Prognostic Biomarkers in Kidney Transplantation: A Systematic Review and Critical Appraisal.

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.

Impact of the COVID-19 pandemic on publication dynamics and non-COVID-19 research production.

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/ .

Renal Transplantation in Patients Older Than 60 Years With High Comorbidity. Is There a Survival Benefit? A Multicenter Study in Argentina.

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.

Infections in the first year after renal transplant.

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.

Las infecciones son complicaciones frecuentes de los trasplantes renales. Los objetivos del estudio fueron determinar la frecuencia y el tipo de infecciones que ocurren en el período post-trasplante temprano (0-1 mes), intermedio (1-6 meses) y tardío (6-12 meses) en nuestro medio y analizar los factores de riesgo de infección. Se realizó un estudio de cohorte retrospectivo que incluyó todos los pacientes con trasplantes renales realizados entre 2009 y 2015 en dos hospitales universitarios de tercer nivel de la ciudad de Córdoba, excluidos los receptores de trasplante simultáneo de múltiples órganos sólidos y los menores de 18 años. Fueron incluidos 375 pacientes, de los cuales 235 (62.7%) tuvieron al menos un episodio de infección. Hubo 504 episodios de infección: 131 (26%) ocurrieron en el período temprano, 272 (53.9%) en el intermedio y 101 (20.1%) en el tardío. La mayoría de las infecciones fueron de origen bacteriano (principalmente del tracto urinario). La mayoría de las infecciones virales ocurrieron en el segundo y el tercer período y Citomegalovirus fue el responsable más frecuente. En el análisis multivariado, los factores de riesgo de infección post-transplante renal fueron: edad > 60 años (odds ratio ajustado [aOR] 1.92; IC95% 1.05-3.49), donante cadavérico (aOR 8.19; IC95% 2.32-28.9), uso de catéter pigtail (aOR 4.06; IC95% 1.27-12.9) y número de días internado postrasplante (aOR 1.05; IC95% 1.01-1.11). En conclusión, confirmamos que las infecciones en pacientes con trasplante renal son muy frecuentes en nuestro medio, por lo cual es importante conocer la epidemiología local y los factores de riesgo.

Enfermedad renal crónica y aparición de metástasis posterior a nefrectomía radical y parcial por carcinoma renal de células claras / Chronic kidney disease and clear renal cell carcinoma metastasis following radical or partial nephrectomy

RESUMEN Introducción: El uso de la nefrectomía parcial para el tratamiento del carcinoma de células 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 país a largo plazo aún se desconocen. En este estudio analizamos la progresión a enfermedad renal crónica y aparición de metástasis posterior a nefrectomía parcial y radical, en pacientes con carcinoma de células renales. Material y métodos: Se realizó un estudio de cohorte retrospectivo. Se incluyeron a todos los pacientes con carcinoma renal de células claras en estadio T1 que, entre 2006 y 2012, se sometieron a nefrectomía parcial en nuestro hospital. Se realizó un seguimiento hasta enero del 2018. Resultados: Se incluyeron 32 pacientes (19 con nefrectomía radical y 13 con nefrectomía parcial). Comparado con el grupo de nefrectomía parcial, los individuos sometidos a nefrectomía radical presentaron mayor progresión a enfermedad renal crónica (nefrectomía radical 63,2% vs nefrectomía parcial 15,4%; p=0,007). No existieron diferencias en el tiempo de seguimiento de ambos grupos (nefrectomía radical 69,3 ± 23,8 vs nefrectomía parcial 72,5 ± 26,9 meses; p=0,73). Los sujetos sometidos a nefrectomía radical tuvieron 11 veces mayor riesgo de progresión a enfermedad renal crónica que los de nefrectomía parcial (HR ajustado 11,12, IC95 1,24-99,9; p=0,031) ajustado por los demás factores de riesgo tradicionales. Ningún paciente con estadio T1a presentó metástasis durante todo el seguimiento, independientemente del tipo de cirugía. Conclusión: En nuestro estudio, la nefrectomía parcial preserva mejor la función renal a largo plazo que la nefrectomía radical y tiene un excelente perfil de seguridad oncológico en pacientes con carcinoma de células renales en estadio T1a. La nefrectomía radical fue un factor de riesgo independiente de progresión a enfermedad renal crónica.

ABSTRACT 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 T1 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.

Infections in the first year after renal transplant / Infecciones en el primer año post-trasplante renal

Abstract 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.

Resumen Las infecciones son complicaciones frecuentes de los trasplantes renales. Los objetivos del estudio fueron determinar la frecuencia y el tipo de infecciones que ocurren en el período post-trasplante temprano (0-1 mes), intermedio (1-6 meses) y tardío (6-12 meses) en nuestro medio y analizar los factores de riesgo de infección. Se realizó un estudio de cohorte retrospectivo que incluyó todos los pacientes con trasplantes renales realizados entre 2009 y 2015 en dos hospitales universitarios de tercer nivel de la ciudad de Córdoba, excluidos los receptores de trasplante simultáneo de múltiples órganos sólidos y los menores de 18 años. Fueron incluidos 375 pacientes, de los cuales 235 (62.7%) tuvieron al menos un episodio de infección. Hubo 504 episodios de infección: 131 (26%) ocurrieron en el período temprano, 272 (53.9%) en el intermedio y 101 (20.1%) en el tardío. La mayoría de las infecciones fueron de origen bacteriano (principalmente del tracto urinario). La mayoría de las infecciones virales ocurrieron en el segundo y el tercer período y Citomegalovirus fue el responsable más frecuente. En el análisis multivariado, los factores de riesgo de infección post-transplante renal fueron: edad > 60 años (odds ratio ajustado [aOR] 1.92; IC95% 1.05-3.49), donante cadavérico (aOR 8.19; IC95% 2.32-28.9), uso de catéter pigtail (aOR 4.06; IC95% 1.27-12.9) y número de días internado postrasplante (aOR 1.05; IC95% 1.01-1.11). En conclusión, confirmamos que las infecciones en pacientes con trasplante renal son muy frecuentes en nuestro medio, por lo cual es importante conocer la epidemiología local y los factores de riesgo.