Objective To perform comprehensive validations of the integrative Box (iBox) system, a prediction model for long term risk of kidney allograft failure, for extension of its context of use in clinical trials as well as for its wider implementation in clinical practice.Design Extended validation study.Setting Paris Transplant Group database (comprising kidney recipients with transplantations between 1 January 2005 and 1 January 2014) and European, North American, and South American hospitals (comprising recipients of kidneys transplanted beween 1 January 2000 and 1 January 2022). Patients were followed until 1 November 2024.Participants 12 683 kidney tranplant recipients from 21 academic centres in Europe, North America, and South America; 4000 patients in the derivation cohort and 8683 in the validation cohorts.Main outcome measures Performance of the iBox, including flexible iBox versions in specific clinical contexts (race-free estimated glomerular filtration rate (eGFR) equations (ie, without including race as a factor in the calculation), in specific clinical contexts (initial nephropathy recurrence, BK virus associated nephropathy, and different immunosuppressive strategies), and over-extended follow-up periods. Predictive performance was assessed by discrimination, calibration, overall fit, and clinical utility.Results 12 683 kidney transplant recipients were included in the study (n=4000 in the derivation cohort and n=8683 in the validation cohorts). Median follow-up time after risk evaluation was 5.78 years (interquartile range (IQR) 3.51-7.00) in the derivation cohort and 4.68 years (2.48-7.00) in the validation cohorts. 549 (13.7%) and 991 (11.4%) patients had graft loss in the derivation and validation cohorts, respectively. All versions of the iBox algorithm maintained good discrimination and overall fit performance in the derivation and validation cohorts (C index range 0.79-0.87, Brier scores 0.08-0.11). Calibration was adequate in some but not all external validation cohorts, with trends toward overestimation or underestimation of predicted risks. Decision curve analysis showed positive and comparable net benefit for all iBox algorithms across decision thresholds up to 40% in the derivation cohort (net benefit 0.07-0.08 at 20% threshold) and validation cohorts (net benefit 0.03-0.11 at 20% threshold). Accounting for the competing risk of death with a functioning graft resulted in similar performance, except for calibration which varied across cohorts, without any model consistently outperforming any other model. The model performed well with different race-free eGFR equations (C index 0.81), in various clinical scenarios, including disease recurrence and BK virus nephropathy, with different immunosuppressive strategies, such as calcineurin inhibitors and mTOR (mechanistic target of rapamycin) inhibitors (C index range 0.74-0.87), and when extending the prediction period to 10 years after risk evaluation (C index 0.79). The iBox predictive performance was not modified when various histological indices were used. The iBox was also superior to eGFR slope (C index 0.81 v 0.62) and circulating anti-HLA donor specific antibodies (C index 0.81 v 0.57) in its predictive ability.Conclusions In this study, the robust predictive performance of the iBox system across diverse real world settings and clinical scenarios was shown. These results highlight the versatility and reliability of the iBox system, and support its use for risk stratification in routine clinical practice and as a surrogate endpoint for clinical trials.

Latin Americans are underrepresented in the current equations used to estimate glomerular filtration rate (GFR), and the applicability of their predictions to this population may therefore be questionable. The objective of this study was to develop a new equation to estimate GFR based on data from Argentina. A cross-sectional study was conducted. We included 583 Argentinian adults in development sample (DS) and 78 in temporary validation sample (TVS). Urinary iothalamate clearance (reference method), and different predictive variables were used to develop candidate equations to estimate GFR. The performance was assessed through 10-fold cross-validation in DS, and by direct validation in TVS, using root mean squared error (RMSE), correlation (r), bias, P15, P30 and correct classification percentage (CC%) in CKD stages. The Argentinian equation (AE) chosen is based on a quasi-likelihood model which predicts GFR from creatinine, age, sex, single kidney, albumin and urea. Within the previous creatinine based equations (MDRD, MCQ, CKD-EPI and EKFC), the ones with the best performance were CKD-EPI 2009 and 2021. In the DS, AE showed lower RMSE, similar r, higher P15, median bias closer to zero and higher CC% compared to CKD-EPI 2009, and very slight differences in comparison to CKD-EPI 2021. In the TVS, AE presented lower RMSE, higher (or equal) r, P30 and CC%, and median bias closer to 0 compared to CKD-EPI in its two versions. In addition, it presented higher P15 than CKD-EPI 2009. In conclusion, AE presented a better performance to estimate GFR in Argentinian people and its use could have a positive impact on the clinical management of these patients.

Significance Statement Why are there so few biomarkers accepted by health authorities and implemented in clinical practice, despite the high and growing number of biomaker studies in medical research ? In this meta-epidemiological study, including 804 studies that were critically appraised by expert reviewers, the authors have identified all prognostic kidney transplant biomarkers and showed overall suboptimal study designs, methods, results, interpretation, reproducible research standards, and transparency. The authors also demonstrated for the first time that the limited number of studies challenged the added value of their candidate biomarkers against standard-of-care routine patient monitoring parameters. Most biomarker studies tended to be single-center, retrospective studies with a small number of patients and clinical events. Less than 5% of the studies performed an external validation. The authors also showed the poor transparency reporting and identified a data beautification phenomenon. These findings suggest that there is much wasted research effort in transplant biomarker medical research and highlight the need to produce more rigorous studies so that more biomarkers may be validated and successfully implemented in clinical practice. Background Despite the increasing number of biomarker studies published in the transplant literature over the past 20 years, demonstrations of their clinical benefit and their implementation in routine clinical practice are lacking. We hypothesized that suboptimal design, data, methodology, and reporting might contribute to this phenomenon. Methods We formed a consortium of experts in systematic reviews, nephrologists, methodologists, and epidemiologists. A systematic literature search was performed in PubMed, Embase, Scopus, Web of Science, and Cochrane Library between January 1, 2005, and November 12, 2022 (PROSPERO ID: CRD42020154747). All English language, original studies investigating the association between a biomarker and kidney allograft outcome were included. The final set of publications was assessed by expert reviewers. After data collection, two independent reviewers randomly evaluated the inconsistencies for 30% of the references for each reviewer. If more than 5% of inconsistencies were observed for one given reviewer, a re-evaluation was conducted for all the references of the reviewer. The biomarkers were categorized according to their type and the biological milieu from which they were measured. The study characteristics related to the design, methods, results, and their interpretation were assessed, as well as reproducible research practices and transparency indicators. Results A total of 7372 publications were screened and 804 studies met the inclusion criteria. A total of 1143 biomarkers were assessed among the included studies from blood (n=821, 71.8%), intragraft (n=169, 14.8%), or urine (n=81, 7.1%) compartments. The number of studies significantly increased, with a median, yearly number of 31.5 studies (interquartile range [IQR], 23.8–35.5) between 2005 and 2012 and 57.5 (IQR, 53.3–59.8) between 2013 and 2022 (P < 0.001). A total of 655 studies (81.5%) were retrospective, while 595 (74.0%) used data from a single center. The median number of patients included was 232 (IQR, 96–629) with a median follow-up post-transplant of 4.8 years (IQR, 3.0–6.2). Only 4.7% of studies were externally validated. A total of 346 studies (43.0%) did not adjust their biomarker for key prognostic factors, while only 3.1% of studies adjusted the biomarker for standard-of-care patient monitoring factors. Data sharing, code sharing, and registration occurred in 8.8%, 1.1%, and 4.6% of studies, respectively. A total of 158 studies (20.0%) emphasized the clinical relevance of the biomarker, despite the reported nonsignificant association of the biomarker with the outcome measure. A total of 288 studies assessed rejection as an outcome. We showed that these rejection studies shared the same characteristics as other studies. Conclusions Biomarker studies in kidney transplantation lack validation, rigorous design and methodology, accurate interpretation, and transparency. Higher standards are needed in biomarker research to prove the clinical utility and support clinical use.

Abstract Background and Aims The iBox is a validated prognostication system predicting long-term kidney allograft failure. Recently, it received regulatory endorsement by EMA, for surrogate endpoint for clinical trials. As the iBox system was primarily built using a deep phenotyped cohort, there is a need for proof of validity in extended clinical scenarios, geographic distinct medico-economic cohorts and transplant allocation systems. Method 10,851 transplant recipients were included from 17 academic medical centers from France, Belgium, Spain, Germany, Finland, United States, Brazil and Argentina. We applied to these cohorts the iBox algorithm that integrates eight independent prognostic factors including the time from transplantation to risk evaluation, functional parameters (eGFR, proteinuria), allograft histological lesions (IFTA, g+ptc, i+t, cg Banff scores), and circulating anti-HLA DSA. We stratified the performances of the iBox according to several real-life scenarios, including: 1) iBox + different eGFR formulas (MDRD186, MDRD175, CKD-Epi); 2) iBox + urinary dipstick; 3) iBox Functional + Structural (absence of DSA measurements); 4) iBox functional + Immunological (absence of histology); 5) iBox in response to treatment in T-cell mediated rejection (TCMR); 6) iBox for in response to treatment antibody mediated rejection (ABMR) clinical trials. The performances of the iBox system were assessed with the discrimination (C-index) and calibration. Results The derivation cohort included 4,000 recipients from France, and the international external validation cohort included 6,851 recipients from Europe (France, Belgium, Spain, Germany, Finland n = 4,643), the United States (n = 1,537) and South America (Brazil, Argentina n = 671). The mean recipient age was 50.26 years (14.05) with a median follow-up after evaluations of 5.41 years [IQR: 3.26 to 7]. 1336 patients (12.31%) lost their graft during the study follow-up. The performances of the iBox were confirmed in the different real-life setting with the following C-Index: 1) iBox + different eGFR formulas (MDRD186, MDRD175, CKD-Epi) 0.81; 2) iBox + urinary dipstick 0.80; 3) iBox Functional + Structural (histology) 0.80 (derivation) and 0.84 (validation); 4) iBox functional + Immunological 0.80 (derivation) and 0.83 (validation); 5) iBox in response to treatment in T-cell mediated rejection 0.81; 6) iBox for in response to treatment antibody mediated rejection trials 0.81. The score showed an accurate calibration in every scenario. Conclusion The iBoxEXTENDED trial confirms in various medico-economic settings the performances transportability and surrogacy of the iBox system, further reinforcing its use as a surrogate end point for clinical trials including TCMR and ABMR.

Background The COVID-19 pandemic has severely affected health systems and medical research worldwide but its impact on the global publication dynamics and non-COVID-19 research has not been measured. We hypothesized that the COVID-19 pandemic may have impacted the scientific production of non-COVID-19 research. Methods We conducted a comprehensive meta-research on studies (original articles, research letters and case reports) published between 01/01/2019 and 01/01/2021 in 10 high-impact medical and infectious disease journals (New England Journal of Medicine, Lancet, Journal of the American Medical Association, Nature Medicine, British Medical Journal, Annals of Internal Medicine, Lancet Global Health, Lancet Public Health, Lancet Infectious Disease and Clinical Infectious Disease). For each publication, we recorded publication date, publication type, number of authors, whether the publication was related to COVID-19, whether the publication was based on a case series, and the number of patients included in the study if the publication was based on a case report or a case series. We estimated the publication dynamics with a locally estimated scatterplot smoothing method. A Natural Language Processing algorithm was designed to calculate the number of authors for each publication. We simulated the number of non-COVID-19 studies that could have been published during the pandemic by extrapolating the publication dynamics of 2019 to 2020, and comparing the expected number to the observed number of studies. Results Among the 22,525 studies assessed, 6319 met the inclusion criteria, of which 1022 (16.2%) were related to COVID-19 research. A dramatic increase in the number of publications in general journals was observed from February to April 2020 from a weekly median number of publications of 4.0 (IQR: 2.8–5.5) to 19.5 (IQR: 15.8–24.8) ( p < 0.001), followed afterwards by a pattern of stability with a weekly median number of publications of 10.0 (IQR: 6.0–14.0) until December 2020 ( p = 0.045 in comparison with April). Two prototypical editorial strategies were found: 1) journals that maintained the volume of non-COVID-19 publications while integrating COVID-19 research and thus increased their overall scientific production, and 2) journals that decreased the volume of non-COVID-19 publications while integrating COVID-19 publications. We estimated using simulation models that the COVID pandemic was associated with a 18% decrease in the production of non-COVID-19 research. We also found a significant change of the publication type in COVID-19 research as compared with non-COVID-19 research illustrated by a decrease in the number of original articles, (47.9% in COVID-19 publications vs 71.3% in non-COVID-19 publications, p < 0.001). Last, COVID-19 publications showed a higher number of authors, especially for case reports with a median of 9.0 authors (IQR: 6.0–13.0) in COVID-19 publications, compared to a median of 4.0 authors (IQR: 3.0–6.0) in non-COVID-19 publications ( p < 0.001). Conclusion In this meta-research gathering publications from high-impact medical journals, we have shown that the dramatic rise in COVID-19 publications was accompanied by a substantial decrease of non-COVID-19 research. Meta-research registration https://osf.io/9vtzp/ .

Introduction: Partial nephrectomy to treat early-stage renal cell carcinoma has become one of the surgeries of choice for patients in Argentina. However, long-term results in the country are unknown. In this study, we analyzed the progression to chronic kidney disease and the appearance of metastasis after partial or radical nephrectomy in renal cell carcinoma patients. Methods: A retrospective, cohort study was conducted. We included all patients suffering from IT1 stage clear cell renal carcinoma who, between 2006 and 2012, underwent partial nephrectomy in our hospital. Follow-up continued until January 2018. Results: Thirty-two patients were included (19 had undergone radical nephrectomy and 13, partial nephrectomy). Subjects who had radical nephrectomy showed a more rapid progression to chronic kidney disease as compared to the subjects in the partial nephrectomy group (radical nephrectomy 63.2% vs. partial nephrectomy 15.4%; p=0.007). There were no differences in the follow-up period in both groups (radical nephrectomy 69.3% +/- 23.8 months vs. partial nephrectomy 72.5 +/- 26.9 months; p=0.73). Risk of progression to end-stage chronic kidney disease was 11 times higher for subjects who had undergone radical nephrectomy as compared to subjects who had had partial nephrectomy (adjusted HR 11.12; 95% CI: 1.24-99.9; p=0.031), adjusted by the rest of traditional risk factors. None of the T1a patients had metastasis during follow-up, regardless of the type of surgery. Conclusion: According to the findings of our study, partial nephrectomy preserves long-term renal function better than radical nephrectomy and has an excellent oncologic safety profile in T1a stage renal cell carcinoma patients. Radical nephrectomy was an independent risk factor of progression to chronic kidney disease.

espanolIntroduccion: El uso de la nefrectomia parcial para el tratamiento del carcinoma de celulas renales en estadios tempranos se ha convertido en una de las intervenciones preferidas para estos pacientes en la Argentina. Sin embargo, sus resultados en el pais a largo plazo aun se desconocen. En este estudio analizamos la progresion a enfermedad renal cronica y aparicion de metastasis posterior a nefrectomia parcial y radical, en pacientes con carcinoma de celulas renales. Material y metodos: Se realizo un estudio de cohorte retrospectivo. Se incluyeron a todos los pacientes con carcinoma renal de celulas claras en estadio T1 que, entre 2006 y 2012, se sometieron a nefrectomia en nuestro hospital. Se realizo un seguimiento hasta enero del 2018. Resultados: Se incluyeron 32 pacientes (19 con nefrectomia radical y 13 con nefrectomia parcial). Comparado con el grupo de nefrectomia parcial, los individuos sometidos a nefrectomia radical presentaron mayor progresion a enfermedad renal cronica (nefrectomia radical 63,2% vs nefrectomia parcial 15,4%; p=0,007). No existieron diferencias en el tiempo de seguimiento de ambos grupos (nefrectomia radical 69,3 ± 23,8 vs nefrectomia parcial 72,5 ± 26,9 meses; p=0,73). Los sujetos sometidos a nefrectomia radical tuvieron 11 veces mayor riesgo de progresion a enfermedad renal cronica que los de nefrectomia parcial (HR ajustado 11,12, IC95 1,24-99,9; p=0,031) ajustado por los demas factores de riesgo tradicionales. Ningun paciente con estadio T1a presento metastasis durante todo el seguimiento, independientemente del tipo de cirugia. Conclusion: En nuestro estudio, la nefrectomia parcial preserva mejor la funcion renal a largo plazo que la nefrectomia radical y tiene un excelente perfil de seguridad oncologico en pacientes con carcinoma de celulas renales en estadio T1a. La nefrectomia radical fue un factor de riesgo independiente de progresion a enfermedad renal cronica. EnglishIntroduction: Partial nephrectomy to treat early-stage renal cell carcinoma has become one of the surgeries of choice for patients in Argentina. However, long-term results in the country are unknown. In this study, we analyzed the progression to chronic kidney disease and the appearance of metastasis after partial or radical nephrectomy in renal cell carcinoma patients. Methods: A retrospective, cohort study was conducted. We included all patients suffering from T1 stage clear cell renal carcinoma who, between 2006 and 2012, underwent nephrectomy in our hospital. Follow-up continued until January 2018. Results: Thirty-two patients were included (19 had undergone radical nephrectomy and 13, partial nephrectomy). Subjects who had radical nephrectomy showed a more rapid progression to chronic kidney disease as compared to the subjects in the partial nephrectomy group (radical nephrectomy 63.2% vs. partial nephrectomy 15.4%; p=0.007). There were no differences in the follow-up period in both groups (radical nephrectomy 69.3% ± 23.8 months vs. partial nephrectomy 72.5 ± 26.9 months; p=0.73). Risk of progression to end-stage chronic kidney disease was 11 times higher for subjects who had undergone radical nephrectomy as compared to subjects who had had partial nephrectomy (adjusted HR 11.12; 95% CI: 1.24-99.9; p=0.031), adjusted by the rest of traditional risk factors. None of the T1a patients had metastasis during follow-up, regardless of the type of surgery. Conclusion: According to the findings of our study, partial nephrectomy preserves long-term renal function better than radical nephrectomy and has an excellent oncologic safety profile in T1a stage renal cell carcinoma patients. Radical nephrectomy was an independent risk factor of progression to chronic kidney disease.

Infections are frequent complications of kidney transplants. We aimed at determining the frequency and type of infections that occur in renal transplant recipients during the early (0-1 month), intermediate (1-6 months) and late (6-12 months) post-transplant period and analyzing the risk factors for infection. To this aim, we conducted a retrospective cohort study on 1-year post-transplant follow-up in two third-level university hospitals in Cordoba city. All consecutive recipients of renal transplants performed between 2009 and 2015 were included, except those with multiple solid organ transplantation and pediatric patients. We included 375 recipients, of which 235 (62.7%) had at least one episode of infection during follow-up. There were 504 episodes of infection, of which 131 (26%) occurred in the early, 272 (53.9%) in the intermediate, and 101 (20.1%) in the late post-transplant period. The most frequent infections in all periods were caused by bacteria (mainly urinary tract infections), and the most frequent viral infection was caused by Cytomegalovirus (mainly in the second and third period). In the multivariate analysis, infection risk factors were: age > 60 years (adjusted odds ratio [aOR] = 1.92; 95% CI = 1.05-3.49), organ transplantation from deceased donor (aOR = 8.19; 95% CI = 2.32-28.9), use of pigtail catheter for urinary tract drainage (aOR = 4.06; 95% CI = 1.27-12.9), and number of days in hospital after transplant (aOR = 1.05; 95% CI = 1.01-1.11). In conclusion, infections in renal transplant recipients represent a very frequent health problem in our hospitals. Understanding the local epidemiology of infection and the potential risk factors for infection acquires utmost importance.

Infections are frequent complications of kidney transplants. We aimed at determining the frequency and type of infections that occur in renal transplant recipients during the early (0-1 month), intermediate (1-6 months) and late (6-12 months) post-transplant period and analyzing the risk factors for infection. To this aim, we conducted a retrospective cohort study on 1-year post-transplant follow-up in two third-level university hospitals in Cordoba city. All consecutive recipients of renal transplants performed between 2009 and 2015 were included, except those with multiple solid organ transplantation and pediatric patients. We included 375 recipients, of which 235 (62.7%) had at least one episode of infection during follow-up. There were 504 episodes of infection, of which 131 (26%) occurred in the early, 272 (53.9%) in the intermediate, and 101 (20.1%) in the late post-transplant period. The most frequent infections in all periods were caused by bacteria (mainly urinary tract infections), and the most frequent viral infection was caused by Cytomegalovirus (mainly in the second and third period). In the multivariate analysis, infection risk factors were: age > 60 years (adjusted odds ratio [aOR] = 1.92; 95% CI = 1.05-3.49), organ transplantation from deceased donor (aOR = 8.19; 95% CI = 2.32-28.9), use of pigtail catheter for urinary tract drainage (aOR = 4.06; 95% CI = 1.27-12.9), and number of days in hospital after transplant (aOR = 1.05; 95% CI = 1.01-1.11). In conclusion, infections in renal transplant recipients represent a very frequent health problem in our hospitals. Understanding the local epidemiology of infection and the potential risk factors for infection acquires utmost importance.

Background. The impact of renal transplantation (RT) in the elderly with many comorbid conditions is a matter of concern. The aim of our study was to assess the impact of RT on the survival of patients older than 60 years compared with those remaining on the waiting list (WL) according to their comorbidities. Methods. In this multicentric observational retrospective cohort study, we included all patients older than 60 years old admitted on the WL from 01 January 2006 to 31 December 2016. The Charlson comorbidity index (CCI) score was calculated for each patient at inclusion on the WL. Kidney donor risk index was used to assess donor characteristics. Results. One thousand and thirty-six patients were included on the WL of which 371 (36%) received an RT during a median follow-up period of 2.5 (1.4–4.1) years. Patient survival was higher after RT compared to patients remaining on the WL, 87%, 80%, and 72% versus 87%, 55%, and 30% at 1, 3, and 5 years, respectively. After RT survival at 5 years was 37% higher for patients with CCI ≥ 3, and 46% higher in those with CCI < 3, compared with patients remaining on the WL. On univariate and multivariate analysis, patient survival was independently associated with a CCI of ≥3 (hazard ratio 1.62; confidence interval 1.09-2.41; P < 0.02) and the use of calcineurin-based therapy maintenance therapy (hazard ratio 0.53; confidence interval 0.34-0.82; P < 0.004). Conclusions. Our study showed that RT improved survival in patients older than 60 years even those with high comorbidities. The survival after transplantation was also affected by comorbidities.