagnosis may be associated with advanced disease and poor outcomes.

Donor-derived cell-free deoxyribonucleic acid (DNA) (dd-cfDNA) and urinary chemokines are promising noninvasive biomarkers for kidney allograft rejection, but direct comparative data are lacking. In this prospective pilot study, we analyzed 194 biopsies (101 for-cause, 93 surveillance) paired with dd-cfDNA and urinary chemokine (CXCL9, CXCL10, CCL2, VEGF-A) concentrations in kidney transplant recipients. We evaluated their correlation, diagnostic accuracy for rejection phenotypes, and integration into diagnostic models with clinical and immunologic variables. Rejection was diagnosed in 32.5% of biopsies, predominantly antibody-mediated. dd-cfDNA showed strong diagnostic performance in both for-cause (area under the receiver operating characteristic curve [AUC] 0.85) and surveillance (AUC 0.91) biopsies. Conversely, urinary chemokines, particularly the composite Score4, showed accuracy mainly in for-cause biopsies (AUC 0.76). Remarkably, Score4 combined with donor-specific antibodies showed similar performance as dd-cfDNA + donor-specific antibodies (AUC 0.90) in for-cause biopsies. Internal bootstrap validation, including calibration metrics, confirmed the consistency of the models. dd-cfDNA provides robust diagnostic accuracy for kidney allograft rejection across distinct clinical settings. Urinary chemokine measures, especially Score4, may offer valuable diagnostic utility in for-cause biopsies. These findings support context-specific integration of noninvasive biomarkers and represent the first direct comparison of dd-cfDNA and urinary chemokines, informing personalized approaches to rejection monitoring.

Living kidney transplantation offers the best results for end-stage renal disease patients, but concerns about cardiovascular risk after nephrectomy for kidney donors have been raised. We aimed to estimate the contribution of renal function to endothelial dysfunction (ED) and subclinical inflammation in a non-interventional, prospective, multicenter, longitudinal study with two cohorts: living kidney donors and their transplant recipients (registered clinical trial NCT02515643). The measured glomerular filtration rate (mGFR) by iohexol clearance, estimated GFR according to the CKD-EPI and MDRD-4 formulas, and levels of endothelial dysfunction (sVCAM-1, sICAM-1, E-selectin, von Willebrand Factor, pentraxin, and urinary albumin-to-creatinine ratio) and subclinical inflammation biomarkers (sIL-6, sTNF-R1, sTNF-R2, sTWEAK, and high-sensitivity C-reactive protein) were determined at baseline and 1-year follow-up. Fifty pairs of donors and recipients were recruited between 2015 and 2018. Among the endothelial dysfunction biomarkers, sVCAM-1 increased in donors and decreased in recipients (p < 0.01) while, among the inflammation biomarkers, sTNFR1 and sTNFR2 significantly increased in donors and decreased in recipients (p < 0.001). After transplantation, parallel increases and decreases in ED and subclinical inflammation biomarkers were observed in the donor and recipient cohorts, respectively. Long-term follow-up is needed to characterize the cardiovascular risk associated with these changes.

A significant proportion of kidney transplants show a high HLA sensitization and should be considered for transplantation across the HLA barrier. The best strategy to manage these patients is still a matter of debate and the benefits of desensitization based on apheresis techniques, intravenous immunoglobulins and rituximab have not been clearly delineated.

Subclinical inflammation in protocol biopsies relates to tacrolimus exposure and human leukocyte antigen (HLA) matching. We aimed to characterize transcripts associated with rejection and tacrolimus exposure and the latter’s association with transplant outcomes. We tested whether gene expression is associated with rejection using strictly normal protocol biopsies (n = 17) and biopsies with T cell-mediated rejection (TCMR) or antibody-mediated rejection (ABMR) according to Banff criteria (n = 12). Subsequently, we analyzed these transcripts in a set of 4-month protocol biopsies (n = 137) to assess their association with donor and recipient characteristics, the intensity of immunosuppression, and the graft outcome. Differential expression (false discovery rate (FDR) < 0.01, fold (change (FC) > 3) between normal and rejection biopsies yielded a set of 111 genes. In the protocol biopsy cohort (n = 137), 19 out of these 111 genes correlated with tacrolimus trough levels at the time of biopsy (TAC-C0), and unsupervised analysis split this cohort into two clusters. The two clusters differed in donor age and tacrolimus trough levels. Subclinical rejection, including borderline lesions, tended to occur in the same cluster. Logistic regression analysis indicated that TAC-C0 at the time of biopsy (OR: 0.83, 95%CI:0.72–0.06, p = 0.0117) was associated with cluster 2. In a follow-up averaging 70 ± 30 months, this patient group displayed a significant decline in renal function (p = 0.0135). The expression of rejection-associated transcripts in early protocol biopsies is associated with tacrolimus exposure and a faster decline in renal function.

Cytomegalovirus (CMV) infection is associated with poor kidney transplant outcomes. While innate and adaptive immune cells have been implicated in its prevention, an in-depth characterization of the in vivo kinetics of multiple cell subsets and their role in protecting against CMV infection has not been achieved. Here, we performed high-dimensional immune phenotyping by mass cytometry, and functional assays, on 112 serially collected samples from CMV seropositive kidney transplant recipients. Advanced unsupervised deep learning analysis was used to assess immune cell populations that significantly correlated with prevention against CMV infection and anti-viral immune function. Prior to infection, kidney transplant recipients who developed CMV infection showed significantly lower CMV-specific cell-mediated immune (CMI) frequencies than those that did not. A broad diversity of circulating cell subsets within innate and adaptive immune compartments were associated with CMV infection or protective CMV-specific CMI. While percentages of CMV (tetramer-stained)-specific T cells associated with high CMI responses and clinical protection, circulating CD3+CD8midCD56+ NK-T cells overall strongly associated with low CMI and subsequent infection. However, three NK-T cell subsets sharing the CD11b surface marker associated with CMV protection and correlated with strong anti-viral CMI frequencies in vitro. These data were validated in two external independent cohorts of kidney transplant recipients. Thus, we newly describe the kinetics of a novel NK-T cell subset that may have a protective role in post-transplantation CMV infection. Our findings pave the way to more mechanistic studies aimed at understanding the function of these cells in protection against CMV infection.

In recent decades, the field of female fertility preservation has experienced substantial growth. Reliable techniques such as cryopreservation of oocytes and ovarian tissue have emerged, along with more established methods such as embryo freezing. Among the group of patients who can benefit from these new techniques are patients with endometriosis, a common disease capable of compromising ovarian reserve and fertility prospects. Unfortunately, comprehensive recommendations for fertility preservation in patients with endometriosis are still lacking. This narrative review comprehensively explores fertility preservation in patients with endometriosis, using a range of relevant literature, including available national and international guidelines. Additionally, it explains the weight of several factors that contribute to the decision-making process for fertility preservation, including age, severity of endometriosis, ovarian reserve, and previous or future surgery. This manuscript summarizes available recommendations that provide guidance for this vital but challenging aspect of reproductive medicine. Underlines the need for personalized care for patients with an early diagnosis of endometriosis and initial medical treatment to try to reduce the deterioration of ovarian reserve and emphasizes the importance of research to refine fertility preservation strategies in people with endometriosis. (c) 2024 Elsevier Espana, S.L.U. All rights reserved.

Chronic hepatitis E virus (HEV) in persons with immune impairment has a progressive course leading to a rapid progression to liver cirrhosis. However, prospective data on chronic HEV is scarce. The aim of this study was to determine the prevalence and risk factors for chronic HEV infection in subjects with immune dysfunction and elevated liver enzymes. CHES is a multicenter prospective study that included adults with elevated transaminases values for at least 6 months and any of these conditions: transplant recipients, HIV infection, haemodialysis, liver cirrhosis, and immunosuppressant therapy. Anti-HEV IgG/IgM (Wantai ELISA) and HEV-RNA by an automated highly sensitive assay (Roche diagnostics) were performed in all subjects. In addition, all participants answered an epidemiological survey. Three hundred and eighty-one patients were included: 131 transplant recipients, 115 cirrhosis, 51 HIV-infected subjects, 87 on immunosuppressants, 4 hemodialysis. Overall, 210 subjects were on immunosuppressants. Anti-HEV IgG was found in 94 (25.6%) subjects with similar rates regardless of the cause for immune impairment. HEV-RNA was positive in 6 (1.6%), all of them transplant recipients, yielding a rate of chronic HEV of 5.8% among solid-organ recipients. In the transplant population, only therapy with mTOR inhibitors was independently associated with risk of chronic HEV, whereas also ALT values impacted in the general model. Despite previous abnormal transaminases values, chronic HEV was only observed among solid-organ recipients. In this population, the rate of chronic HEV was 5.8% and only therapy with mTOR inhibitors was independently associated with chronic hepatitis E. La infección crónica por el virus de la hepatitis E (VHE) en personas con disfunción inmunitaria tiene un curso progresivo conllevando una rápida progresión a cirrosis hepática. Sin embargo, los datos prospectivos a este respecto son escasos. El objetivo de este estudio fue determinar la prevalencia y factores de riesgo para la infección crónica VHE en sujetos con disfunción inmunitaria y elevación de enzimas hepáticos. CHES es un estudio prospectivo multicéntrico que incluyó adultos con transaminasas elevadas durante al menos 6 meses y alguno de estos factores: receptores de trasplante, infección por VIH, hemodiálisis, cirrosis hepática o tratamiento inmunosupresor. En todos los sujetos se realizaron IgG/IgM anti-VHE (Wantai Elisa) y ARN-VHE por una técnica super sensible (Roche Diagnostics). Además, todos los participantes contestaron una encuesta epidemiológica. 381 pacientes fueron incluidos: 131 trasplantados, 115 cirróticos, 51 infectados por VIH, 87 bajo inmunosupresores, 4 hemodiálisis. En total, 210 sujetos recibían inmunosupresores. La IgG anti-VHE fue positiva en 94 (25,6%) sujetos, con tasas similares en todas la causas de disfunción inmunitaria. El ARN-VHE fue positivo en 6 (1,6%) pacientes, todos ellos trasplantados, siendo la tasa de infección crónica VHE en receptores de órgano sólido del 5,8%. En la población de trasplantados, solo el tratamiento con inhibidores de mTOR se asoció de forma independiente a la hepatitis crónica VHE, mientras que los niveles de ALT impactaron en el modelo general. A pesar de los niveles anormales de transaminasas, solo se objetivó hepatitis crónica VHE en trasplantados de órgano sólido. En esta población, la tasa de hepatitis crónica VHE fue del 5,8% y solo el tratamiento con inhibidores de mTOR se asoció de forma independiente a la hepatitis crónica E.

Introduction: There is no consensus on the most appropriate treatment for chronic active antibody-mediated rejection (cAMR). Recent studies suggest that treatment with tocilizumab (TCZ) may stabilize graft function, decrease the intensity of donor-specific HLA antibodies (DSAs) and reduce inflammation of microcirculation. Patients and methods: Observational study with renal allograft recipients diagnosed with cAMR (n = 5) who had not submitted a response to traditional treatment based on the combination of plasma replacements, immunoglobulins, and rituximab. Patients were told to be treated with TCZ as compassionate use in six doses per month (8 mg/kg/month). Renal function, proteinuria, and the intensity of DSAs were monitored during follow-up. Results: Five patients, average age 60 +/- 13 years, three male and two retrasplants (cPRA average 55%) with preformed DSAs. Treatment with TCZ was initiated within 47 +/- 52 days of biopsy. In two cases treatment was discontinued after the first dose, by severe bicitopenia with cytomegalovirus viremia and by graft failure, respectively. In the three patients who completed treatment, no stability of renal function (serum creatinine from 1.73 +/- 0.70 to 2.04 +/- 0.52 mg/dL, e-FGR 4 6 +/- 15 to 36 +/- 16 mL/min), showed increased proteinuria (3.2 +/- 4.0 to 6.9 +/- 11.0 g/g) and the intensity of DSAs maintain stable. No changes were observed in the degree of inflammation of microcirculation (g + pt 4.2 +/- 0.8 vs. 4.3 +/- 1.0) or in the degree of transplant glomerulopathy (cg 1.2 +/- 0.4 vs. 1.8 +/- 1.0). Conclusions: TCZ therapy does not appear to be effective in modifying the natural history of chronic active antibody-mediated rejection, does not improve the degree of inflammation of microcirculation and does not reduces the intensity of DSAs. (C) 2021 Sociedad Espanola de Nefrologia. Published by Elsevier Espana, S.L.U.

[This corrects the article DOI: 10.3389/ti.2022.10693.].

ABSTRACT Background Small cohort studies have reported high parathyroid hormone (PTH) levels in patients with Bartter syndrome and lower serum phosphate levels have anecdotally been reported in patients with Gitelman syndrome. In this cross-sectional study, we assessed PTH and phosphate homeostasis in a large cohort of patients with salt-losing tubulopathies. Methods Clinical and laboratory data of 589 patients with Bartter and Gitelman syndrome were provided by members of the European Rare Kidney Diseases Reference Network (ERKNet) and the European Society for Paediatric Nephrology (ESPN). Results A total of 285 patients with Bartter syndrome and 304 patients with Gitelman syndrome were included for analysis. Patients with Bartter syndrome type I and II had the highest median PTH level (7.5 pmol/L) and 56% had hyperparathyroidism (PTH >7.0 pmol/L). Serum calcium was slightly lower in Bartter syndrome type I and II patients with hyperparathyroidism (2.42 versus 2.49 mmol/L; P = .038) compared to those with normal PTH levels and correlated inversely with PTH (rs −0.253; P = .009). Serum phosphate and urinary phosphate excretion did not correlate with PTH. Overall, 22% of patients had low serum phosphate levels (phosphate—standard deviation score < −2), with the highest prevalence in patients with Bartter syndrome type III (32%). Serum phosphate correlated with tubular maximum reabsorption of phosphate/glomerular filtration rate (TmP/GFR) (rs 0.699; P < .001), suggesting renal phosphate wasting. Conclusions Hyperparathyroidism is frequent in patients with Bartter syndrome type I and II. Low serum phosphate is observed in a significant number of patients with Bartter and Gitelman syndrome and appears associated with renal phosphate wasting.

Resumen: Introducción: No existe consenso sobre el tratamiento más adecuado para el rechazo humoral crónico activo (RHCa). Estudios recientes sugieren que el tratamiento con tocilizumab (TCZ) puede estabilizar la función del injerto, disminuir la intensidad de los anticuerpos anti-HLA donante-específicos (ADEs) y reducir la inflamación de la microcirculación. Pacientes y métodos: Estudio observacional con pacientes trasplantados renales diagnosticados de RHCa (n = 5) que no habían presentado respuesta al tratamiento tradicional basado en la combinación de recambios plasmáticos, inmunoglobulinas y rituximab. A los pacientes se les indicó tratamiento con TCZ como uso compasivo en seis dosis mensuales (8 mg/kg/mes). Durante el seguimiento se monitorizó la función renal, proteinuria y la intensidad de los ADEs. Resultados: Cinco pacientes, de edad media 60 ± 13 años, tres de género masculino y dos retrasplantes (cPRA medio 55%) con ADEs preformados. El tratamiento con TCZ se inició a los 47 ± 52 días de la biopsia. En dos casos se suspendió el tratamiento tras la primera dosis, por bicitopenia severa con viremia por citomegalovirus y por fracaso del injerto, respectivamente. En los tres pacientes que completaron el tratamiento no se observó estabilidad de la función renal (creatinina sérica [Cr-s] de 1,73 ± 0,70 a 2,04 ± 0,52 mg/dL, filtrado glomerular estimado [FGRe] de 46 ± 15 a 36 ± 16 mL/min), presentaron aumento de la proteinuria (3,2 ± 4,0 a 6,9 ± 11,0 g/g) y la intensidad de los ADEs se mantuvo estable. No se observaron cambios en el grado de inflamación de la microcirculación (glomerulitis y capilaritis peritubular [g+cpt] 4,2 ± 0,8 vs. 4,3 ± 1,0), ni en el grado de glomerulopatía del trasplante (glomerulopatía crónica [cg] 1,2 ± 0,4 vs. 1,8 ± 1,0). Conclusiones: La terapia con TCZ no parece ser eficaz en modificar la historia natural del rechazo humoral crónico activo, no mejora el grado de la inflamación de la microcirculación ni reduce la intensidad de ADEs. Abstract: Introduction: There is no consensus on the most appropriate treatment for chronic active antibody-mediated rejection (cAMR). Recent studies suggest that treatment with tocilizumab (TCZ) may stabilize graft function, decrease the intensity of donor-specific HLA antibodies (DSAs) and reduce inflammation of microcirculation. Patients and methods: Observational study with renal allograft recipients diagnosed with cAMR (n = 5) who had not submitted a response to traditional treatment based on the combination of plasma replacements, immunoglobulins, and rituximab. Patients were told to be treated with TCZ as compassionate use in six doses per month (8 mg/kg/month). Renal function, proteinuria, and the intensity of DSAs were monitored during follow-up. Results: Five patients, average age 60 ± 13 years, three male and two retrasplants (cPRA average 55%) with preformed DSAs. Treatment with TCZ was initiated within 47 ± 52 days of biopsy. In two cases treatment was discontinued after the first dose, by severe bicitopenia with cytomegalovirus viremia and by graft failure, respectively. In the three patients who completed treatment, no stability of renal function (serum creatinine from 1.73 ± 0.70 to 2.04 ± 0.52 mg/dL, e-FGR 4 6 ± 15 to 36 ± 16 mL/min), showed increased proteinuria (3.2 ± 4.0 to 6.9 ± 11.0 g/g) and the intensity of DSAs maintain stable. No changes were observed in the degree of inflammation of microcirculation (g + pt 4.2 ± 0.8 vs. 4.3 ± 1.0) or in the degree of transplant glomerulopathy (cg 1.2 ± 0.4 vs. 1.8 ± 1.0). Conclusions: TCZ therapy does not appear to be effective in modifying the natural history of chronic active antibody-mediated rejection, does not improve the degree of inflammation of microcirculation and does not reduces the intensity of DSAs.

Thrombotic Microangiopathy Secondary to COVID-19 in a Recent ABO-Incompatible Kidney Transplant. Archives of Clinical and Medical Case 6 173-181. Abstract De novo Thrombotic Microangiopathy (TMA) after renal transplantation is an uncommon complication which has been related with viral infections like the coronavirus disease (COVID-19). Severely immunosuppressed patients who acquire COVID-19 are at high risk of Respiratory Distress Syndrome (ARDS) in a recent ABO-incompatible kidney transplant. Eculizumab was initiated; and after 4 weekly doses, she recovered her renal function. Two months later, she was readmitted due to suspected organizing pneumonia, and received treatment with steroids. During the second week of admission, ARDS and TMA with neurological involvement were observed. Positive tests in blood and broncho-alveolar lavage for SARS-CoV-2 were obtained. A new cycle of eculizumab was started and convalescent plasma was associated due to persistent infection. The patient experienced progressive clinical improvement with resolution of respiratory function, neurological symptoms and hemolysis. Our case confirms that TMA could be triggered by COVID-19 and eculizumab is useful to control hemolysis and attenuate organ damage. Convalescent plasma should be considered in immune deficient high-risk patients with COVID-19.

Multicenter, prospective, observational study to compare the relative bioavailability of once-daily tacrolimus formulations in de novo kidney transplant recipients. De novo kidney transplant recipients who started a tacrolimus-based regimen were included 14 days post-transplant and followed up for 6 months. Data from 218 participants were evaluated: 129 in the LCPT group (Envarsus) and 89 in the PR-Tac (Advagraf) group. Patients in the LCPT group exhibited higher relative bioavailability (C-min /total daily dose [TDD]) vs. PR-Tac (61% increase; P < .001) with similar C-min and 30% lower TDD levels (P < .0001). The incidence of treatment failure was 3.9% in the LCPT group and 9.0% in the PR-Tac group (P = .117). Study discontinuation rates were 6.2% in the LCPT group and 12.4% in the PR-Tac group (P = .113). Adverse events, renal function and other complications were comparable between groups. The median accumulated dose of tacrolimus in the LCPT group from day 14 to month 6 was 889 mg. Compared to PR-Tac, LCPT showed higher relative bioavailability, similar effectiveness at preventing allograft rejection, comparable effect on renal function, safety, adherence, treatment failure and premature discontinuation rates.

Background. Recently, different therapeutic lines have been tried in the initial stage of the disease of COVID-19, including remdesivir and molnupiravir. There is scarce evidence on the efficacy and safety of molnupiravir in kidney transplant recipients (KTRs). Methods. ingle-center prospective cohort study‚ all adult KTRs diagnosed with COVID-19 and treated with molnupiravir or remdesivir from January to April 2022 were included. Results. Nine KTRs with SARS-CoV-2 (Omicron variant) infection and mild symptoms received molnupiravir in an outpatient basis and were compared with a cohort of similar patients treated with remdesivir (n = 7). Three patients in the molnupiravir cohort were in the early posttransplant period and received a basiliximab (n = 2) or antithymocite globulin–based induction (n = 1). One of the patients had been treated with methylprednisolone bolus and antithymocite globulin for an episode of acute rejection in the previous months. They were all vaccinated with mRNA vaccines‚ and all but 1 had serological response. Only one of the patients experienced clinical worsening despite molnupiravir treatment and developed pneumonia requiring hospital admission. None of the patients suffered adverse effects attributed to molnupiravir‚ and no adjustment of tacrolimus dose was needed. None of the patients treated with remdesivir progressed in COVID-19 severity. Conclusions. Our study suggests that KTRs with SARS-CoV-2 infection under treatment with molnupiravir have a good clinical evolution with a probable lower risk for hospitalization and no adverse effects. At the renal level, molnupiravir was well tolerated, with no evidence of nephrotoxicity secondary to the drug nor interactions with the immunosuppressive therapy.

Background Subclinical inflammation, including borderline lesions (BL), is very common (30–40%) after kidney transplantation (KT), even in low immunological risk patients, and can lead to interstitial fibrosis/tubular atrophy (IFTA) and worsening of renal function with graft loss. Few controlled studies have analyzed the therapeutic benefit of treating these BL on renal function and graft histology. Furthermore, these studies have only used bolus steroids, which may be insufficient to slow the progression of these lesions. Klotho, a transmembrane protein produced mainly in the kidney with antifibrotic properties, plays a crucial role in the senescence-inflammation binomial of kidney tissue. Systemic and local inflammation decrease renal tissue expression and soluble levels of α-klotho. It is therefore important to determine whether treatment of BL prevents a decrease in α-klotho levels, progression of IFTA, and loss of kidney function. Methods The TRAINING study will randomize 80 patients with low immunological risk who will receive their first KT. The aim of the study is to determine whether the treatment of early BL (3rd month post-KT) with polyclonal rabbit antithymocyte globulin (Grafalon®) (6 mg/kg/day) prevents or decreases the progression of IFTA and the worsening of graft function compared to conventional therapy after two years post-KT, as well as to analyze whether treatment of BL with Grafalon® can modify the expression and levels of klotho, as well as the pro-inflammatory cytokines that regulate its expression. Discussion This phase IV investigator-driven, randomized, placebo-controlled clinical trial will examine the efficacy and safety of Grafalon® treatment in low-immunological-risk KT patients with early BL. Trial registration clinicaltrials.gov : NCT04936282. Registered June 23, 2021, https://clinicaltrials.gov/ct2/show/NCT04936282?term=NCT04936282&draw=2&rank=1 . Protocol Version 2 of 21 January 2022. Sponsor: Canary Isles Institute for Health Research Foundation, Canary Isles (FIISC). mgomez@fciisc.org.

The combination of tacrolimus (TAC) and mycophenolate is the most widely employed maintenance immunosuppression in renal transplants. Different surrogates of tacrolimus exposure or metabolism such as tacrolimus trough levels (TAC-C0), coefficient of variation of tacrolimus (CV-TAC-C0), time in therapeutic range (TTR), and tacrolimus concentration dose ratio (C/D) have been associated with graft outcomes. We explore in a cohort of low immunological risk renal transplants (n = 85) treated with TAC, mycophenolate mofetil (MMF), and steroids and then monitored by paired surveillance biopsies the association between histological lesions and TAC-C0 at the time of biopsy as well as CV-TAC-C0, TTR, and C/D during follow up. Interstitial inflammation (i-Banff score ≥ 1) in the first surveillance biopsy was associated with TAC-C0 (odds ratio (OR): 0.69, 95% confidence interval (CI): 0.50–0.96; p = 0.027). In the second surveillance biopsy, inflammation was associated with time below the therapeutic range (OR: 1.05 and 95% CI: 1.01–1.10; p = 0.023). Interstitial inflammation in scarred areas (i-IFTA score ≥ 1) was not associated with surrogates of TAC exposure/metabolism. Progression of interstitial fibrosis/tubular atrophy (IF/TA) was observed in 35 cases (41.2%). Multivariate regression logistic analysis showed that mean C/D (OR: 0.48; 95% CI: 0.25–0.92; p = 0.026) and IF/TA in the first biopsy (OR: 0.43, 95% CI: 0.24–0.77, p = 0.005) were associated with IF/TA progression between biopsies. A low C/D ratio is associated with IF/TA progression, suggesting that TAC nephrotoxicity may contribute to fibrosis progression in well immunosuppressed patients. Our data support that TAC exposure is associated with inflammation in healthy kidney areas but not in scarred tissue.