Novel predictive biomarkers for acute injury superimposed on chronic kidney disease

Introduction and objectivesChronic kidney disease (CKD) is a risk factor for the development of acute kidney injury (AKI). Recent studies have revealed numerous biomarkers eligible for AKI prediction. However, the expression and performance of AKI biomarkers in acute injury superimposed on preexisting CKD (AonC) remain elusive. The aim of this study was to evaluate whether biomarkers which robustly expressed in acute kidney injury could predict acute injury based on CKD.Materials and methodsMice were classified into cohorts: AKI, CKD, AonC and sham. The AonC model mice were subjected to renal bilateral ischemia/reperfusion (I/R) injury fourteen days after intraperitoneally administrated with 20 mg/kg aristolochic acid. Severity of acute ischemic injury was stratified by clamping the dissected bilateral renal arteries with non-traumatic microvascular clips for 20 or 35 min. The AKI mice were induced with renal bilateral I/R injury and CKD mice were crafted with 20 mg/kg aristolochic acid administrated intraperitoneally. Histology, genetic and protein expression of biomarkers were measured in three cohorts.ResultsWe found that serum creatinine dramatically increased in severe (sAonC) but not in moderate (mAonC) injury mice. Upregulation of Kidney injury molecule-1 (KIM-1) mRNA, tissue inhibitor of metalloproteinase-2 (TIMP-2), Syndecan-1 (SDC-1) mRNA and insulin-like growth factor binding protein-7 (IGFBP7) protein indicated the onset of mAonC. An increase in neutrophil gelatinase-associated lipocalin (NGAL), rhomboid-like protein 2 (RHBDL2), Syndecan-1 (SDC-1) mRNA and protein, and a decrease in IGFBP7 protein were associated with sAonC.ConclusionsOur study revealed the variational expression of AKI biomarkers in AonC kidneys, and uncovered IGFBP7 protein can be used as a sensitive biomarker to predict and differentiate AonC severity. The performance of RHBDL2 and SDC-1 in predicting severe AonC was promising, providing new biomarkers for predicting AonC.     

Targeting of regulated necrosis in kidney disease

The term acute tubular necrosis was thought to represent a misnomer derived from morphological studies of human necropsies and necrosis was thought to represent an unregulated passive form of cell death which was not amenable to therapeutic manipulation. Recent advances have improved our understanding of cell death in acute kidney injury. First, apoptosis results in cell loss, but does not trigger an inflammatory response. However, clumsy attempts at interfering with apoptosis (e.g. certain caspase inhibitors) may trigger necrosis and, thus, inflammation-mediated kidney injury. Second, and most revolutionary, the concept of regulated necrosis emerged. Several modalities of regulated necrosis were described, such as necroptosis, ferroptosis, pyroptosis and mitochondria permeability transition regulated necrosis. Similar to apoptosis, regulated necrosis is modulated by specific molecules that behave as therapeutic targets. Contrary to apoptosis, regulated necrosis may be extremely pro-inflammatory and, importantly for kidney transplantation, immunogenic. Furthermore, regulated necrosis may trigger synchronized necrosis, in which all cells within a given tubule die in a synchronized manner. We now review the different modalities of regulated necrosis, the evidence for a role in diverse forms of kidney injury and the new opportunities for therapeutic intervention.     

Urinary epidermal growth factor in kidney disease: A systematic review

Urinary epidermal growth factor (uEGF) is primarily produced by the kidney, and alterations of it have been associated with several kidney diseases. The aim of this review was to describe uEGF levels in presence or progression of kidney diseases. We conducted a systematic review of observational studies with uEGF determination, patients with acute kidney injury, chronic kidney disease, primary or secondary nephropathy, or renal cancer were included. Studies were searched in Medline, Google Scholar, Science Direct, and EBSCO up to August 2, 2021. Participants and measurements characteristics from which uEGF were determined as the specificity, sensitivity, and the area under the ROC curve, whenever available, were gathered. 53 studies were included, the most frequent kidney diseases studied were acute kidney injury, chronic kidney disease, and diabetic nephropathy. In most studies, uEGF levels were lower in cases than in controls. Studies showed that uEGF levels can predict presence or progression of acute kidney injury, chronic kidney disease, and nephropathy. Heterogeneity in the reported uEGF values can be attributed to the different techniques, sampling, and ways of reporting uEGF values.Although uEGF values are lower in patients with almost all kidney diseases and their progression, uEGF evaluation methods should be standardised to be used as a biomarker in clinical practice.     

Acute kidney injury and chronic kidney disease after liver transplant: A retrospective observational study

Background and rationaleChronic kidney disease remains an important risk factor for morbidity and mortality among LT recipients, but its exact incidence and risk factors are still unclear.Material and methodsWe carried out a retrospective cohort study of consecutive adults who underwent liver transplant (January 2009–December 2018) and were followed (at least 6 months) at our institution. CKD was defined following the Kidney Disease: Improving Global Outcomes (KDIGO) 2012 Clinical Practice Guidelines. Long-term kidney function was classified into 4 groups: no CKD (eGFR, ≥60 mL/min/1.73 m²), mild CKD (eGFR, 30–59 mL/min/1.73 m²), severe CKD (eGFR, 15–29 mL/min/1.73 m²), and end-stage renal disease (ESRD).ResultsWe enrolled 410 patients followed for 53.2 ± 32.6 months. 39 had CKD at baseline, and 95 developed de novo CKD over the observation period. There were 184 (44.9%) anti-HCV positive, 47 (11.5%) HBsAg positive, and 33 (8.1%) HBV/HDV positive recipients. Recipient risk factors for baseline CKD were advanced age (P = 0.044), raised levels of serum uric acid (P < 0.0001), and insulin dependent DM (P = 0.0034). Early post-transplant AKI was common (n = 95); logistic regression analysis found that baseline serum creatinine was an independent predictor of early post-LT AKI (P = 0.0154). According to our Cox proportional hazards model, recipient risk factors for de novo CKD included aging (P < 0.0001), early post-transplant AKI (P = 0.007), and baseline serum creatinine (P = 0.0002). At the end of follow-up, there were 116 LT recipients with CKD – 109 (93.9%) and 7 (6.1%) had stage 3 and advanced CKD, respectively. Only two of them are undergoing long-term dialysis.ConclusionThe incidence of CKD was high in our cohort of LT recipients, but only a slight decline in kidney function over time was recorded. Prevention of post-transplant AKI will improve kidney function in the long run. We need more studies to analyze the function of kidneys among LT recipients over extended follow-ups and their impact on mortality.     

Enfermedad renal crónica en el trasplante hepático: evaluación de la función renal

Chronic kidney disease is one of the main comorbidities affecting liver transplant recipients. Most of those patients have some degree of acute or chronic kidney dysfunction at the time of transplantation, moreover they can also develop de novo chronic kidney disease once transplanted. An important increase in the incidence of chronic kidney disease in the «MELD era» has been observed. This phenomenon has partially been attributed to the weight that kidney function carries for organ allocation. In addition, the generalized use of calcineurin inhibitors has also been a contributing factor. It is of the utmost importance for us to be familiar with the current methods for evaluating kidney function before and after a liver transplantation. The two main biomarkers available today for that purpose are serum creatinine and cystatin C. Several equations have been derived from those biomarkers and have been tested in that context with mixed results, due to their biologic variability and the lack of standardization in their measurement. The gold standard continues to be the direct determination of the glomerular filtration rate through different methods; however, that is only done for research purposes. It is also essential to know the current classification of acute kidney injury and chronic kidney disease in order to make early diagnosis. The present review focuses on the recognition, diagnosis, and classification of chronic kidney disease and acute kidney injury in liver transplantation recipients.     

Colistimethate sodium and acute kidney injury: Incidence,risk factors,outcome and prognosis of renal function

BackgroundColistimethate sodium (CMS) treatment has increased over the last years, being acute kidney injury (AKI) its main drug-related adverse event. Therefore, this study aimed to evaluate the incidence and risk factors associated with AKI, as well as identifying the factors that determine renal function (RF) outcomes at six months after discharge.Materials and methodsThis retrospective study included adult septic patients receiving intravenous CMS for at least 48 h (January 2007–December 2014). AKI was assessed using KDIGO criteria. The glomerular filtration rate (GFR) was estimated by the 4-variable MDRD equation. Logistic and linear models were performed to evaluate the risk factors for AKI and chronic kidney disease (CKD).ResultsAmong 126 patients treated with CMS; the incidence of AKI was 48.4%. Sepsis–severe sepsis (OR 8.07, P = 0.001), sepsis–septic shock (OR 42.9, P < 0.001), and serum creatinine (SCr) at admission (OR 6.20, P = 0.009) were independent predictors.Eighty-four patients survived; the main factors for RF evolution at the 6-month follow-up was baseline eGFR (0.58, P < 0.001) and at discharge (0.34, P < 0.001). Fifty-six percent (34/61) of the patients that developed AKI survived. At six months, 32% had CKD.ConclusionsThe development of AKI in septic patients with CMS treatment was associated with sepsis severity and SCr at admission. Baseline eGFR and eGFR at discharge were and important determinant of the RF at the 6-month follow-up. These predictors may assist in clinical decision making for this patient population.     

Epidemiology,clinical profile,management, and two-year risk complications among patients with chronic kidney disease in Spain

ObjectivesTo describe the epidemiology, clinical profile, treatments, and to determine cardiovascular and renal outcomes after two years of follow-up in a contemporary chronic kidneay disease (CKD) population in Spain. This was also analyzed among the DAPA-CKD-like population (patients who met most inclusion criteria of DAPA-CKD trial).MethodsObservational, retrospective, population-based study using BIG-PAC database. The CKD population was defined as patients ≥18 years, with at least one diagnostic code of CKD prior to the index date (January 1st, 2018). CKD was defined as estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m² (CKD-EPI), or albuminuria >30 mg/g.ResultsWe identified 56,435 CKD patients after exclusions (76.4 years, 52.2% men, urine albumin-to-creatinine ratio 390.8 mg/g, eGFR 49.7 mL/min/1.73 m²). CKD prevalence was 4.91% and incidence 2.10 per 1000 patient-years. Regarding treatments, 69.2% were taking renin-angiotensin system inhibitors (only 4.2% at maximal doses) and 3.5% of diabetic patients SGLT-2 inhibitors. During the two years of follow-up, rates of heart failure, all-cause death, myocardial infarction, stroke, and CKD were 17.9, 12.1, 7.2, 6.3, and 5.9 events per 100 patient-years, respectively. During this period, 44% of patients were hospitalized, and 6.8% died during hospitalization. Cardiovascular outcomes were more common in the DAPA-CKD-like population.ConclusionsIn Spain, CKD population is older and comorbidities, including diabetes and heart failure, are common. Cardiovascular and renal outcomes are frequent. There is room for improvement in CKD management, particularly through the use of drugs with proven cardiovascular and renal benefit.     

Targeting the Linear Ubiquitin Assembly Complex to Modulate the Host Response and Improve Influenza A Virus Induced Lung Injury

Influenza virus infection is characterized by symptoms ranging from mild congestion and body aches to severe pulmonary edema and respiratory failure. While the majority of those exposed have minor symptoms and recover with little morbidity, an estimated 500,000 people succumb to IAV-related complications each year worldwide. In these severe cases, an exaggerated inflammatory response, known as “cytokine storm”, occurs which results in damage to the respiratory epithelial barrier and development of acute respiratory distress syndrome (ARDS). Data from retrospective human studies as well as experimental animal models of influenza virus infection highlight the fine line between an excessive and an inadequate immune response, where the host response must balance viral clearance with exuberant inflammation. Current pharmacological modulators of inflammation, including corticosteroids and statins, have not been successful in improving outcomes during influenza virus infection. We have reported that the amplitude of the inflammatory response is regulated by Linear Ubiquitin Assembly Complex (LUBAC) activity and that dampening of LUBAC activity is protective during severe influenza virus infection. Therapeutic modulation of LUBAC activity may be crucial to improve outcomes during severe influenza virus infection, as it functions as a molecular rheostat of the host response. Here we review the evidence for modulating inflammation to ameliorate influenza virus infection-induced lung injury, data on current anti-inflammatory strategies, and potential new avenues to target viral inflammation and improve outcomes.     

Obesity,chronic kidney disease progression and the role of the adipokine C1q/TNF related protein-3

Introduction and aimsObesity is a risk factor for incident chronic kidney disease (CKD). C1q/TNF related protein 3 (CTRP3) is an adipokine with multiple effects and may modulate the association between obesity and vascular diseases. The aim of the study is to explore potential links between obesity, CTRP3 levels and CKD progression.MethodsPatients with stage 3 and 4 CKD without previous cardiovascular events were enrolled and divided into groups according to body mass index (BMI) and sex. Demographic, clinical, analytical data and CTRP3 levels were collected at baseline. During follow-up, renal events (defined as dialysis initiation, serum creatinine doubling or a 50% decrease in estimated glomerular filtration rate were registered).Results81 patients were enrolled. 27 were obese and 54 non-obese. Baseline CTRP3 was similar between both groups (90.1 ± 23.8 vs 84.5 ± 6.2; p = 0.28). Of the sum, 54 were men and 27 women, with higher CTRP3 in women (81.4 ± 24.7 vs 106 ± 24.7; p < 0.01). During a mean follow-up of 68 months, 15 patients had a renal event. Patients in the higher CTRP3 tertile had less events but without statistical significance (p = 0.07). Obese patients in the higher CTRP3 tertile significantly had less renal events (p = 0.049). By multiple regression analysis CTRP3 levels could not predict renal events (HR 0.98; CI95% 0.96–1.06).ConclusionsCTRP3 levels are higher in woman than men in patients with CKD, with similar levels between obese and non obese. Higher CTRP3 levels at baseline were associated with better renal outcomes in obese patients.     

Burden and challenges of heart failure in patients with chronic kidney disease. A call to action

Patients with the dual burden of chronic kidney disease (CKD) and chronic congestive heart failure (HF) experience unacceptably high rates of symptom load, hospitalization, and mortality. Currently, concerted efforts to identify, prevent and treat HF in CKD patients are lacking at the institutional level, with emphasis still being placed on individual specialty views on this topic. The authors of this review paper endorse the need for a dedicated cardiorenal interdisciplinary team that includes nephrologists and renal nurses and jointly manages appropriate clinical interventions across the inpatient and outpatient settings. There is a critical need for guidelines and best clinical practice models from major cardiology and nephrology professional societies, as well as for research funding in both specialties to focus on the needs of future therapies for HF in CKD patients. The implementation of cross-specialty educational programs across all levels in cardiology and nephrology will help train future specialists and nurses who have the ability to diagnose, treat, and prevent HF in CKD patients in a precise, clinically effective, and cost-favorable manner.     

Kidney disease associated with androgenic–anabolic steroids and vitamin supplements abuse: Be aware!

The excessive chase for beauty standards and the rise of muscle dysmorphia have ultimately led to an increase in androgenic–anabolic steroids (AAS) and intramuscular injections of vitamins A, D and E (ADE) abuse, which is associated with several adverse effects and has become a public health issue. This review of literature discusses kidney injury associated with the use of AAS and ADE, highlighting the mechanisms of acute and chronic renal lesion, such as direct renal toxicity, glomerular hyperfiltration and hypercalcemia. Future perspectives regarding evaluation and early diagnosis of kidney injury in these patients are also discussed.     

Acute kidney injury in hospitalized patients with COVID-19: A Portuguese cohort

IntroductionThe incidence of acute kidney injury (AKI) in coronavirus disease 2019 (COVID-19) patients ranges from 0.5% to 35% and has been associated with worse prognosis. The purpose of this study was to evaluate the incidence, severity, duration, risk factors and prognosis of AKI in hospitalized patients with COVID-19.MethodsWe conducted a retrospective single-center analysis of 192 hospitalized COVID-19 patients from March to May of 2020. AKI was diagnosed using the Kidney Disease Improving Global Outcome (KDIGO) classification based on serum creatinine (SCr) criteria. Persistent and transient AKI were defined according to the Acute Disease Quality Initiative (ADQI) workgroup definitions.ResultsIn this cohort of COVID-19 patients, 55.2% developed AKI (n = 106). The majority of AKI patients had persistent AKI (n = 64, 60.4%). Overall, in-hospital mortality was 18.2% (n = 35) and was higher in AKI patients (28.3% vs. 5.9%, p < 0.001, unadjusted OR 6.03 (2.22–16.37), p < 0.001). In this multivariate analysis, older age (adjusted OR 1.07 (95% CI 1.02–1.11), p = 0.004), lower Hb level (adjusted OR 0.78 (95% CI 0.60–0.98), p = 0.035), duration of AKI (adjusted OR 7.34 for persistent AKI (95% CI 2.37–22.72), p = 0.001) and severity of AKI (adjusted OR 2.65 per increase in KDIGO stage (95% CI 1.32–5.33), p = 0.006) were independent predictors of mortality.ConclusionAKI was frequent in hospitalized patients with COVID-19. Persistent AKI and higher severity of AKI were independent predictors of in-hospital mortality.     

Intravenous iron in heart failure and chronic kidney disease

Intravenous iron therapy is increasingly being used worldwide to treat anemia in chronic kidney disease and more recently iron deficiency in heart failure. Promising results were obtained in randomized clinical trials in the latter, showing symptomatic and functional capacity improvement with intravenous iron therapy. Meanwhile, confirmation of clinical benefit in hard-endpoints such as mortality and hospitalization is expected in large clinical trials that are already taking place. In chronic kidney disease, concern about iron overload is being substituted by claims of direct cardiovascular benefit of iron supplementation, as suggested by preliminary studies in heart failure.We discuss the pitfalls of present studies and gaps in knowledge, stressing the known differences between iron metabolism in heart and renal failure. Systemic and cellular iron handling and the role of hepcidin are reviewed, as well as the role of iron in atherosclerosis, especially in view of its relevance to patients undergoing dialysis. We summarize the evidence available concerning iron overload, availability and toxicity in CKD, that should be taken into account before embracing aggressive intravenous iron supplementation.     

Rapid decline of kidney function in diabetic kidney disease is associated with high soluble Klotho levels

Background

Klotho is found in two forms: a transmembrane form and a soluble form (s-Klotho). In order to be excreted, s-Klotho, that is too large to be filtered, will probably reach the proximal convoluted tubule by a transcytosis process. The aim of our study was to show the relationship between the levels of s-Klotho and tubular injury in patients with diabetic kidney disease (DKD), using as tubular injury marker the kidney injury molecule-1 (KIM-1).

The Spanish Society of Nephrology (SENEFRO) commentary to the Spain GBD 2016 report: Keeping chronic kidney disease out of sight of health authorities will only magnify the problem

The Global Burden of Disease (GBD) study measures the health of populations worldwide and by country on an annual basis and aims at helping guide public policy on health issues. The GBD estimates for Spain in 2016 and recent trends in mortality and morbidity from 2006 to 2016 were recently published. According to these estimates, chronic kidney disease was the 8th cause of death in Spain in 2016. Among the top ten causes of death, chronic kidney disease was the fastest growing from 2006 to 2016, after Alzheimer disease. At the current pace of growth, chronic kidney disease is set to become the second cause of death in Spain, after Alzheimer disease, by 2100. Additionally, among major causes of death, chronic kidney disease also ranked second only to Alzheimer as the fastest growing cause of Years Lived with Disability (YLDs) and Disability Adjusted Life Years (DALYs). Public resources devoted to prevention, care and research on kidney disease should be in line with both its current and future burden.     

The role of an electronic alert system to detect acute kidney injury in hospitalized patients: DETECT-H Project

Background and aimsAcute kidney injury (AKI) is associated with higher mortality and length of stay (LOS) for hospitalized patients. To improve outcomes, an electronic detection system could be a useful tool for early diagnosis.MethodsA fully automated real-time system for detecting decreased glomerular filtration rate in adult patients was developed in our hospital, DETECT-H project. AKI was established according to KDIGO guidelines.ResultsIn six months, 1241 alerts from 11,022 admissions were issued. Overall incidence of AKI was 7.7%. Highest AKI stage reached was: stage 1 (49.8%), 2 (24.5%) and 3 (25.8%), in-hospital mortality was 10.9%, 22.7%, 33.9% respectively and 57.1% in AKI requiring dialysis; mortality in stable CKD was 4.3%. Median LOS was 8 days versus 5 days for all patients. AKI was associated with a mortality of 3.18 (95% CI 1.80–5.59) and a LOS 1.52 (1.11–2.08) times as high as that for admissions without AKI. Multivariate analysis indicated that a LOS higher than 8 days was associated with AKI. Previous CKD was noted in 31.9% and AKI in 45.3% at discharge. As compared to the use of the detect system, only one third of CKD patients and half of AKI episodes were identified.ConclusionsCKD and in-hospital AKI are under-recognized entities. Mortality and LOS are increased in-hospital patients with renal dysfunction. AKI severity was associated with higher mortality and LOS. An automated electronic detection system for identifying renal dysfunction would be a useful tool to improve renal outcomes.     

Pica en enfermedad renal crónica avanzada: revisión de la literatura

Pica is an individual entity in the patient with chronic kidney disease (CKD), which phenomenon has not been widely studied despite the high reported prevalence. Moreover, pica complications (anemia, altered electrolytes, poor absorption of micro and macronutrients and malnutrition) could be exacerbated in CKD and limit the quality of renal replacement therapy.The intake of non-caloric and non-nutritional substances could be harmful and cause effects on satiety and metabolic / electrolyte imbalance and modify the biocompatibility of micronutrients, toxins and pathogens worsening health status.In daily practice, pica could be under-reported because patient's shame to recognize it, or fear that such behavior influences their treatment. Additionally, clinicians who not investigate the presence of pica or its complications contribute to the lack of information about the magnitude and relevance of this problem in CKD.     

Mortalidad precoz en pacientes con enfermedad renal crónica que inician hemodiálisis por urgencia en una población peruana: Incidencia y factores de riesgo

Objectives

To estimate early mortality in patients with chronic kidney disease who started emergency haemodialysis between 2012 and 2014 in a national referral hospital in Lima, Peru, and to identify risk factors.

Neutrophil,lymphocyte and platelet ratio as a predictor of mortality in septic-acute kidney injury patients

BackgroundAKI is frequent in critically ill patients, in whom the leading cause of AKI is sepsis. The role of intrarenal and systemic inflammation appears to be significant in the pathophysiology of septic-AKI. The neutrophils to lymphocytes and platelets (N/LP) ratio is an indirect marker of inflammation. The aim of this study was to evaluate the prognostic ability of N/LP ratio at admission in septic-AKI patients admitted to an intensive care unit (ICU).MethodsThis is a retrospective analysis of 399 septic-AKI patients admitted to the Division of Intensive Medicine of the Centro Hospitalar Universitário Lisboa Norte between January 2008 and December 2014. The Kidney Disease Improving Global Outcomes (KDIGO) classification was used to define AKI. N/LP ratio was calculated as: (Neutrophil count × 100)/(Lymphocyte count × Platelet count).ResultsFifty-two percent of patients were KDIGO stage 3, 25.8% KDIGO stage 2 and 22.3% KDIGO stage 1. A higher N/LP ratio was an independent predictor of increased risk of in-hospital mortality in septic-AKI patients regardless of KDIGO stage (31.59 ± 126.8 vs 13.66 ± 22.64, p = 0.028; unadjusted OR 1.01 (95% CI 1.00–1.02), p = 0.027; adjusted OR 1.01 (95% CI 1.00–1.02), p = 0.015). The AUC for mortality prediction in septic-AKI was of 0.565 (95% CI (0.515–0.615), p = 0.034).ConclusionsThe N/LP ratio at ICU admission was independently associated with in-hospital mortality in septic-AKI patients.