Assessment of Acute Kidney Injury using MRI.

There has been growing interest in using quantitative magnetic resonance imaging (MRI) to describe and understand the pathophysiology of acute kidney injury (AKI). The ability to assess kidney blood flow, perfusion, oxygenation, and changes in tissue microstructure at repeated timepoints is hugely appealing, as this offers new possibilities to describe nature and severity of AKI, track the time-course to recovery or progression to chronic kidney disease (CKD), and may ultimately provide a method to noninvasively assess response to new therapies. This could have significant clinical implications considering that AKI is common (affecting more than 13 million people globally every year), harmful (associated with short and long-term morbidity and mortality), and currently lacks specific treatments. However, this is also a challenging area to study. After the kidney has been affected by an initial insult that leads to AKI, complex coexisting processes ensue, which may recover or can progress to CKD. There are various preclinical models of AKI (from which most of our current understanding derives), and these differ from each other but more importantly from clinical AKI. These aspects are fundamental to interpreting the results of the different AKI studies in which renal MRI has been used, which encompass different settings of AKI and a variety of MRI measures acquired at different timepoints. This review aims to provide a comprehensive description and interpretation of current studies (both preclinical and clinical) in which MRI has been used to assess AKI, and discuss future directions in the field. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY: Stage 3.

Randomized trial comparing standard versus thermocontrolled haemodialysis using intradialytic cardiac, brain and renal magnetic resonance imaging.

BACKGROUND: Ischaemic end-organ damage during haemodialysis (HD) is a significant problem that may be ameliorated by intradialytic cooling. A randomised trial was performed to compare standard HD (SHD; dialysate temperature 37°C) and programmed cooling of the dialysate [thermocontrolled HD (TCHD)] using multiparametric magnetic resonance imaging (MRI) to assess structural, functional and blood flow changes in the heart, brain and kidneys. METHODS: Prevalent HD patients were randomly allocated to receive either SHD or TCHD for 2 weeks before undergoing serial MRI at four time points: pre-, during (30 min and 180 min) and post-dialysis. MRI measures include cardiac index, myocardial strain, longitudinal relaxation time (T1), myocardial perfusion, internal carotid and basilar artery flow, grey matter perfusion and total kidney volume. Participants then crossed to the other modality to repeat the study protocol. RESULTS: Eleven participants completed the study. Separation in blood temperature between TCHD (-0.1 ± 0.3°C) and SHD (+0.3 ± 0.2°C; P = .022) was observed, although there was no difference in tympanic temperature changes between arms. There were significant intradialytic reductions in cardiac index, cardiac contractility (left ventricular strain), left carotid and basilar artery blood flow velocities, total kidney volume, longitudinal relaxation time (T1) of the renal cortex and transverse relaxation rate (T2*) of the renal cortex and medulla, but no differences between arms. Pre-dialysis T1 of the myocardium and left ventricular wall mass index were lower after 2 weeks of TCHD compared with SHD [1266 ms (interquartile range 1250-1291) versus 1311 ± 58 ms, P = .02; 66 ± 22 g/m2 versus 72 ± 23 g/m2, P = .004]. CONCLUSIONS: HD adversely affects cardiac function, reduces carotid and basilar artery blood flow and total kidney volume, but mild dialysate cooling using a biofeedback module did not result in differences in intradialytic MRI measures compared with SHD.

Multiparametric Renal Magnetic Resonance Imaging for Prediction and Annual Monitoring of the Progression of Chronic Kidney Disease over Two Years.

BACKGROUND: Multiparametric renal Magnetic Resonance Imaging (MRI) provides a non-invasive method to assess kidney structure and function, but longitudinal studies are limited. METHODS: A total of 22 patients with CKD category G3-4 (estimated glomerular filtration rate (eGFR) 15-59 mL/min/1.73 m2) were recruited. Annual 3T multiparametric renal MRI scans were performed, comprising total kidney volume (TKV), longitudinal relaxation time (T1), apparent diffusion coefficient (ADC), Arterial Spin Labelling, and Blood Oxygen Level Dependent relaxation time (T2*), with 15 patients completing a Year 2 scan. CKD progression over 2 years was defined as eGFR_slope ≥ -5 mL/min/1.73 m2/year. RESULTS: At baseline, T1 was higher (cortex p = 0.05, medulla p = 0.03) and cortex perfusion lower (p = 0.015) in participants with subsequent progression versus stable eGFR. A significant decrease in TKV and ADC and an increase in cortex T1 occurred in progressors at Year 1 and Year 2, with a significant decrease in perfusion in progressors only at Year 2. The only decline in the stable group was a reduction in TKV. There was no significant change in cortex or medulla T2* at Year 1 or Year 2 for progressors or stable participants. CONCLUSION: Lower renal cortex perfusion and higher T1 in the cortex and medulla may predict CKD progression, while renal cortex T1, TKV, and ADC may be useful to monitor progression. This study provides pilot data for future large-scale studies.

Feedback control in hemodialysis.

A number of systems of feedback control during dialysis have been developed, which have the shared characteristic of prospectively measuring physiological parameters and then automatically altering dialysis parameters in real time according to a pre-specified dialysis prescription. These include feedback systems aimed at reducing intradialytic hypotension based on relative blood volume monitoring linked to adjustments in ultrafiltration and dialysate conductivity, and blood temperature monitoring linked to alterations in dialysate temperature. Feedback systems also exist that manipulate sodium balance during dialysis by assessing and adjusting dialysate conductivity. In this review article, we discuss the rationale for automated feedback systems during dialysis, describe how the different feedback systems work, and provide a review of the current evidence on their clinical effectiveness.

A comprehensive description of kidney disease progression after acute kidney injury from a prospective, parallel-group cohort study.

Acute kidney injury (AKI) is associated with adverse long-term outcomes, but many studies are retrospective, focused on specific patient groups or lack adequate comparators. The ARID (AKI Risk in Derby) Study was a five-year prospective parallel-group cohort study to examine this. Hospitalized cohorts with and without exposure to AKI were matched 1:1 for age, baseline kidney function, and diabetes. Estimated glomerular filtration rate (eGFR) and the urinary albumin:creatinine ratio (uACR) were measured at three-months, one-, three- and five-years. Outcomes included kidney disease progression, heart failure episodes and mortality. In 866 matched individuals, kidney disease progression at five years was found to be significantly increased in 30% of the exposed group versus 7% of those non-exposed (adjusted odds ratio 2.49 [95% confidence interval 1.43 to 4.36]). In the AKI group, this was largely characterized by incomplete recovery of kidney function by three months. Further episodes of AKI during follow-up were significantly more common in the exposed group (odds ratio 2.71 [1.94 to 3.77]) and had an additive effect on risk of kidney disease progression. Mortality and heart failure episodes were more frequent in the exposed group, but the association with AKI was no longer significant when models were adjusted for three-month eGFR and uACR. In a general hospitalized population, kidney disease progression after five years was common and strongly associated with AKI. Thus, the time course of changes and the attenuation of associations with adverse outcomes after adjustment for three-month eGFR and uACR suggest non-recovery of kidney function is an important assessment in post-AKI care and a potential future target for intervention. STUDY REGISTRATION: ISRCTN25405995.

Electronic alerts in acute kidney injury: why does evidence of benefit remain elusive?

PURPOSE OF REVIEW: Acute kidney injury (AKI) is a common syndrome characterized by a sudden reduction in kidney function. It is strongly associated with high mortality and longer, more expensive hospital stays. As AKI often presents silently, a lack of recognition can prevent recommended standards of care. Over the last decade or more, electronic alerts (eAlerts) for AKI have been studied and implemented to address this. This review will summarize the major randomized trials in this area. RECENT FINDINGS: A number of randomized trials now exist that study the effectiveness of AKI eAlerts in isolation or as part of more complex interventions. Varying results arise from differences in study design, healthcare system in which the eAlert is introduced, nature of alert, supporting interventions, implementation plan, stated aim (prevention or treatment of established AKI) and choice of outcome measures. SUMMARY: Current randomized trial evidence does not show any benefit of eAlerts on mortality. However, variously reported reductions in AKI incidence, AKI progression and AKI duration support a conclusion that strategies incorporating eAlerts can meaningfully benefit delivery of AKI care. Future work should consider how best eAlerts can be utilised, targeted and implemented.

Digital health and acute kidney injury: consensus report of the 27th Acute Disease Quality Initiative workgroup.

Acute kidney injury (AKI), which is a common complication of acute illnesses, affects the health of individuals in community, acute care and post-acute care settings. Although the recognition, prevention and management of AKI has advanced over the past decades, its incidence and related morbidity, mortality and health care burden remain overwhelming. The rapid growth of digital technologies has provided a new platform to improve patient care, and reports show demonstrable benefits in care processes and, in some instances, in patient outcomes. However, despite great progress, the potential benefits of using digital technology to manage AKI has not yet been fully explored or implemented in clinical practice. Digital health studies in AKI have shown variable evidence of benefits, and the digital divide means that access to digital technologies is not equitable. Upstream research and development costs, limited stakeholder participation and acceptance, and poor scalability of digital health solutions have hindered their widespread implementation and use. Here, we provide recommendations from the Acute Disease Quality Initiative consensus meeting, which involved experts in adult and paediatric nephrology, critical care, pharmacy and data science, at which the use of digital health for risk prediction, prevention, identification and management of AKI and its consequences was discussed.

An exploration of successful psychosocial adjustment to long-term in-centre haemodialysis.

OBJECTIVES: Haemodialysis extends life for people with end-stage kidney disease (ESKD) worldwide, but it imposes significant psychosocial burdens and there is little evidence about successful adjustment. This study aimed to improve understanding of successful psychosocial adjustment to in-centre haemodialysis (ICHD; dialysis in a hospital or satellite unit). METHODS: Individual semi-structured interviews were conducted with a purposive sample of 18 people with ESKD who had all received in-centre haemodialysis in the UK for at least 90 days in the last two years. An inductive thematic analysis was employed to identify themes from the verbatim interview transcripts. RESULTS: There were four themes: 1) reaching a state of acceptance, which described the importance of accepting the necessity of dialysis; 2) taking an active role in treatment, which described how being actively involved in treatment gave participants greater feelings of autonomy and control; 3) utilising social support networks, which described the benefits of instrumental and emotional support; and 4) building emotional resilience, which described the importance of optimism and positivity. CONCLUSIONS: The themes demonstrated elements of successful adjustment that could be targeted by interventions to promote psychological flexibility and positive adjustment among people receiving in-centre haemodialysis worldwide.

Magnetic Resonance Imaging to Evaluate Kidney Structure, Function, and Pathology: Moving Toward Clinical Application.

Recent advances in multiparametric magnetic resonance imaging (MRI) allow multiple quantitative measures to assess kidney morphology, tissue microstructure, oxygenation, kidney blood flow, and perfusion to be collected in a single scan session. Animal and clinical studies have investigated the relationship between the different MRI measures and biological processes, although their interpretation can be complex due to variations in study design and generally small participant numbers. However, emerging themes include the apparent diffusion coefficient derived from diffusion-weighted imaging, T1 and T2 mapping parameters, and cortical perfusion being consistently associated with kidney damage and predicting kidney function decline. Blood oxygen level-dependent (BOLD) MRI has shown inconsistent associations with kidney damage markers but has been predictive of kidney function decline in several studies. Therefore, multiparametric MRI of the kidneys has the potential to address the limitations of existing diagnostic methods to provide a noninvasive, noncontrast, and radiation-free method to assess whole kidney structure and function. Barriers to be overcome to facilitate widespread clinical application include improved understanding of biological factors that impact MRI measures, development of a larger evidence base for clinical utility, standardization of MRI protocols, automation of data analysis, determining optimal combination of MRI measures, and health economic evaluation.

National recommendations to standardise acute kidney injury detection and alerting.

BACKGROUND: National Health Service England issued a Patient Safety Alert in 2014 mandating all acute Trusts in England to implement Acute Kidney Injury (AKI) warning stage results and to do so using a standardised algorithm. In 2021, the Renal and Pathology Getting It Right First Time (GIRFT) teams found significant variation in AKI reporting across the UK. A survey was designed to capture information on the entire AKI detection and alerting process to investigate the potential sources of this unwarranted variation. METHODS: In August 2021, an online survey consisting of 54 questions was made available to all UK laboratories. The questions covered creatinine assays, laboratory information management systems (LIMS), the AKI algorithm and AKI reporting. RESULTS: We received 101 responses from laboratories. Data were reviewed for England only - 91 laboratories. Findings included that 72% used enzymatic creatinine. In addition, 7 manufacturer-analytical platforms, 15 different LIMS and a wide range of creatinine reference ranges were in use. In 68% of laboratories, the AKI algorithm was installed by the LIMS provider. Marked variation was found in the minimum age of AKI reporting with only 18% starting at the recommended 1 month/28-days. Some 89% phoned all new AKI2s and AKI3s, as per AKI guidance while 76% provided comments/hyperlinks in reports. CONCLUSIONS: The national survey has identified laboratory practices that potentially contribute to unwarranted variation in the reporting of AKI in the England. This has formed the basis for improvement work to remedy the situation, including national recommendations, included within this article.

Plasma Soluble Tumor Necrosis Factor Receptor Concentrations and Clinical Events After Hospitalization: Findings From the ASSESS-AKI and ARID Studies.

RATIONALE & OBJECTIVE: The role of plasma soluble tumor necrosis factor receptor 1 (sTNFR1) and sTNFR2 in the prognosis of clinical events after hospitalization with or without acute kidney injury (AKI) is unknown. STUDY DESIGN: Prospective cohort. SETTING & PARTICIPANTS: Hospital survivors from the ASSESS-AKI (Assessment, Serial Evaluation, and Subsequent Sequelae of Acute Kidney Injury) and ARID (AKI Risk in Derby) studies with and without AKI during the index hospitalization who had baseline serum samples for biomarker measurements. PREDICTORS: We measured sTNFR1 and sTNFR2 from plasma samples obtained 3 months after discharge. OUTCOMES: The associations of biomarkers with longitudinal kidney disease incidence and progression, heart failure, and death were evaluated. ANALYTICAL APPROACH: Cox proportional hazard models. RESULTS: Among 1,474 participants with plasma biomarker measurements, 19% had kidney disease progression, 14% had later heart failure, and 21% died during a median follow-up of 4.4 years. For the kidney outcome, the adjusted HRs (AHRs) per doubling in concentration were 2.9 (95% CI, 2.2-3.9) for sTNFR1 and 1.9 (95% CI, 1.5-2.5) for sTNFR2. AKI during the index hospitalization did not modify the association between biomarkers and kidney events. For heart failure, the AHRs per doubling in concentration were 1.9 (95% CI, 1.4-2.5) for sTNFR1 and 1.5 (95% CI, 1.2-2.0) for sTNFR2. For mortality, the AHRs were 3.3 (95% CI, 2.5-4.3) for sTNFR1 and 2.5 (95% CI, 2.0-3.1) for sTNFR2. The findings in ARID were qualitatively similar in terms of the magnitude of association between biomarkers and outcomes. LIMITATIONS: Different biomarker platforms and AKI definitions; limited generalizability to other ethnic groups. CONCLUSIONS: Plasma sTNFR1 and sTNFR2 measured 3 months after hospital discharge were independently associated with clinical events regardless of AKI status during the index admission. sTNFR1 and sTNFR2 may assist with the risk stratification of patients during follow-up.

Circulating Levels of Endotrophin Are Prognostic for Long-Term Mortality after AKI.

Background: AKI involves a rapid decrease in kidney function that may be associated with structural damage. Early markers predicting AKI are emerging, but tools to assess patients' long-term health risks after AKI are still lacking. Endotrophin (ETP) is a bioactive molecule released during the formation of collagen type VI. We evaluated the potential of circulating ETP as a prognostic biomarker of adverse outcomes after AKI. Methods: We measured ETP in plasma samples collected 1 year after an episode of AKI, using the PRO-C6 ELISA in 801 patients (393 patients with AKI and 408 controls) from the prospective AKI Risk in Derby (ARID) study (ISRCTN25405995), who were then followed until year 3. Kidney disease progression was defined as ≥25% decline in eGFR combined with a decline in CKD stage. Results: ETP levels were significantly higher in the AKI group compared with controls (P<0.001). In the AKI group, ETP could discriminate patients with kidney disease progression at year 3 (AUC=0.67, P<0.01), whereas eGFR could not (AUC=0.51, P=0.57). In logistic regression including common risk factors, ETP was independently associated with kidney disease progression in patients with AKI (OR=1.10, P<0.01). ETP could discriminate survivors from nonsurvivors at year 3 (AUC=0.64, P<0.01). In a Cox proportional hazards regression for mortality after AKI that included common risk factors, only ETP (HR=1.05; P<0.001) and age (HR=1.06, P<0.01) were retained in the final model. Conclusions: Patients in the AKI group had higher levels of plasma ETP at year 1 as compared with those who had not had AKI. In the AKI group, ETP levels predict kidney disease progression and mortality. Because ETP is a profibrotic molecule, our findings may indicate that ETP identifies patients with active fibrogenesis after AKI, suggestive of long-term renal remodeling, which is associated with patient outcome.

Opportunities in digital health and electronic health records for acute kidney injury care.

PURPOSE OF REVIEW: The field of digital health is evolving rapidly with applications relevant to the prediction, detection and management of acute kidney injury (AKI). This review will summarize recent publications in these areas. RECENT FINDINGS: Machine learning (ML) approaches have been applied predominantly for AKI prediction, but also to identify patients with AKI at higher risk of adverse outcomes, and to discriminate different subgroups (subphenotypes) of AKI. There have been multiple publications in this area, but a smaller number of ML models have robust external validation or the ability to run in real-time in clinical systems. Recent studies of AKI alerting systems and clinical decision support systems continue to demonstrate variable results, which is likely to result from differences in local context and implementation strategies. In the design of AKI alerting systems, choice of baseline creatinine has a strong effect on performance of AKI detection algorithms. SUMMARY: Further research is required to overcome barriers to the validation and implementation of ML models for AKI care. Simpler electronic systems within the electronic medical record can lead to improved care in some but not all settings, and careful consideration of local context and implementation strategy is recommended.

Simple, high-throughput measurement of gut-derived short-chain fatty acids in clinically relevant biofluids using gas chromatography-mass spectrometry.

Introduction: The quantitative measurement of circulating gut bacteria-derived metabolites has increased in recent years due to their associations with health and disease. While much of the previous attention has been placed on metabolites considered as deleterious to health, a shift to the investigation of short-chain fatty acids (SCFAs) as potential health promotors has been observed. Objectives: To develop a simple, high-throughput and quantitative assay to measure gut-derived SCFAs in clinically relevant biofluids using gas chromatography-mass spectrometry (GC-MS). Methods: A short (7.5 min) GC-MS assay was optimized for measurement of seven straight- and branched-chain SCFAs and their deuterated isotopes using a wax-based column for analysis without prior derivatization. The assay was validated using routine criteria to assess precision, accuracy, matrix effects, recovery, and extraction reproducibility. Assay applicability was tested in cohorts of healthy individuals and kidney disease patients. Results: The assay was demonstrated to be precise, accurate and reproducible with acceptable levels of matrix effect and analyte recovery. Lower limits of detection and quantitation were in the low ng/mL range. An investigation into different blood collection tube chemistries demonstrated that lithium heparin plasma and serum clotting activator tubes are recommended for use in future cross-study comparisons. Kidney disease patient analyses demonstrated variable differences across SCFAs when comparing hemodialysis to earlier stages of chronic kidney disease, demonstrating the suitability of the assay for translation to clinical analyses. Conclusion: The assay has been validated and identified as reliable for use in larger-scale studies for the analysis of SCFAs in human plasma and serum.

Room for improvement: diagnosing and managing acute coronary syndromes in persons with reduced eGFR.

Cardiovascular events are the leading cause of death in chronic kidney disease. A recent analysis from the High-Sensitivity Troponin in the Evaluation of Patients With Suspected Acute Coronary Syndrome trial focused on results in those with reduced estimated glomerular filtration rate. This commentary discusses aspects of acute coronary syndrome diagnosis in this group and the differential approach to acute coronary syndrome management that was observed between those with normal and reduced kidney function.

Repeatability of Contrast-Enhanced Ultrasound to Determine Renal Cortical Perfusion.

Alterations in renal perfusion play a major role in the pathogenesis of renal diseases. Renal contrast-enhanced ultrasound (CEUS) is increasingly applied to quantify renal cortical perfusion and to assess its change over time, but comprehensive assessment of the technique's repeatability is lacking. Ten adults attended two renal CEUS scans within 14 days. In each session, five destruction/reperfusion sequences were captured. One-phase association was performed to derive the following parameters: acoustic index (AI), mean transit time (mTT), perfusion index (PI), and wash-in rate (WiR). Intra-individual and inter-operator (image analysis) repeatability for the perfusion variables were assessed using intra-class correlation (ICC), with the agreement assessed using a Bland-Altman analysis. The 10 adults had a median (IQR) age of 39 years (30-46). Good intra-individual repeatability was found for mTT (ICC: 0.71) and PI (ICC: 0.65). Lower repeatability was found for AI (ICC: 0.50) and WiR (ICC: 0.56). The correlation between the two operators was excellent for all variables: the ICCs were 0.99 for PI, 0.98 for AI, 0.87 for mTT, and 0.83 for WiR. The Bland-Altman analysis showed that the mean biases (± SD) between the two operators were 0.03 ± 0.16 for mTT, 0.005 ± 0.09 for PI, 0.04 ± 0.19 for AI, and -0.02 ± 0.11 for WiR.

Hidden risks associated with conventional short intermittent hemodialysis: A call for action to mitigate cardiovascular risk and morbidity.

The development of maintenance hemodialysis (HD) for end stage kidney disease patients is a success story that continues to save many lives. Nevertheless, intermittent renal replacement therapy is also a source of recurrent stress for patients. Conventional thrice weekly short HD is an imperfect treatment that only partially corrects uremic abnormalities, increases cardiovascular risk, and exacerbates disease burden. Altering cycles of fluid loading associated with cardiac stretching (interdialytic phase) and then fluid unloading (intradialytic phase) likely contribute to cardiac and vascular damage. This unphysiologic treatment profile combined with cyclic disturbances including osmotic and electrolytic shifts may contribute to morbidity in dialysis patients and augment the health burden of treatment. As such, HD patients are exposed to multiple stressors including cardiocirculatory, inflammatory, biologic, hypoxemic, and nutritional. This cascade of events can be termed the dialysis stress storm and sickness syndrome. Mitigating cardiovascular risk and morbidity associated with conventional intermittent HD appears to be a priority for improving patient experience and reducing disease burden. In this in-depth review, we summarize the hidden effects of intermittent HD therapy, and call for action to improve delivered HD and develop treatment schedules that are better tolerated and associated with fewer adverse effects.

EDTAKI: a Nephrology and Public Policy Committee platform call for more European involvement in acute kidney injury.

BACKGROUND: Acute kidney injury (AKI) is an often neglected but crucial element of clinical nephrology. The aim of the Nephrology and Public Policy Committee (NPPC) of the European Renal Association-European Dialysis and Transplant Association is to promote several key aspects of European nephrology. One of the targets proposed by the NPPC was to advance European nephrology involvement in AKI. METHODS: We undertook a literature analysis to define the current position of European nephrology in the field of AKI compared with other regions and to determine how different European countries compare with each other. RESULTS: It appeared that vis-à-vis countries with a comparable socio-economic status (the USA, Australia, New Zealand and Canada), the European contribution was almost 50% less. Within Europe, Central and Eastern Europe and countries with a lower gross domestic product showed lower scientific output. Nephrologists contributed to less than half of the output. There was no trend of a change over the last decade. CONCLUSIONS: There is room to improve the contribution of European nephrology in the field of AKI. We propose a model on how to promote clinical collaboration on AKI across Europe and the creation of a pan-European nephrology network of interested units to improve clinical outcomes, increase nephrologist involvement and awareness outside nephrology and stimulate research on AKI in Europe. Accordingly, we also propose a list of research priorities and stress the need for more European funding of AKI research.