Precision management of acute kidney injury in the intensive care unit: current state of the art.

Acute kidney injury (AKI) is a prototypical example of a common syndrome in critical illness defined by consensus. The consensus definition for AKI, traditionally defined using only serum creatinine and urine output, was needed to standardize the description for epidemiology and to harmonize eligibility for clinical trials. However, AKI is not a simple disease, but rather a complex and multi-factorial syndrome characterized by a wide spectrum of pathobiology. AKI is now recognized to be comprised of numerous sub-phenotypes that can be discriminated through shared features such as etiology, prognosis, or common pathobiological mechanisms of injury and damage. The characterization of sub-phenotypes can serve to enable prognostic enrichment (i.e., identify subsets of patients more likely to share an outcome of interest) and predictive enrichment (identify subsets of patients more likely to respond favorably to a given therapy). Existing and emerging biomarkers will aid in discriminating sub-phenotypes of AKI, facilitate expansion of diagnostic criteria, and be leveraged to realize personalized approaches to management, particularly for recognizing treatment-responsive mechanisms (i.e., endotypes) and targets for intervention (i.e., treatable traits). Specific biomarkers (e.g., serum renin; olfactomedin 4 (OLFM4); interleukin (IL)-9) may further enable identification of pathobiological mechanisms to serve as treatment targets. However, even non-specific biomarkers of kidney injury (e.g., neutrophil gelatinase-associated lipocalin, NGAL; [tissue inhibitor of metalloproteinases 2, TIMP2]·[insulin like growth factor binding protein 7, IGFBP7]; kidney injury molecule 1, KIM-1) can direct greater precision management for specific sub-phenotypes of AKI. This review will summarize these evolving concepts and recent innovations in precision medicine approaches to the syndrome of AKI in critical illness, along with providing examples of how they can be leveraged to guide patient care.

Using the Cecal Ligation and Puncture Model of Sepsis to Induce Rats to Multiple Organ Dysfunction.

Sepsis is a dysregulated hyperinflammatory disease caused by infection. Sepsis leads to multiple organ dysfunction syndrome (MODS), which is associated with high rates of mortality. The cecal ligation and puncture (CLP) model has been widely used in animals and has become the gold-standard method of replicating features of sepsis in humans. Despite several studies and modified CLP protocols, there are still open questions regarding the multifactorial determinants of its reproducibility and medical significance. In our protocol, which is also aimed at mimicking the sepsis observed in clinical practice, male Wistar rats are submitted to CLP with adequate fluid resuscitation (0.15 M NaCl, 25 ml/kg BW i.p.) immediately after surgery. At 6 h after CLP, additional fluid therapy (0.15 M NaCl, 25 ml/kg BW s.c.) and antibiotic therapy with imipenem-cilastatin (single dose of 14 mg/kg BW s.c.) are administered. The timing of the fluid and antibiotic therapy correspond to the initial care given when patients are admitted to the intensive care unit. This model of sepsis provides a useful platform for simulating human sepsis and could lay the groundwork for the development of new treatments.

Early Start Peritoneal Dialysis: Technique Survival in Long-Term Follow-Up.

BACKGROUND/AIMS: Peritoneal dialysis (PD) has gained interest over the last decade as a viable option for early start dialysis. It is still unknown if shorter break-in periods and less time for proper patient evaluation and training could influence technique survival in comparison to planned-start PD. METHODS: A prospective and observational study that compared technique survival in a cohort of patients who started either early or planned PD. Early start PD was defined as break-in period from 3 to 14 days with no previous nephrologist follow-up or patient training. RESULTS: A total of 154 patients were included (40 as early start PD), followed by a median time of 381 days. Comparing early vs. planned-start PD, groups were similar concerning age 56 (40; 70) vs. 48 (32; 63) years, p=0.071, body mass index (BMI) 23.3 ± 4.2 vs. 23.8 ± 4.0 kg/m2, p=0.567 and male gender (60 vs. 48%, p=0.201), respectively. Comparing early vs. planned-start groups, there were no differences regarding PD dropout for peritonitis (7.5 vs. 11.4%, p=0.764), catheter dysfunction (12.5 vs. 17.5%, p=0.619) and patient burnout (0 vs. 4.4%, p=0.328), respectively. Less patients in early start group quit PD for peritoneal membrane failure in comparison to planned-start group (2.5 vs. 16.7%, p=0.026). In multivariate cox-regression analysis, the only factors independently associated with technique failure were BMI> 25 kg/m² (p=0.033) and Diabetes Mellitus (p=0.013), whereas no differences regarding early vs. planned-PD start were observed (p=0.184). CONCLUSION: Despite the adverse scenario for initiating dialysis, early start PD had similar outcomes in comparison to planned-start PD in long-term follow-up.

Acute Kidney Injury as a Condition of Renal Senescence.

Acute kidney injury (AKI), characterized by a sharp drop in glomerular filtration, continues to be a significant health burden because it is associated with high initial mortality, morbidity, and substantial health-care costs. There is a strong connection between AKI and mechanisms of senescence activation. After ischemic or nephrotoxic insults, a wide range of pathophysiological events occur. Renal tubular cell injury is characterized by cell membrane damage, cytoskeleton disruption, and DNA degradation, leading to tubular cell death by necrosis and apoptosis. The senescence mechanism involves interstitial fibrosis, tubular atrophy, and capillary rarefaction, all of which impede the morphological and functional recovery of the kidneys, suggesting a strong link between AKI and the progression of chronic kidney disease. During abnormal kidney repair, tubular epithelial cells can assume a senescence-like phenotype. Cellular senescence can occur as a result of cell cycle arrest due to increased expression of cyclin kinase inhibitors (mainly p21), downregulation of Klotho expression, and telomere shortening. In AKI, cellular senescence is aggravated by other factors including oxidative stress and autophagy. Given this scenario, the main question is whether AKI can be repaired and how to avoid the senescence process. Stem cells might constitute a new therapeutic approach. Mesenchymal stem cells (MSCs) can ameliorate kidney injury through angiogenesis, immunomodulation, and fibrosis pathway blockade, as well as through antiapoptotic and promitotic processes. Young umbilical cord-derived MSCs are better at increasing Klotho levels, and thus protecting tissues from senescence, than are adipose-derived MSCs. Umbilical cord-derived MSCs improve glomerular filtration and tubular function to a greater degree than do those obtained from adult tissue. Although senescence-related proteins and microRNA are upregulated in AKI, they can be downregulated by treatment with umbilical cord-derived MSCs. In summary, stem cells derived from young tissues, such as umbilical cord-derived MSCs, could slow the post-AKI senescence process.

Treatment With Human Wharton's Jelly-Derived Mesenchymal Stem Cells Attenuates Sepsis-Induced Kidney Injury, Liver Injury, and Endothelial Dysfunction.

UNLABELLED: : The pathophysiology of sepsis involves complex cytokine and inflammatory mediator networks. Downregulation of endothelial nitric oxide synthase contributes to sepsis-induced endothelial dysfunction. Human Wharton's jelly-derived mesenchymal stem cells (WJ-MSCs) are known to reduce expression of proinflammatory cytokines and markers of apoptosis. We hypothesized that treatment with WJ-MSCs would protect renal, hepatic, and endothelial function in a cecal ligation and puncture (CLP) model of sepsis in rats. Rats were randomly divided into three groups: sham-operated rats; rats submitted to CLP and left untreated; and rats submitted to CLP and intraperitoneally injected, 6 hours later, with 1 × 10(6) WJ-MSCs. The glomerular filtration rate (GFR) was measured at 6 and 24 hours after CLP or sham surgery. All other studies were conducted at 24 hours after CLP or sham surgery. By 6 hours, GFR had decreased in the CLP rats. At 24 hours, Klotho renal expression significantly decreased. Treatment with WJ-MSCs improved the GFR; improved tubular function; decreased the CD68-positive cell count; decreased the fractional interstitial area; decreased expression of nuclear factor κB and of cytokines; increased expression of eNOS, vascular endothelial growth factor, and Klotho; attenuated renal apoptosis; ameliorated hepatic function; increased glycogen deposition in the liver; and improved survival. Sepsis-induced acute kidney injury is a state of Klotho deficiency, which WJ-MSCs can attenuate. Klotho protein expression was higher in WJ-MSCs than in human adipose-derived MSCs. Because WJ-MSCs preserve renal and hepatic function, they might play a protective role in sepsis. SIGNIFICANCE: Sepsis is the leading cause of death in intensive care units. Although many different treatments for sepsis have been tested, sepsis-related mortality rates remain high. It was hypothesized in this study that treatment with human Wharton's jelly-derived mesenchymal stem cells (WJ-MSCs) would protect renal, hepatic, and endothelial function in a model of sepsis in rats. Treatment with WJ-MSCs improved the glomerular filtration rate, improved tubular function, decreased expression of nuclear factor κB and of cytokines, increased expression of eNOS and of Klotho, attenuated renal apoptosis, and improved survival. Sepsis-induced acute kidney injury is a state of Klotho deficiency, which WJ-MSCs can attenuate.

Conversion from temporary to tunneled catheters by nephrologists: report of a single-center experience.

BACKGROUND: Nephrologists have increasingly participated in the conversion from temporary catheters (TC) to tunneled-cuffed catheters (TCCs) for hemodialysis. OBJECTIVE: To prospectively analyze the outcomes associated with TCC placement by nephrologists with expertise in such procedure, in different time periods at the same center. The impact of vancomycin or cefazolin as prophylactic antibiotics on the infection outcomes was also tested. PATIENTS AND METHODS: Hemodialysis patients who presented to such procedure were divided into two cohorts: A (from 2004 to 2008) and B (from 2013 to 2015). Time from TC to TCC conversion, prophylactic antibiotics, and reasons for TCC removal were evaluated. RESULTS: One hundred and thirty patients were included in cohort A and 228 in cohort B. Sex, age, and follow-up time were similar between cohorts. Median time from TC to TCC conversion was longer in cohort A than in cohort B (14 [3; 30] vs 4 [1; 8] days, respectively; P⩽0.0001). Infection leading to catheter removal occurred in 26.4% vs 18.9% of procedures in cohorts A and B, respectively, and infection rate was 0.93 vs 0.73 infections per 1,000 catheter-days, respectively (P=0.092). Infection within 30 days from the procedure occurred in 1.4% of overall cohort. No differences were observed when comparing vancomycin and cefazolin as prophylactic antibiotics on 90-day infection-free TCC survival in a Kaplan-Meier model (log-rank = 0.188). TCC removal for low blood flow occurred in 8.9% of procedures. CONCLUSION: Conversion of TC to TCC by nephrologists had overall infection, catheter patency, and complications similar to data reported in the literature. Vancomycin was not superior to cefazolin as a prophylactic antibiotic.

Adesão ao tratamento da hipertensão e do diabetes: compreensão de elementos intervenientes segundo usuários de um serviço de atenção a saúde / Adherence to treatment for hypertension and diabetes: understanding factors involved for users of a primary health care service

Este trabalho teve como objetivo compreender os elementos intervenientes no processo de adesão ao tratamento da hipertensão arterial e do diabetes mellitus, segundo usuários de um serviço de atenção primária à saúde. Estudo qualitativo, descritivo e exploratório, com utilização de entrevista semiestruturada, realizado em um município do interior Baiano. A análise dos dados seguiu a modalidade categorial temática. Da análise dos 24 depoimentos, emergiram três categorias: 1. Elementos relacionados aos serviços de saúde; 2. Elementos relacionados aos indivíduos e ao seu estilo de vida e; 3. O medicamento como elemento central do tratamento. Tais elementos explicitam que o processo de adesão constitui-se um evento multifacetado e multideterminado, perpassando por fatores vinculados no tripé indivíduo, terapêutica e serviços de saúde, de modo que a sua compreensão deve estar alicerçada nessa visão paradigmática ampliada.

This study aimed to understand the elements involved in the process of adherence to the treatment of hypertension and diabetes mellitus, according to users of a primary health care service. A qualitative study, descriptive and exploratory, using semi-structured interviews, conducted in an inland city of Bahia. Data analysis followed the thematic category method. The analysis of 24 interviews revealed three categories:1-elements related to health services, 2-elements related to individuals and their lifestyle, and 3-medication as a central element of treatment. These elements clearly show that the adherence process is a multifaceted and multidimensional event, involving factors linked to the individual, therapy, and health services tripod, so that their understanding should be grounded in this expanded paradigmatic vision.

Effects of continuous erythropoietin receptor activator in sepsis-induced acute kidney injury and multi-organ dysfunction.

BACKGROUND: Despite advances in supportive care, sepsis-related mortality remains high, especially in patients with acute kidney injury (AKI). Erythropoietin can protect organs against ischemia and sepsis. This effect has been linked to activation of intracellular survival pathways, although the mechanism remains unclear. Continuous erythropoietin receptor activator (CERA) is an erythropoietin with a unique pharmacologic profile and long half-life. We hypothesized that pretreatment with CERA would be renoprotective in the cecal ligation and puncture (CLP) model of sepsis-induced AKI. METHODS: RATS WERE RANDOMIZED INTO THREE GROUPS: control; CLP; and CLP+CERA (5 µg/kg body weight, i.p. administered 24 h before CLP). At 24 hours after CLP, we measured creatinine clearance, biochemical variables, and hemodynamic parameters. In kidney tissue, we performed immunoblotting--to quantify expression of the Na-K-2Cl cotransporter (NKCC2), aquaporin 2 (AQP2), Toll-like receptor 4 (TLR4), erythropoietin receptor (EpoR), and nuclear factor kappa B (NF-κB)--and immunohistochemical staining for CD68 (macrophage infiltration). Plasma interleukin (IL)-2, IL-1ß, IL-6, IL-10, interferon gamma, and tumor necrosis factor alpha were measured by multiplex detection. RESULTS: Pretreatment with CERA preserved creatinine clearance and tubular function, as well as the expression of NKCC2 and AQP2. In addition, CERA maintained plasma lactate at normal levels, as well as preserving plasma levels of transaminases and lactate dehydrogenase. Renal expression of TLR4 and NF-κB was lower in CLP+CERA rats than in CLP rats (p<0.05 and p<0.01, respectively), as were CD68-positive cell counts (p<0.01), whereas renal EpoR expression was higher (p<0.05). Plasma levels of all measured cytokines were lower in CLP+CERA rats than in CLP rats. CONCLUSION: CERA protects against sepsis-induced AKI. This protective effect is, in part, attributable to suppression of the inflammatory response.

Tuberculosis-associated collapsing glomerulopathy: remission after treatment.

Collapsing glomerulopathy (CG) is a severe form of nephrotic syndrome and has been mostly associated with human immunodeficiency virus (HIV) infection. Treatment response is poor, and the disease frequently leads to end-stage renal disease. More recently, CG has been described in association with other conditions, such as drug exposure and other infections, but renal prognosis remains unfavorable. This paper reports an interesting case of an HIV-negative patient with tuberculosis-related CG who needed dialysis for five months but presented full renal recovery after tuberculosis (TB) treatment and corticotherapy.

The potential role of C-reactive protein in distinguishing cytomegalovirus from tuberculosis and bacterial infections in renal transplant recipients.

INTRODUCTION: The delay in the diagnosis of infections can be deleterious in renal transplant recipients. Thus, laboratory tests leading to an earlier diagnosis are very useful for these patients. PURPOSE: To assess the behavior of C-reactive protein (CRP) in renal transplant recipients with a diagnosis of cytomegalovirus (CMV) infection, tuberculosis (TB) and bacterial infection (BI). METHODS: A retrospective analysis of 129 patients admitted at our hospital, from 2006 to 2008 because of CMV, TB or BI, was carried out. Appropriate statistical analysis was done and values were expressed as medians, range. RESULTS: When CRP levels were compared among the groups with CMV disease, TB or BI, the group with CMV disease presented lower levels of CRP (18.4 mg/L, 0.28-44 mg/L) than the TB and BI (p < 0.05) groups. The area under the receiver-operating characteristics curve, distinguishing CMV disease from TB/BI, was 0.96 (p < 0.0001), resulting in 100% sensitivity and 90.63% specificity to detect CMV disease when CRP < 44.5 mg/L. The subgroup analysis of CMV infection showed increasing levels of CRP (0.28, 16 and 29.5 mg/L) in the asymptomatic, symptomatic and invasive disease subgroups, respectively (p < 0.05). CONCLUSION: The measurement of CRP levels may be a useful tool for differentiating CMV infection from the other types (bacterial or TB) of infection in kidney transplant recipients.

Prevalência e fatores de risco para asma em estudantes de Veterinária e Medicina / Prevalence of asthma and asthama risk factors among veterinarian and medical students

Objetivo: Estudos epidemiologicos recentes têm documentado um aumento da prevalência de doenças alérgicas em todo o mundo, com grande impactos socio-econômico. Estes estudos apresentam resultados variáveis, em grande parte dos casos devido à falta de um critério diagnóstico adequado. Em nosso meio, ainda não se encontra disponível um questionário padronizado e validado para o diagnóstico de asma em população adulta. O objetivo deste estudo é realizar a validação do diagnóstico ISAAC em população adulta de 17 a 30 anos de idade, e estabelecer escore global de corte para asma baseado neste questionário. Determinar e analisar comparativamente a prevalência de asma em população de estudantes de Medicina e Medicina Veterinária (população esta com elevada exposição a animais domésticos), avaliando também a influência da exposição aos animais domésticos e tabagismo nas populações estudadas. Métodos: As populações estudadas compreenderam estudantes de Medicina Veterinária do primeiro ao quinto ano da Faculdade de Medicina Veterinária da UNIP e estudantes do primeiro ao quinto ano da Faculdade de Medicina da Universidade de São Paulo – USP, que foram selecionados aleatoriamente. As informações foram obtidas como questionário previamente validado e padronizado para o estudo que foi preenchido pelo próprio participante. Este questionário foi composto pelo módulo de asma do questionário ISAAC aplicado para a faixa etária de 17 a 30 anos e por um módulo adicional contendo questões sobre tabagismo e exposição a animais domésticos na residência. Resultados: O escore global de corte encontrado capaz de separar asmáticos de não asmáticos foi quatro, com sensibilidade de 95 e especificidade de 92. A prevalência de asma segundo este escore foi de 16,5 para...