Eliah Aronoff-Spencer

International Society of Nephrology's 0by25 initiative for acute kidney injury (zero preventable deaths by 2025): a human rights case for nephrology

Executive summary Acute kidney injury (AKI) is a major contributor to poor patient outcomes. AKI occurs in about 13·3 million people per year, 85% of whom live in the developing world, and, although no direct link between AKI and death has yet been shown, AKI is thought to contribute to about 1·7 million deaths every year. The course of AKI varies with the setting in which it occurs, and the severity and duration of AKI aff ects outcomes such as dialysis requirement, renal functional recovery, and survival. Recognition is increasing for the eff ect of AKI on patients, and the resulting societal burden from its longterm eff ects, including development of chronic kidney disease and end-stage renal disease needing dialysis or trans plantation. Few systematic eff orts to manage (prevent, diagnose, and treat) AKI have been put in place and few resources have been allocated to inform health-care professionals and the public of the importance of AKI as a preventable and treatable disease. Several factors have contributed to the paucity of information. Most importantly, there have been few population-level epidemiological studies in several regions of the world. Diffi culties in defi nition of the incidence of AKI are especially evident in searches for data from low-income and middle-income countries, where more than 85% of the world’s population resides. No nationwide data collection systems are available, and data are usually from isolated centres and probably largely underestimate the true extent of AKI because they mostly do not include patients with AKI who were not able to reach a hospital for treatment. A recent metaanalysis that included 312 cohort studies and more than 49 million patients shows a scarcity of data from Africa and large parts of southeast Asia. We did an updated meta-analysis that used the most recent KDIGO (Kidney Disease: Improving Global Outcomes) defi nitions, which confi rms the high incidence and resulting outcomes of AKI, particularly in Africa, Asia, and Latin America, for which data were previously absent. The strong relation between the severity of AKI and consequent mortality is reiterated by our fi ndings and is evident across heterogeneous populations and specifi c disease cohorts. However, large gaps remain in knowledge about the factors that aff ect the geographical variation of AKI and poor outcomes. Many diff erences exist in the aetiology, pathophysiology, and management of AKI across the world. In high-income countries, AKI develops mainly in patients in hospitals. In low-income and middle-income countries, AKI occurs mainly in the community setting in acute illness, usually in association with diarrhoeal states and dehydration, infections such as malaria, and toxins (venoms and poisons). Public health issues (eg, contaminated water, poor sanitation, endemic infections such as malaria and dengue fever, venomous snakes, and toxic traditional medicines) and socioeconomic factors (eg, availability of health-care facilities) aff ect the epidemiology of AKI. Additionally availability of trained personnel and access to diagnostic tests and dialysis aff ect practice patterns and impose barriers to care. The extent to which these factors contribute to mortality and non-recovery of renal function has not been quantifi ed. AKI is potentially preventable and treatable with timely intervention, but there continues to be a high human burden. Which specifi c factors account for the poor outcomes and to what extent variations in care delivery contribute are unclear. The ability to provide lifesaving treatments for AKI provides a compelling argument to consider therapy for AKI as much of a basic right as it is to give antiretroviral drugs to treat HIV in low-resource regions, especially because care needs only be given for a Published Online March 13, 2015 http://dx.doi.org/10.1016/ S0140-6736(15)60126-X

Recognition and management of acute kidney injury in the International Society of Nephrology 0by25 Global Snapshot: a multinational cross-sectional study

BACKGROUND Epidemiological data for acute kidney injury are scarce, especially in low-income countries (LICs) and lower-middle-income countries (LMICs). We aimed to assess regional differences in acute kidney injury recognition, management, and outcomes. METHODS In this multinational cross-sectional study, 322 physicians from 289 centres in 72 countries collected prospective data for paediatric and adult patients with confirmed acute kidney injury in hospital and non-hospital settings who met criteria for acute kidney injury. Signs and symptoms at presentation, comorbidities, risk factors for acute kidney injury, and process-of-care data were obtained at the start of acute kidney injury, and need for dialysis, renal recovery, and mortality recorded at 7 days, and at hospital discharge or death, whichever came earlier. We classified countries into high-income countries (HICs), upper-middle-income countries (UMICs), and combined LICs and LMICs (LLMICs) according to their 2014 gross national income per person. FINDINGS Between Sept 29 and Dec 7, 2014, data were collected from 4018 patients. 2337 (58%) patients developed community-acquired acute kidney injury, with 889 (80%) of 1118 patients in LLMICs, 815 (51%) of 1594 in UMICs, and 663 (51%) of 1241 in HICs (for HICs vs UMICs p=0.33; p<0.0001 for all other comparisons). Hypotension (1615 [40%] patients) and dehydration (1536 [38%] patients) were the most common causes of acute kidney injury. Dehydration was the most frequent cause of acute kidney injury in LLMICs (526 [46%] of 1153 vs 518 [32%] of 1605 in UMICs vs 492 [39%] of 1260 in HICs) and hypotension in HICs (564 [45%] of 1260 vs 611 [38%%] of 1605 in UMICs vs 440 [38%] of 1153 LLMICs). Mortality at 7 days was 423 (11%) of 3855, and was higher in LLMICs (129 [12%] of 1076) than in HICs (125 [10%] of 1230) and UMICs (169 [11%] of 1549). INTERPRETATION We identified common aetiological factors across all countries, which might be amenable to a standardised approach for early recognition and treatment of acute kidney injury. Study limitations include a small number of patients from outpatient settings and LICs, potentially under-representing the true burden of acute kidney injury in these areas. Additional strategies are needed to raise awareness of acute kidney injury in community health-care settings, especially in LICs. FUNDING International Society of Nephrology.

Lyophilized visually readable loop-mediated isothermal reverse transcriptase nucleic acid amplification test for detection Ebola Zaire RNA

Recent viral outbreaks highlight the need for reliable, yet broadly deployable diagnostics for detection of epidemic and emerging pathogens. In this study we designed and optimized methods to visually detect viral nucleic acid by isothermal amplification and SYBR dye intercalation. We designed and tested loop-mediated isothermal amplification (LAMP) primers and lyophilized reactions to optimize the detection of Zaire Ebola Virus (ZEBOV) and further evolved the LAMP platform to allow room-temperature storage for deployment in resource limited settings. Our results demonstrated excellent sensitivity and specificity for viral nucleic acid sequences with lower limits of detection of less than 100 copies. Moreover, lyophilized reaction mixtures retained activity for prolonged periods under dry conditions at room temperature. This approach offers a way for detection of emerging viruses in resource limited settings.

Innovative Strategies for Transforming Internal Medicine Residency Training in Resource-Limited Settings: The Mozambique Experience

With approximately 4 physicians per 100,000 inhabitants, Mozambique faces one of the most severe health care provider shortages in Sub-Saharan Africa. The lack of sufficient well-trained medical school faculty is one of Mozambique’s major barrier to producing new physicians annually. A partnership between the Universidade Eduardo Mondlane and the University of California, San Diego, has addressed this challenge with support from the Medical Education Partnership Initiative. After an initial needs assessment involving questionnaires and focus groups of residents, and working with key members from the Ministry of Health, the Medical Council, and Maputo Central Hospital, a set of interventions was designed. The hospital’s internal medicine residency program was chosen as the focus for the plan. Interventions included curriculum design, new teaching methodologies, investment in an informatics infrastructure for access to digital references, building capacity to support clinical research, and providing financial incentives to retain junior faculty. The number of candidates entering the internal medicine residency program has increased, and detailed monitoring and evaluation is measuring the impact of these changes on the quality of training. These changes are expected to improve the long-term quality of postgraduate training in general through dissemination to other departments. They also have the potential to facilitate equitable distribution of specialists nationwide by expanding postgraduate training to other hospitals and universities.

Clinical detection of Hepatitis C viral infection by yeast-secreted HCV-core:Gold-binding-peptide

Access to affordable and field deployable diagnostics are key barriers to the control and eradication of many endemic and emerging infectious diseases. While cost, accuracy, and usability have all improved in recent years, there remains a pressing need for even less expensive and more scalable technologies. To that end, we explored new methods to inexpensively produce and couple protein-based biosensing molecules (affinity reagents) with scalable electrochemical sensors. Previous whole-cell constructs resulted in confounding measurements in clinical testing due to significant cross-reactivity when probing for host-immune (antibody) response to infection. To address this, we developed two complimentary strategies based on either the release of surface displayed or secretion of fusion proteins. These dual affinity biosensing elements couple antibody recognition (using antigen) and sensor surface adhesion (using gold-binding peptide-GBP) to allow single-step reagent production, purification, and biosensor assembly. As a proof-of-concept, we developed Hepatitis C virus (HCV)-core antigen-GBP fusion proteins. These constructs were first tested and optimized for consistent surface adhesion then the assembled immunosensors were tested for cross-reactivity and evaluated for performance in vitro. We observed loss of function of the released reagents while secreted constructs performed well in in vitro testing with 2 orders of dynamic range, and a limit of detection of 32 nM. Finally, we validated the secreted platform with clinical isolates (n = 3) with statistically significant differentiation of positive vs. non-infected serum (p < 0.0001) demonstrating the ability to clearly distinguish HCV positive and negative clinical samples.

A 64×64 high-density redox amplified coulostatic discharge-based biosensor array in 180nm CMOS

This paper describes the design of a high-density 4,096-pixel electrochemical biosensor array in 180nm CMOS for biomedical applications that require multiple analyte detection from small (5μL) samples. Each pixel of the array contains an exposed 45×45μm2 interdigitated micro-electrode surrounded by a ∼9pL nanowell fabricated using only a standard CMOS process along with a simple electroless gold plating procedure without the need for further post processing. Directly underneath each transducer is a complete ultra-low-leakage (sub-fA) readout circuitry, which leverages the Coulostatic Discharge sensing technique and interdigitated electrode (IDE) geometry to minimize both the complexity and overall size of the array. By evaluating IDE designs with different feature sizes (2–5μm), an average maximum amplification factor of 10.5x was achieved using redox cycling coupled with the higher collection efficiency of trenches formed from opening the passivation. The arrays sensor density is comparable to or better than state-of-the-art sensor arrays, all without augmenting the sensors with additional materials or structures. Using the array, detection of anti-Rubella is demonstrated as progress towards a complete vaccination panel.

DesignX in the Emergency Department: Requirements of a Digital Antibiogram

Even simple interventions in healthcare may defy a straightforward solution due to incompatible constraints imposed by multiple stakeholders and the nature of the resulting system. This paper presents one of these so-called DesignX problems by describing the design of a digital antibiogram and a first use case in Emergency Medicine. The Infectious Disease department conceived a digital treatment selection tool [antibiogram] to improve antibiotic stewardship and appropriate care in the emergency department where antimicrobial -therapy is usually based on heuristics and limited microbiologic data. Using contextual interviews, observations and paper prototyping, we found that multiple perspectives, expectations and social roles were closely intertwined. The case of the antibiogram demonstrates the complexity of small technological changes in hospitals. Social and technical implications and dependencies turn apparently minor technological interventions into DesignX problems. Accordingly, even small interventions in healthcare call for a careful iterative design process to deliver appropriate solutions.