Recipient age as a determinant factor of patient and graft survival

Producción CientíficaBackground. Age of renal transplants has been related to death, alloimmune response and graft outcome. We reviewed the influence of patient age on transplant outcome in three cohorts of patients transplanted in Spain during the 1990s. Methods. Patient age was categorized into four groups (I, 18–40; II, 41–50; III, 51–60; and IV, > 60 years). Risks factors for acute rejection were evaluated by logistic regression adjusting for transplant centre and transplantation year, while a Cox proportional hazard model was employed for analysing patient and graft survival. Results. Older patients had a higher death rate (I, 3.5%; II, 7.7%; III, 13.2%; and IV, 16.9%; P<0.001), but a lower standardized mortality index (I, 7.6; II, 7.0; III, 5.8; and IV, 4.1; P = 0.0019). Older patients had the lowest risk of acute rejection [odds ratio (OR) 0.79 and 95% confidence interval (CI) 0.66–0.97 for group II; OR 0.75 and 95% CI 0.62–0.91 for group III; OR 0.43 and 95% CI 0.33–0.56 for group IV). Death-censored graft survival was poorer in patients older than 60 years (relative risk 1.40; 95% CI 1.09–1.80), but this result was not explained by any combination of patient age with donor age, delayed graft function or immunosuppression. Conclusions. Patient age is a main determinant of transplant outcome. Although death rate is higher for older patients, standardized mortality was not. Thus, the efforts to reduce mortality should be also implemented in younger patients. Old patients have a low risk of acute rejection but a poorer death-censored graft survival. This last result was not explained by any controlled variable in our study

Outcome of Kidney Transplants from Viremic and Non-Viremic Hepatitis C Virus Positive Donors into Negative Recipients: Results of the Spanish Registry

Graft outcome; Hepatitis C virus; Viremic donorResultado del injerto; Virus de la hepatitis C; Donante virémicoResultat de l'empelt; Virus de l'hepatitis C; Donant virèmicHistorically, donor infection with hepatitis-C virus (HCV) has been a barrier to kidney transplantation. However, in recent years, it has been reported that HCV positive kidney donors transplanted into HCV negative recipients offer acceptable mid-term results. However, acceptance of HCV donors, especially viremic, has not broadened in the clinical practice. This is an observational, multicenter, retrospective study including kidney transplants from HCV positive donors into negative recipients reported to the Spanish group from 2013 to 2021. Recipients from viremic donors received peri-transplant treatment with direct antiviral agents (DAA) for 8–12 weeks. We included 75 recipients from 44 HCV non-viremic donors and 41 from 25 HCV viremic donors. Primary non function, delayed graft function, acute rejection rate, renal function at the end of follow up, and patient and graft survival were not different between groups. Viral replication was not detected in recipients from non-viremic donors. Recipient treatment with DAA started pre-transplant avoids (n = 21) or attenuates (n = 5) viral replication but leads to non-different outcomes to post-transplant treatment with DAA (n = 15). HCV seroconversion was more frequent in recipients from viremic donors (73% vs. 16%, p < 0.001). One recipient of a viremic donor died due to hepatocellular carcinoma at 38 months. Donor HCV viremia seems not to be a risk factor for kidney transplant recipients receiving peri-transplant DAA, but continuous surveillance should be advised

Change in Estimated GFR and Risk of Allograft Failure in Patients Diagnosed With Late Active Antibody-mediated Rejection Following Kidney Transplantation

Malaltia renal en fase terminal; Trasplantament de ronyóEnfermedad renal en etapa terminal; Transplante de riñónEnd-stage renal disease; Kidney TransplantBackground. There are challenges in designing adequate, well-controlled studies of patients with active antibody-mediated rejection (AMR) after kidney transplantation (KTx). Methods. We assessed the functional relationship between change in estimated glomerular filtration rate (eGFR) following the diagnosis of AMR and the risk of subsequent death-censored graft failure using the joint modeling framework. We included recipients of solitary KTx between 1995 and 2013 at 4 transplant centers diagnosed with biopsy-proven active AMR at least 1 year post-KTx, who had a minimum of 3-year follow-up. Results. A total of 91 patients across participating centers were included in the analysis. Of the 91 patients, n = 54 patients (59%) met the death-censored graft failure endpoint and n = 62 patients (68%) met the all-cause graft failure composite endpoint. Kaplan-Meier death-censored graft survival rates at 12, 36, and 60 months postdiagnosis of AMR pooled across centers were 88.9%, 58.9%, and 36.4%, respectively. Spaghetti plots indicated a linear trend in the change in eGFR, especially in the first 12 months postdiagnosis of active AMR. A significant change in eGFR was observed within the first 12 months postdiagnosis of active AMR, getting worse by a factor of −0.757 mL/min/1.73 m2 per month during the 12-month analysis period (a delta of −9.084 mL/min/1.73 m2 at 1 y). Notably, an extrapolated 30% improvement in the slope of eGFR in the first 12 months was associated with a 10% improvement in death-censored graft failure at 5 years. Conclusions. If prospectively validated, this study may inform the design of pivotal clinical trials for therapies for late AMR

Use and Safety of Remdesivir in Kidney Transplant Recipients With COVID-19

Coronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Trasplantament de ronyó; RemdesivirCoronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Trasplante de riñón; RemdesivirCoronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Kidney transplantation; RemdesivirIntroduction Remdesivir has demonstrated antiviral activity against coronavirus, shortening the time to recovery in adults hospitalized with moderate/severe COVID-19. Severe adverse events such as acute kidney injury have been reported. Scant data are available on the use and safety of remdesivir in kidney transplant recipients. Methods We present a multicenter cohort study of 51 kidney transplant recipients with COVID-19 treated with remdesivir. Outcomes and safety were assessed. Results Mean age at diagnosis was 60 years, with a median time since kidney transplant of 4.5 years. Mean time since admission to remdesivir was 2 days. Twenty-eight patients (54.9%) required mechanical ventilation (19 noninvasive). Mortality was 18.9% and markedly higher if aged ≥65 years (45% vs. 3.2% in younger patients). Acute kidney injury was present in 27.7% of patients, but was diagnosed in 50% before treatment. No patients required remdesivir discontinuation because of adverse events. We did not find significant hepatoxicity or systemic symptoms resulting from the drug. Conclusion In our cohort of kidney transplant recipients, remdesivir was well tolerated and safe in renal and hepatic toxicity, but randomized trials are needed to assess its efficacy

The Role of Vascular Lesions in Diabetes Across a Spectrum of Clinical Kidney Disease

Albuminuria; Diabetes; HistologyAlbuminuria; Diabetes; HistologíaAlbuminúria; Diabetis; HistologiaIntroduction The clinical-histologic correlation in diabetic nephropathy is not completely known. Methods We analyzed nephrectomy specimens from 90 patients with diabetes and diverse degrees of proteinuria and glomerular filtration rate (GFR). Results Thirty-six (40%) subjects had normoalbuminuria, 33 (37%) microalbuminuria, and 21 (23%) non-nephrotic proteinuria. Mean estimated GFR (eGFR) was 65±23 (40% 10% to 20% of the sample. Moderate hyalinosis and arteriolar sclerosis were observed in 80% to 100% of cases with normoalbuminuria, microalbuminuria, proteinuria, as well as in class I, II, or III. Conclusions Weak correspondence between analytical parameters and kidney histology was found. Thus, disease may progress undetected from the early clinical stages of the disease. Finally, vascular damage was a very common finding, which highlights the role of ischemic intrarenal disease in diabetes.This study was funded by the ERA-EDTA (European Renal Association-European Dialysis and Transplant Association). The European Nephrectomy Biobank Project (Appendix). FIS/Fondos FEDER (PI17/00257, PI16/01814, PI19/01756, PI18/01386, PI19/00588, PI19/00815, DTS18/00032, ERA-PerMed-JTC2018 (KIDNEY ATTACK AC18/00064 and PERSTIGAN AC18/00071, ISCIII-RETIC REDinREN RD016/0009), Sociedad Española de Nefrología, FRIAT, Comunidad de Madrid en Biomedicina B2017/BMD-3686 CIFRA2-CM

La fragilidad en candidatos a trasplante renal

Candidat; Fragilitat; Trasplantament renalCandidato; Fragilidad; Trasplante renalCandidate; Frailty; Kidney transplantEl concepto de fragilidad ha sido desarrollado principalmente en el campo de la geriatría y surgió para identificar a aquellos pacientes que presentaban vulnerabilidad al enfrentarse a un evento clínico estresante. Los pacientes frágiles tienen mayor riesgo de mortalidad, complicaciones y discapacidad, independientemente de su edad o comorbilidades. Se ha descrito una alta prevalencia de fragilidad entre sujetos con enfermedad renal crónica, sobre todo en terapia renal sustitutiva. El porcentaje de pacientes frágiles o prefrágiles en lista de espera de trasplante renal se sitúa en torno a un 20-30% y se ha demostrado que estos pacientes tienen peores resultados tras el trasplante renal, que constituye un evento estresante. Las herramientas para evaluar la fragilidad, escalas e índices, pueden ser útiles para identificar qué pacientes están en riesgo de padecer más complicaciones postrasplante, lo que resulta necesario para adaptar nuestra práctica clínica y evitar morbilidad. La más utilizada en pacientes renales es la escala de Fried, que se basa en la detección de cinco dimensiones fenotípicas. Además, conocer la fragilidad de nuestros pacientes permite plantear intervenciones prehabilitadoras durante el tiempo que estén en lista de espera, con el objetivo de mejorar esta vulnerabilidad pretrasplante, y así optimizar los resultados postrasplante. Se necesitan estudios en población renal para mejorar y prevenir la fragilidad.Frailty is a concept that has been mainly developed in geriatrics and it came from the need of identifying subjects at risk to develop complications when they faced a stressful event. Frail patients have higher risk of mortality, poor outcomes and disability, and this is independent from their age or comorbidities. Chronic kidney disease patients present with high prevalence of frailty, especially those who are in renal replacement therapy. Frail or pre-frail patients on the kidney transplant waiting list represent 20-30%, and these patients are proven to have poorer results after the transplant, which is a stressful event itself. Tools for frailty assessment, both scales or indexes, may be usefulto identify which subjects might be at risk for complications after transplant, and this is necessary to adapt our clinical practice and minimize morbidity. The most used frailty scale in kidney patients is Fried scale, which is based in five phenotypic items. Besides that, knowing frail population allows potential interventions such as prehabilitation while the patient is waiting for the kidney transplant, which the aim of improving their vulnerability prior to transplant and, therefore, optimizing results after transplant. More studies are needed amongst kidney patients to improve and prevent frailtyMJPS y JP están financiados con el proyecto FIS-FEDER PI19/00037 del ISCII

Kidney transplantation and COVID-19 renal and patient prognosis

Coronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Síndrome de dificultat respiratòria aguda; Trasplantament renalCoronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Síndrome de dificultad respiratoria aguda; Trasplante renalCoronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Acute respiratory distress syndrome; Renal transplantationCoronavirus disease 2019 (COVD-19) emerged as a pandemic in December 2019. Infection has spread quickly and renal transplant recipients receiving chronic immunosuppression have been considered a population at high risk of infection, complications and infection-related death. During this year a large amount of information from nationwide registries, multicentre and single-centre studies have been reported. The number of renal transplant patients diagnosed with COVID-19 was higher than in the general population, but the lower threshold for testing may have contributed to its better identification. Major complications such as acute kidney injury and acute respiratory distress syndrome were very frequent in renal transplant patients, with a high comorbidity burden, but further studies are needed to support that organ transplant recipients receiving chronic immunosuppression are more prone to develop these complications than the general population. Kidney transplant recipients experience a high mortality rate compared with the general population, especially during the very early post-transplant period. Despite the fact that some studies report more favourable outcomes in patients with a kidney transplant than in patients on the kidney waiting list, the higher mortality described in the very early post-transplant period would advise against performing a kidney transplant in areas where the spread of infection is high, especially in recipients >60 years of age. Management of transplant recipients has been challenging for clinicians and strategies such as less use of lymphocyte-depleting agents for new transplants or anti-metabolite withdrawal and calcineurin inhibitor reduction for transplant patients with COVID-19 are not based on high-quality evidence.The authors received grants from Red de Investigación Renal (REDinREN RD16/0009/0030) and Fondo de Investigación Sanitaria del Instituto de Salud Carlos III (PI 18/01704, PI 18/01382). B.C. is supported by a Vall d’Hebron Institute of Research grant. This article is part of a supplement supported by Fresenius Medical Care without any influence on its content

Induction immunosuppression and outcome in kidney transplant recipients with early COVID-19 after transplantation

COVID-19 infection; Basiliximab; Renal transplantationInfección por COVID-19; Basiliximab; Trasplante renalInfecció per COVID-19; Basiliximab; Trasplantament renalCoronavirus disease 2019 (COVID-19) in kidney transplant recipients has a high risk of complications and mortality, especially in older recipients diagnosed during the early period after transplantation. Management of immunosuppression has been challenging during the pandemic. We investigated the impact of induction immunosuppression, either basiliximab or thymoglobulin, on the clinical evolution of kidney transplant recipients developing COVID-19 during the early period after transplantation. We included kidney transplant recipients with ˂6 months with a functioning graft diagnosed with COVID-19 from the initial pandemic outbreak (March 2020) until 31 July 2021 from different Spanish centres participating in a nationwide registry. A total of 127 patients from 17 Spanish centres developed COVID-19 during the first 6 months after transplantation; 73 (57.5%) received basiliximab and 54 (42.5%) thymoglobulin. Demographics were not different between groups but patients receiving thymoglobulin were more sensitized [calculated panel reactive antibodies (cPRAs) 32.7 ± 40.8% versus 5.6 ± 18.5%] and were more frequently retransplants (30% versus 4%). Recipients ˃65 years of age treated with thymoglobulin showed the highest rate of acute respiratory distress syndrome [64.7% versus 37.1% for older recipients receiving thymoglobulin and basiliximab (P .05)], respectively, and the poorest survival [mortality rate 64.7% and 42.9% for older recipients treated with thymoglobulin and basiliximab, respectively (P .05), respectively]. Older recipients treated with thymoglobulin showed the poorest survival in the Cox regression model adjusted for comorbidities. Thus thymoglobulin should be used with caution in older recipients during the present pandemic era

Tacrolimus CYP3A Single-Nucleotide Polymorphisms and Preformed T- and B-Cell Alloimmune Memory Improve Current Pretransplant Rejection-Risk Stratification in Kidney Transplantation

Rechazo agudo; Genética; InmunobiologíaRebuig agut; Genètica; ImmunobiologiaAcute rejection; Genetics; ImmunobiologyAchieving fast immunosuppression blood exposure after kidney transplantation is key to abrogating both preformed and de novo anti-donor humoral and cellular alloresponses. However, while tacrolimus (TAC) is the cornerstone immunosuppressant inhibiting adaptive alloimmunity, its blood exposure is directly impacted by different single-nucleotide polymorphisms (SNPs) in CYP3A TAC-metabolizing enzymes. Here, we investigated how functional TAC-CYP3A genetic variants (CYP3A4*22/CYP3A5*3) influence the main baseline clinical and immunological risk factors of biopsy-proven acute rejection (BPAR) by means of preformed donor-specific antibodies (DSAs) and donor-specific alloreactive T cells (DSTs) in a large European cohort of 447 kidney transplants receiving TAC-based immunosuppression. A total of 70 (15.7%) patients developed BPAR. Preformed DSAs and DSTs were observed in 12 (2.7%) and 227 (50.8%) patients, respectively. According to the different CYP3A4*22 and CYP3A5*3 functional allele variants, we found 4 differential new clusters impacting fasting TAC exposure after transplantation; 7 (1.6%) were classified as high metabolizers 1 (HM1), 71 (15.9%) as HM2, 324 (72.5%) as intermediate (IM), and 45 (10.1%) as poor metabolizers (PM1). HM1/2 showed significantly lower TAC trough levels and higher dose requirements than IM and PM (p < 0.001) and more frequently showed TAC underexposure (<5 ng/ml). Multivariate Cox regression analyses revealed that CYP3A HM1 and IM pharmacogenetic phenotypes (hazard ratio (HR) 12.566, 95% CI 1.99-79.36, p = 0.007, and HR 4.532, 95% CI 1.10-18.60, p = 0.036, respectively), preformed DSTs (HR 3.482, 95% CI 1.99-6.08, p < 0.001), DSAs (HR 4.421, 95% CI 1.63-11.98, p = 0.003), and delayed graft function (DGF) (HR 2.023, 95% CI 1.22-3.36, p = 0.006) independently predicted BPAR. Notably, a significant interaction between T-cell depletion and TAC underexposure was observed, showing a reduction of the BPAR risk (HR 0.264, 95% CI 0.08-0.92, p = 0.037). Such variables except for DSAs displayed a higher predictive risk for the development of T cell-mediated rejection (TCMR). Refinement of pretransplant monitoring by incorporating TAC CYP3A SNPs with preformed DSAs as well as DSTs may improve current rejection-risk stratification and help induction treatment decision-making.This work was supported by the Instituto de Salud Carlos III (ISCIII) (grant numbers PI16/01321, PI19/01710, and PI18/P1740) (co-funded by European Regional Development Fund, ERDF, a way to build Europe). Also, this work was partly supported by the SLT002/16/00183 grant, from the Department of Health of the Generalitat de Catalunya by the call “Acció instrumental de programes de recerca orientats en l’àmbit de la recerca i la innovació en salut.” The authors thank the Research Centers of Catalonia (CERCA) Programme/Generalitat de Catalunya for institutional support. OB was awarded an intensification grant from the “Instituto de Salud Carlos III” [NT19/00051]

Fascin-1 is released from proximal tubular cells in response to calcineurin inhibitors (CNIs) and correlates with isometric vacuolization in kidney transplanted patients

Fascin-1; Nephrotoxicity; TransplantFascina-1; Nefrotoxicitat; TrasplantamentFascina-1; Nefrotoxicidad; TrasplanteImmunosuppression based on calcineurin inhibitors (CNIs) has greatly improved organ transplantation, although subsequent nephrotoxicity significantly hinders treatment success. There are no currently available specific soluble biomarkers for CNI-induced nephrotoxicity and diagnosis relies on renal biopsy, which is costly, invasive and may cause complications. Accordingly, identification of non-invasive biomarkers distinguishing CNI-induced kidney tubular damage from that of other etiologies would greatly improve diagnosis and enable more precise dosage adjustment. For this purpose, HK-2 cells, widely used to model human proximal tubule, were treated with CNIs cyclosporine-A and FK506, or staurosporine as a calcineurin-independent toxic compound, and secretomes of each treatment were analyzed by proteomic means. Among the differentially secreted proteins identified, only fascin-1 was specifically released by both CNIs but not by staurosporine. To validate fascin-1 as a biomarker of CNI-induced tubular toxicity, fascin-1 levels were analyzed in serum and urine from kidney-transplanted patients under CNIs treatment presenting or not isometric vacuolization (IV), which nowadays represents the main histological hallmark of CNI-induced tubular damage. Patients with chronic kidney disease (CKD) and healthy volunteers were used as controls. Our results show that urinary fascin-1 was only significantly elevated in the subset of CNI-treated patients presenting IV. Moreover, fascin-1 anticipated the rise of sCr levels in serially collected urine samples from CNI-treated pulmonary-transplanted patients, where a decline in kidney function and serum creatinine (sCr) elevation was mainly attributed to CNIs treatment. In conclusion, our results point towards fascin-1 as a putative soluble biomarker of CNI-induced damage in the kidney tubular compartment