Septic acute kidney injury and gut microbiome: Should we change our approach?

Incidence of acute kidney injury (AKI) remained relatively stable over the last decade and the adjusted risks for it and mortality are similar across different continents and regions. Also, the mortality of septic-AKI can reach 70% in critically-ill patients. These sole facts can give rise to a question: is there something we do not understand yet? Currently, there are no specific therapies for septic AKI and the treatment aims only to maintain the mean arterial pressure over 65mmHg by ensuring a good fluid resuscitation and by using vasopressors, along with antibiotics. On the other hand, there is an increased concern about the different hemodynamic changes in septic AKI versus other forms and the link between the gut microbiome and the severity of septic AKI. Fortunately, progress has been made in the form of administration of pre- and probiotics, short chain fatty acids (SCFA), especially acetate, and also broad-spectrum antibiotics or selective decontaminants of the digestive tract in a successful attempt to modulate the microbial flora and to decrease both the severity of AKI and mortality. In conclusion, septic-AKI is a severe form of kidney injury, with particular hemodynamic changes and with a strong link between the kidney and the gut microbiome. By modulating the immune response we could not only treat but also prevent severe forms. The most difficult part is to categorize patients and to better understand the key mechanisms of inflammation and cellular adaptation to the injury, as these mechanisms can serve in the future as target therapies.

Septic acute kidney injury and gut microbiome: Should we change our approach? / Lesión renal aguda secundaria a sepsis y microbioma intestinal: ¿debemos modificar nuestro enfoque?

Incidence of acute kidney injury (AKI) remained relatively stable over the last decade and the adjusted risks for it and mortality are similar across different continents and regions. Also, the mortality of septic-AKI can reach 70% in critically-ill patients. These sole facts can give rise to a question: is there something we do not understand yet? Currently, there are no specific therapies for septic AKI and the treatment aims only to maintain the mean arterial pressure over 65mmHg by ensuring a good fluid resuscitation and by using vasopressors, along with antibiotics. On the other hand, there is an increased concern about the different hemodynamic changes in septic AKI versus other forms and the link between the gut microbiome and the severity of septic AKI. Fortunately, progress has been made in the form of administration of pre- and probiotics, short chain fatty acids (SCFA), especially acetate, and also broad-spectrum antibiotics or selective decontaminants of the digestive tract in a successful attempt to modulate the microbial flora and to decrease both the severity of AKI and mortality. In conclusion, septic-AKI is a severe form of kidney injury, with particular hemodynamic changes and with a strong link between the kidney and the gut microbiome. By modulating the immune response we could not only treat but also prevent severe forms. The most difficult part is to categorize patients and to better understand the key mechanisms of inflammation and cellular adaptation to the injury, as these mechanisms can serve in the future as target therapies.(AU)

La incidencia de la lesión renal aguda (LRA) se ha mantenido relativamente estable a lo largo de la última década, con unos riesgos ajustados de padecer y morir a consecuencia de esta enfermedad similares en los distintos continentes y regiones. La mortalidad asociada a la LRA secundaria a sepsis puede llegar a 70% en los pacientes que se encuentran en estado crítico. Estos hechos, por sí mismos, deben llevarnos a plantearnos la siguiente pregunta: ¿se nos escapa algo que aún no comprendemos? Actualmente no se dispone de terapias específicas para la LRA secundaria a sepsis y el tratamiento se centra únicamente en mantener la presión arterial media por encima de los 65mmHg mediante una rehidratación adecuada, vasopresores y antibióticos. Asimismo, cada vez existe mayor interés por las diferentes alteraciones hemodinámicas que se producen en comparación con otras formas de la enfermedad, así como por la relación existente entre el microbioma intestinal y la gravedad. Afortunadamente, se ha avanzado notablemente en la forma en la que se administran los prebióticos y los probióticos, los ácidos grasos de cadena corta (AGCC), especialmente el acetato, los antibióticos de amplio espectro o los detoxificantes selectivos del tracto digestivo, en un intento exitoso de modular la flora microbiana y disminuir tanto la gravedad de la LRA como su mortalidad. En conclusión, la LRA secundaria a sepsis es una forma grave de lesión renal que provoca unos cambios hemodinámicos específicos y en la que se observa una estrecha relación entre la función renal y el microbioma intestinal. La modulación de la respuesta inmunitaria no solo permitiría tratar esta enfermedad, sino también prevenir las formas graves de la misma. La parte más difícil de este enfoque radica en clasificar correctamente a los pacientes y comprender mejor los mecanismos clave de la inflamación y la adaptación celular a la lesión, ya que estos pueden convertirse en futuras dianas terapéuticas.(AU)

The Impact of Patient Characteristics, Risk Factors, and Surgical Intervention on Survival in a Cohort of Patients Undergoing Neoadjuvant Treatment for Cervical Cancer.

Introduction: Cervical cancer is among the most frequent types of neoplasia worldwide and remains the fourth leading cause of cancer death in women, a fact that raises the necessity for further development of therapeutic strategies. NCCN guidelines recommend radiation therapy with or without chemotherapy as the gold standard for locally advanced cervical cancer. Also, some studies claim that performing surgery after chemo-radiation therapy does not necessarily improve the therapeutic outcome. This study aims to determine the impact of the risk factors, various characteristics, and surgical treatment for patients in different stages of the disease on survival rate. Material and methods: Our study started as a retrospective, observational, unicentric one, carried out on a cohort of 96 patients diagnosed with cervical cancer from the surgical department of the Bucharest Oncological Institute, followed from 1 January 2019 for a period of 3 years. After the registration of the initial parameters, however, the study became prospective, as the patients were closely monitored through periodical check-ups. The end-point of the study is either the death of the participants or reaching the end of the follow-up period, and, therefore, we divided the cohort into two subgroups: the ones who survived after three years and the ones who did not. All 96 patients, with disease stages ranging from IA2 to IIIB, underwent radio-chemotherapy followed by adjuvant surgery. Results: Among the 96 patients, 45 (46%) presented residual tumor after radio-chemotherapy. Five patients (5%) presented positive resection margins at the post-operative histopathological examination. The presence of residual tumor, the FIGO stage post-radiotherapy, positive resection margins, and lympho-vascular and stromal invasions differed significantly between the subgroups, being more represented in the subgroup that reached the end-point. Variables correlated with the worst survival in Kaplan-Meier were the pelvic lymph node involvement-50% at three years (p-0.015)-and the positive resection margins-only 20% at three years (p < 0.001). The univariate Cox model identified as mortality-associated risk factors the same parameters as above, but also the intraoperative stage III FIGO (p < 0.001; HR 9.412; CI: 2.713 to 32.648) and the presence of post-radiotherapy adenopathy (p-0.031; HR: 3.915; CI: 1.136 to 13.487) identified through imagistic methods. The independent predictors of the overall survival rate identified were the positive resection margins (p-0.002; HR: 6.646; CI 2.0 to 22.084) and the post-radiotherapy stage III FIGO (p-0.003; HR: 13.886; CI: 2.456 to 78.506). Conclusions: The most important predictor factors of survival rate are the positive resection margins and the FIGO stage after radiotherapy. According to the NCCN guidelines in stages considered advanced (beyond stages IB3, IIA2), the standard treatment is neoadjuvant chemoradiotherapy. In our study, with radical surgery after neoadjuvant therapy, 46% of patients presented residual tumor at the intraoperative histopathological examination, a fact that makes the surgical intervention an important step in completing the treatment of these patients. In addition, based on the patient's features/comorbidities and the clinical response to chemotherapy/radiotherapy, surgeons could carefully tailor the extent of radical surgery, thus resulting in a personalized surgical approach for each patient. However, a potential limitation can be represented by the relatively small number of patients (96) and the unicentric nature of our study.

The Impact of Infections on the Progression of Chronic Kidney Disease.

Background and Objective: Infectious diseases continue to be a global burden and their impact is even worse if the patients already have other comorbidities. Because chronic kidney disease is very frequent, affecting 10% of the population, our study aims to explore the impact that infectious events have on its progression. Material and Methods: This is a retrospective, observational study based on a cohort of 238 dialyzed patients from the Nephrology Clinic of "Dr. Carol Davila" Clinical Hospital of Nephrology, Bucharest, who were followed from their first visit for five years, between 1 January 2007 and 1 January 2022. For each of them, the presence of an infectious event and the moment of the initiation of dialysis were recorded. Results: Statistical analysis showed that the patients who had at least one infectious episode were older (p = 0.004), their hemoglobin and lymphocytes were significantly lower (p = 0.03 and p = 0.02, respectively) and the time until the initiation of dialysis was lower (p = 0.007). Also, the preservation of kidney function was influenced by the number and the severity of infectious episodes. In the univariate Cox model, the following variables were associated with increased risk of dialysis: advanced age (p: 0.009; HR: 1.021; CI: 1.005 to 1.036), low hemoglobin (p: 0.001; HR: 0.861; CI: 0.786 to 0.943), previous diagnosis of chronic obstructive pulmonary disease (p: 0.002; HR: 2.467; CI: 1.376 to 4.424), presence of hematuria (p: 0.03; HR: 1.604; CI: 1.047 to 2.457) and increased values of proteinuria (p: 0.01; HR: 1.122; CI: 1.028 to 1.224) and of serum creatinine measured both at the time of the first visit and at the time of each infectious event (p: <0.001; HR: 1.262; CI: 1.141 to 1.396). Also, the presence of an infectious episode was associated with a 1.7-fold increase in the risk of dialysis initiation. The independent predictors of survival identified by the multivariate Cox model were age (p: 0.004; HR: 1.034; CI: 1.010-1.058), serum creatinine (p: <0.001; HR: 1.421; CI: 1.203 to 1.658) and proteinuria (p: <0.001; HR: 1.241; CI: 1.126 to 1.369) at the time of enrollment, but also the presence of an infectious episode during the patient's evolution (p: 0.04; HR: 1.705; CI: 1.013 to 2.868). Conclusions: In the evolution of patients with chronic kidney disease, an active search for individual factors favoring the occurrence of infectious episodes should be taken into consideration to prevent a faster progression toward end-stage kidney disease.

Chronic Kidney Disease, Urinary Tract Infections and Antibiotic Nephrotoxicity: Are There Any Relationships?

Chronic kidney disease (CKD) has been a constant burden worldwide, with a prevalence of more than 10% of the population and with mortality reaching 1.2 million deaths and 35.8 million disability-adjusted life years (DALYs) in 2017, as it is claimed by the Global Burden of Diseases. Moreover, an increase in its prevalence is expected in the next years due to a rise in the number of people suffering from obesity, diabetes mellitus and hypertension. On the other hand, with cardiovascular morbidity and mortality showing a downward trend, maybe it is time to focus on CKD, to minimize the preventable risk factors involved in its progression toward end-stage kidney disease (ESKD) and to offer a better quality of life. Another major health burden is represented by infectious diseases, particularly urinary tract infections (UTIs), as it is considered that approximately 40-50% of women and 5% of men will have at least one episode during their lifetime. Additionally, CKD consists of a constellation of immunological and metabolical disturbances that lead to a greater risk of UTIs: increased apoptosis of lymphocytes, elevated levels of tumor necrosis factor α and interleukin 6, which lower the function of neutrophils and increased levels of uremic toxins like p-cresyl sulfate and indoxyl sulfate, which alter the adherence and migration of leukocytes to the sites of injury. Moreover, UTIs can lead to a more rapid decline of kidney function, especially in stages G3-G5 of CKD, with all the complications involved. Last, but not least, antibiotherapy is often complicated in this category of patients, as antibiotics can also negatively affect the kidneys. This review will try to focus on the particularities of the urinary microbiome, asymptomatic bacteriuria and UTIs and the subtle balance between the risks of them and the risks of antibiotherapy in the evolution of CKD.