Combination of the chemokine receptor type 2 (CCR2) antagonist DMX-200 and candesartan for COVID-19: a randomised controlled trial.

OBJECTIVE: To determine whether a chemokine receptor type 2 antagonist, DMX-200 (repagermanium), in combination with an angiotensin receptor blocker, candesartan, improves clinical outcomes in people with COVID-19. DESIGN: Prospective, multicentre, double-blind, placebo-controlled trial. SETTING: Ten acute care hospitals in India. PARTICIPANTS: Adults <65 years old intended for hospital admission with moderate/severe COVID-19 disease (respiratory rate ≥24 breaths per minute or oxygen saturation ≤93% on room air). INTERVENTION: DMX-200 120 mg two times per day, or placebo, on background of titratable candesartan commencing at 4 mg two times per day, for 28 days. MAIN OUTCOME MEASURES: The primary endpoint was COVID-19 disease severity on a modified WHO Clinical Progression Scale (WHO scale) on day 14. Secondary outcomes included the WHO scale at days 28, 60, 90 and 180; intensive care unit (ICU) admission, respiratory failure or death within 28 days; length of hospitalisation; and requirement for ventilatory support or dialysis. RESULTS: Between December 2021 and August 2022, 518 people were screened, with 49 randomised to DMX-200 or placebo on a background of candesartan. The study was terminated early due to recruitment barriers, including an external requirement to restrict enrolment to adults <65 years old, contributing to a 91% screen failure rate. The median WHO Clinical Progression Scale (WHO scale) score at day 14 for both groups was 1 (IQR 1-1), indicating most participants were discharged with no limitations on activities by this time. Formal comparison was not performed due to the small sample size. One participant receiving DMX-200 died of COVID-19 disease progression. No participants required ICU admission, ventilation or dialysis. Median length of hospitalisation in both groups was 6 days (IQR 6-7 days). WHO scale scores were similar at 28, 60, 90 and 180 days. CONCLUSION: Due to recruitment barriers, the study was unable to determine whether DMX-200 improves clinical outcomes in people with COVID-19. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT05122182.

Structures for quality assurance and measurements for kidney replacement therapies: A multinational study from the ISN-GKHA.

AIM: Optimal care for patients with kidney failure reduces the risks of adverse health outcomes, including cardiovascular events and death. We evaluated data from the third iteration of the International Society of Nephrology Global Kidney Health Atlas (ISN-GKHA) to assess the capacity for quality service delivery for kidney failure care across countries and regions. METHOD: We explored the quality of kidney failure care delivery and the monitoring of quality indicators from data provided by an international survey of stakeholders from countries affiliated with the ISN from July to September 2022. RESULTS: One hundred and sixty seven countries participated in the survey, representing about 97.4% of the world's population. In countries where haemodialysis (HD) was available, 81% (n = 134) provided standard HD sessions (three times weekly for 3-4 h per session) to patients. Among countries with peritoneal dialysis (PD) services, 61% (n = 101) were able to provide standard PD care (3-4 exchanges per day). In high-income countries, 98% (n = 62) reported that >75% of centers regularly monitored dialysis water quality for bacteria compared to 28% (n = 5) of low-income countries (LICs). Capacity to monitor the administration of immunosuppression drugs was generally available in 21% (n = 4) of LICs, compared to 90% (n = 57) of high-income countries. There was significant variability between and within regions and country income groups in reporting the quality of services utilized for kidney replacement therapies. CONCLUSION: Quality assurance standards on diagnostic and treatment tools were variable and particularly infrequent in LICs. Standardization of delivered care is essential for improving outcomes for people with kidney failure.

Sodium-glucose cotransporter-2 (SGLT-2) inhibitors for adults with chronic kidney disease: a clinical practice guideline.

CLINICAL QUESTION: What is the impact of sodium-glucose cotransporter-2 (SGLT-2) inhibitors on survival and on cardiovascular and kidneyoutcomes for adults living with chronic kidney disease (CKD)? CURRENT PRACTICE: Few therapies slow kidney disease progression and improve long term prognosis for adults living with CKD. SGLT-2 inhibitors have demonstrated cardiovascular and kidney benefits in adults with CKD with and without type 2 diabetes. Existing guidance for SGLT-2 inhibitors does not account for the totality of current best evidence for adults with CKD and does not provide fully stratified treatment effects and recommendations across all risk groups based on risk of CKD progression and complications. RECOMMENDATIONS: The guideline panel considered evidence regarding benefits and harms of SGLT-2 inhibitor therapy for adults with CKD over a five year period, along with contextual factors, and provided the following recommendations:1. For adults at low risk of CKD progression and complications, we suggest administering SGLT-2 inhibitors (weak recommendation in favour)2. For adults at moderate risk of CKD progression and complications, we suggest administering SGLT-2 inhibitors (weak recommendation in favour)3. For adults at high risk of CKD progression and complications, we recommend administering SGLT-2 inhibitors (strong recommendation in favour)4. For adults at very high risk of CKD progression and complications, we recommend administering SGLT-2 inhibitors (strong recommendation in favour).Recommendations are applicable to all adults with CKD, irrespective of type 2 diabetes status. HOW THIS GUIDELINE WAS CREATED: An international panel including patients, clinicians, and methodologists produced these recommendations following standards for trustworthy guidelines and using the GRADE approach. The panel identified typical risk strata of adults with CKD (from low to very high risk of CKD progression and related complications) using the classification system developed by Kidney Disease Improving Global Outcomes (KDIGO), and applied an individual patient perspective in moving from evidence to recommendations. Effects of SGLT-2 inhibitors were interpreted in absolute terms applicable to different risk strata with varying baseline risks for outcomes of benefit over a five year period. The panel explicitly considered the balance of benefits, harms, and burdens of starting an SGLT-2 inhibitor, incorporating the values and preferences of adults with different risk profiles. Interactive evidence summaries and decision aids accompany multilayered recommendations, developed in an online authoring and publication platform (www.magicapp.org) that allows reuse and adaptation. THE EVIDENCE: A linked systematic review and pairwise meta-analysis (13 trials including 29 614 participants) of benefits and harms associated with SGLT-2 inhibitors in adults with CKD with or without type 2 diabetes informed guidance. Among individuals at very high risk of CKD progression and complications, moderate to high certainty evidence shows SGLT-2 inhibitors (relative to placebo or standard care without SGLT-2 inhibitors) decrease all-cause and cardiovascular mortality, hospitalisation for heart failure, kidney failure, non-fatal myocardial infarction, and non-fatal stroke. Among individuals at high risk, moderate to high certainty evidence shows SGLT-2 inhibitors result in similar benefits across outcomes except demonstrating little or no effect on hospitalisation for heart failure and kidney failure. Among individuals at moderate and low risk, moderate to high certainty evidence shows SGLT-2 inhibitors probably reduce all-cause mortality and non-fatal stroke, with little or no effect for other outcomes of benefit. Risk-stratified estimates were unavailable for outcomes of harm; the panel therefore considered absolute effects summarised across risk strata. SGLT-2 inhibitors are associated with little or no effect on acute kidney injury requiring dialysis, bone fractures, lower limb amputations, ketoacidosis, genital infections, or symptomatic hypovolaemia, although a residual possibility of harms at the individual patient level remains. UNDERSTANDING THE RECOMMENDATION: In order to apply recommendations, clinicians must appropriately identify adults with CKD, consider the underlying aetiology, and risk stratify them based on glomerular filtration rate (estimated or measured) and degree of albuminuria. In addition to classifying individuals into risk strata, further estimation of a given patient's risk based on the extent of their kidney disease and other comorbidities may be warranted to inform individual-level decisions and shared decision making. Available risk calculators may help estimate a given patient's risk of CKD progression and complications.

Progress of nations in the organisation of, and structures for, kidney care delivery between 2019 and 2023: cross sectional survey in 148 countries.

OBJECTIVE: To assess changes in key measures of kidney care using data reported in 2019 and 2023. DESIGN: Cross sectional survey in 148 countries. SETTING: Surveys from International Society of Nephrology Global Kidney Health Atlas between 2019 and 2023 that included participants from countries in Africa (n=36), Eastern and Central Europe (n=16), Latin America (n=18), the Middle East (n=11), Newly Independent States and Russia (n=10), North America and the Caribbean (n=8), North and East Asia (n=6), Oceania and South East Asia (n=15), South Asia (n=7), and Western Europe (n=21). PARTICIPANTS: Countries that participated in both surveys (2019 and 2023). MAIN OUTCOME MEASURES: Comparison of 2019 and 2023 data for availability of kidney replacement treatment services, access, health financing, workforce, registries, and policies for kidney care. Data for countries that participated in both surveys (2019 and 2023) were included in our analysis. Country data were aggregated by International Society of Nephrology regions and World Bank income levels. Proportionate changes in the status of these measures across both periods were reported. RESULTS: Data for 148 countries that participated in both surveys were available for analysis. The proportions of countries that provided public funding (free at point of delivery) increased from 27% in 2019 to 28% in 2023 for haemodialysis, 23% to 28% for peritoneal dialysis, and 31% to 36% for kidney transplantation services. Centres for these treatments increased from 4.4 per million population (pmp) to 4.8 pmp (P<0.001) for haemodialysis, 1.4 pmp to 1.6 pmp for peritoneal dialysis, and 0.43 pmp to 0.46 pmp for kidney transplantation services. Overall, access to haemodialysis and peritoneal dialysis improved, however, access to kidney transplantation decreased from 30 pmp to 29 pmp. The global median prevalence of nephrologists increased from 9.5 pmp to 12.4 pmp (P<0.001). Changes in the availability of kidney registries and in national policies and strategies for kidney care were variable across regions and country income levels. The reporting of specific barriers to optimal kidney care by countries increased from 55% to 59% for geographical factors, 58% to 68% (P=0.043) for availability of nephrologists, and 46% to 52% for political factors. CONCLUSIONS: Important changes in key areas of kidney care delivery were noted across both periods globally. These changes effected the availability of, and access to, kidney transplantation services. Countries and regions need to enact enabling strategies for preserving access to kidney care services, particularly kidney transplantation.

A global snapshot on health systems capacity for detection, monitoring, and management of acute kidney injury: A multinational study from the ISN-GKHA.

Acute kidney injury (AKI) is a significant cause of morbidity and mortality, especially in low and lower-middle income countries. Data from the third iteration of the International Society of Nephrology Global Kidney Health Atlas (ISN-GKHA) were used to evaluate the organization of structures and services for the provision of AKI care in world countries and ISN regions. An international survey of key stakeholders (clinicians, policymakers, and patient advocates) from countries affiliated with the ISN was conducted from July to September 2022 to assess structures and services for AKI care across countries. Main findings of the study show that overall, 167 countries or jurisdictions participated in the survey, representing 97.4% of the world's population. Only 4% of countries had an AKI detection program based on national policy or guideline, and 50% of these countries used a reactive approach for AKI identification (i.e., cases managed as identified through clinical practice). Only 19% of national governments recognized AKI as a healthcare priority. Almost all countries (98% of the countries surveyed) reported capacity to provide acute hemodialysis (HD) for AKI, but in 31% of countries, peritoneal dialysis (PD) was unavailable for AKI. About half of all countries (44% of countries surveyed) provided acute dialysis (HD or PD) via public funding, but funding availability varied across ISN regions, including less than a quarter of countries in Oceania and South East Asia (17%) and Africa (24%) and highest availability in Western Europe (91%). Availability increased with the increasing country income level. Initiatives have been developed to propose and promote optimal care for AKI (including the ISN 0-by-25 initiative), but capacity for optimal AKI care remains low, particularly in low- and lower-middle-income countries. Concerted efforts by the global community are required to close these gaps, to improve AKI outcomes across the world.

Transplantation: A Priority in the Healthcare Agenda.

BACKGROUND: In November 2023, in the context of the Spanish Presidency of the Council of the European Union, the Organization National de Transplante organized a global summit discussing global action in transplantation for the next decade. This article reports the recommendations supporting the need to prioritize transplantation in healthcare systems. METHODS: The working group investigated how transplantation addresses noncommunicable disease mortality, particularly related to kidney and liver disease. They also investigated how transplantation can contribute to the achievement of several of the United Nations Sustainable Development Goals, especially Goal 3 (good health and well-being), Goal 8 (sustained, inclusive, and sustainable economic growth and employment for all), and Goal 13 (combat climate change and its impact). RESULTS: By prioritizing transplantation, the increased availability and accessibility of life-saving organs and tissues to the public will not only lead to saving more lives and improving health outcomes for individual patients but also contribute to the development of a resilient health system in general in that country as a consequence of developing the infrastructure required for transplantation. CONCLUSIONS: The ethical principles associated with transplantation promote the principles of solidarity in society by fostering the donation process and equity in access to therapy. This article aims to advocate for the widespread availability of solid organ, tissue, and cell transplantation for all patients.

A global overview of health system financing and available infrastructure and oversight for kidney care.

BACKGROUND: Governance, health financing, and service delivery are critical elements of health systems for provision of robust and sustainable chronic disease care. We leveraged the third iteration of the International Society of Nephrology Global Kidney Health Atlas (ISN-GKHA) to evaluate oversight and financing for kidney care worldwide. METHODS: A survey was administered to stakeholders from countries affiliated with the ISN from July to September 2022. We evaluated funding models utilized for reimbursement of medications, services for the management of chronic kidney disease, and provision of kidney replacement therapy (KRT). We also assessed oversight structures for the delivery of kidney care. RESULTS: Overall, 167 of the 192 countries and territories contacted responded to the survey, representing 97.4% of the global population. High-income countries tended to use public funding to reimburse all categories of kidney care in comparison with low-income countries (LICs) and lower-middle income countries (LMICs). In countries where public funding for KRT was available, 78% provided universal health coverage. The proportion of countries that used public funding to fully reimburse care varied for non-dialysis chronic kidney disease (27%), dialysis for acute kidney injury (either hemodialysis or peritoneal dialysis) (44%), chronic hemodialysis (45%), chronic peritoneal dialysis (42%), and kidney transplant medications (36%). Oversight for kidney care was provided at a national level in 63% of countries, and at a state/provincial level in 28% of countries. CONCLUSION: This study demonstrated significant gaps in universal care coverage, and in oversight and financing structures for kidney care, particularly in in LICs and LMICs.

Global data monitoring systems and early identification for kidney diseases.

BACKGROUND: Data monitoring and surveillance systems are the cornerstone for governance and regulation, planning, and policy development for chronic disease care. Our study aims to evaluate health systems capacity for data monitoring and surveillance for kidney care. METHODS: We leveraged data from the third iteration of the International Society of Nephrology Global Kidney Health Atlas (ISN-GKHA), an international survey of stakeholders (clinicians, policymakers and patient advocates) from 167 countries conducted between July and September 2022. ISN-GKHA contains data on availability and types of kidney registries, the spectrum of their coverage, as well as data on national policies for kidney disease identification. RESULTS: Overall, 167 countries responded to the survey, representing 97.4% of the global population. Information systems in forms of registries for dialysis care were available in 63% (n = 102/162) of countries, followed by kidney transplant registries (58%; n = 94/162), and registries for non-dialysis chronic kidney disease (19%; n = 31/162) and acute kidney injury (9%; n = 14/162). Participation in dialysis registries was mandatory in 57% (n = 58) of countries; however, in more than half of countries in Africa (58%; n = 7), Eastern and Central Europe (67%; n = 10), and South Asia (100%; n = 2), participation was voluntary. The least-reported performance measures in dialysis registries were hospitalization (36%; n = 37) and quality of life (24%; n = 24). CONCLUSIONS: The variability of health information systems and early identification systems for kidney disease across countries and world regions warrants a global framework for prioritizing the development of these systems.

A global assessment of kidney care workforce.

BACKGROUND: An adequate workforce is needed to guarantee optimal kidney care. We used the International Society of Nephrology Global Kidney Health Atlas (ISN-GKHA) to provide an assessment of the global kidney care workforce. METHODS: We conducted a multinational cross-sectional survey to evaluate the global capacity of kidney care and assessed data on the number of adult and paediatric nephrologists, the number of trainees in nephrology and shortages of various cadres of the workforce for kidney care. Data are presented according to the ISN region and World Bank income categories. RESULTS: Overall, stakeholders from 167 countries responded to the survey. The median global prevalence of nephrologists was 11.75 per million population (pmp) (interquartile range [IQR] 1.78-24.76). Four regions had median nephrologist prevalences below the global median: Africa (1.12 pmp), South Asia (1.81 pmp), Oceania and Southeast Asia (3.18 pmp) and newly independent states and Russia (9.78 pmp). The overall prevalence of paediatric nephrologists was 0.69 pmp (IQR 0.03-1.78), while overall nephrology trainee prevalence was 1.15 pmp (IQR 0.18-3.81), with significant variations across both regions and World Bank income groups. More than half of the countries reported shortages of transplant surgeons (65%), nephrologists (64%), vascular access coordinators (59%), dialysis nurses (58%) and interventional radiologists (54%), with severe shortages reported in low- and lower-middle-income countries. CONCLUSIONS: There are significant limitations in the available kidney care workforce in large parts of the world. To ensure the delivery of optimal kidney care worldwide, it is essential to develop national and international strategies and training capacity to address workforce shortages.

Global structures, practices, and tools for provision of chronic peritoneal dialysis.

BACKGROUND: Worldwide, the uptake of peritoneal dialysis (PD) compared with hemodialysis remains limited. This study assessed organizational structures, availability, accessibility, affordability and quality of PD worldwide. METHODS: This cross-sectional study relied on data from kidney registries as well as survey data from stakeholders (clinicians, policymakers and advocates for people living with kidney disease) from countries affiliated with the International Society of Nephrology (ISN) from July to September 2022. RESULTS: Overall, 167 countries participated in the survey. PD was available in 79% of countries with a median global prevalence of 21.0 [interquartile range (IQR) 1.5-62.4] per million population (pmp). High-income countries (HICs) had an 80-fold higher prevalence of PD than low-income countries (LICs) (56.2 pmp vs 0.7 pmp). In 53% of countries, adults had greater PD access than children. Only 29% of countries used public funding (and free) reimbursement for PD with Oceania and South East Asia (6%), Africa (10%) and South Asia (14%) having the lowest proportions of countries in this category. Overall, the annual median cost of PD was US$18 959.2 (IQR US$10 891.4-US$31 013.8) with full private out-of-pocket payment in 4% of countries and the highest median cost in LICs (US$30 064.4) compared with other country income levels (e.g. HICs US$27 206.0). CONCLUSIONS: Ongoing large gaps and variability in the availability, access and affordability of PD across countries and world regions were observed. Of note, there is significant inequity in access to PD by children and for people in LICs.

Global structures, practices, and tools for provision of hemodialysis.

BACKGROUND: Hemodialysis (HD) is the most commonly utilized modality for kidney replacement therapy worldwide. This study assesses the organizational structures, availability, accessibility, affordability and quality of HD care worldwide. METHODS: This cross-sectional study relied on desk research data as well as survey data from stakeholders (clinicians, policymakers and patient advocates) from countries affiliated with the International Society of Nephrology from July to September 2022. RESULTS: Overall, 167 countries or jurisdictions participated in the survey. In-center HD was available in 98% of countries with a median global prevalence of 322.7 [interquartile range (IQR) 76.3-648.8] per million population (pmp), ranging from 12.2 (IQR 3.9-103.0) pmp in Africa to 1575 (IQR 282.2-2106.8) pmp in North and East Asia. Overall, home HD was available in 30% of countries, mostly in countries of Western Europe (82%). In 74% of countries, more than half of people with kidney failure were able to access HD. HD centers increased with increasing country income levels from 0.31 pmp in low-income countries to 9.31 pmp in high-income countries. Overall, the annual cost of in-center HD was US$19 380.3 (IQR 11 817.6-38 005.4), and was highest in North America and the Caribbean (US$39 825.9) and lowest in South Asia (US$4310.2). In 19% of countries, HD services could not be accessed by children. CONCLUSIONS: This study shows significant variations that have remained consistent over the years in availability, access and affordability of HD across countries with severe limitations in lower-resourced countries.

Global access and quality of conservative kidney management.

BACKGROUND: Conservative kidney management (CKM) describes supportive care for people living with kidney failure who choose not to receive or are unable to access kidney replacement therapy (KRT). This study captured the global availability of CKM services and funding. METHODS: Data came from the International Society of Nephrology Global Kidney Health survey conducted between June and September 2022. Availability of CKM, infrastructure, guidelines, medications and training were evaluated. RESULTS: CKM was available in some form in 61% of the 165 responding countries. CKM chosen through shared decision-making was available in 53%. Choice-restricted CKM-for those unable to access KRT-was available in 39%. Infrastructure to provide CKM chosen through shared decision-making was associated with national income level, reported as being "generally available" in most healthcare settings for 71% of high-income countries, 50% of upper-middle-income countries, 33% of lower-middle-income countries and 42% of low-income countries. For choice-restricted CKM, these figures were 29%, 50%, 67% and 58%, respectively. Essential medications for pain and palliative care were available in just over half of the countries, highly dependent upon income setting. Training for caregivers in symptom management in CKM was available in approximately a third of countries. CONCLUSIONS: Most countries report some capacity for CKM. However, there is considerable variability in terms of how CKM is defined, as well as what and how much care is provided. Poor access to CKM perpetuates unmet palliative care needs, and must be addressed, particularly in low-resource settings where death from untreated kidney failure is common.

Worldwide organization and structures for kidney transplantation services.

BACKGROUND: Kidney transplantation (KT) is the preferred modality of kidney replacement therapy with better patient outcomes and quality of life compared with dialytic therapies. This study aims to evaluate the epidemiology, accessibility and availability of KT services in countries and regions around the world. METHODS: This study relied on data from an international survey of relevant stakeholders (clinicians, policymakers and patient advocates) from countries affiliated with the International Society of Nephrology that was conducted from July to September 2022. Survey questions related to the availability, access, donor type and cost of KT. RESULTS: In total, 167 countries responded to the survey. KT services were available in 70% of all countries, including 86% of high-income countries, but only 21% of low-income countries. In 80% of countries, access to KT was greater in adults than in children. The median global prevalence of KT was 279.0 [interquartile range (IQR) 58.0-492.0] per million people (pmp) and the median global incidence was 12.2 (IQR 3.0-27.8) pmp. Pre-emptive KT remained exclusive to high- and upper-middle-income countries, and living donor KT was the only available modality for KT in low-income countries. The median cost of the first year of KT was $26 903 USD and varied 1000-fold between the most and least expensive countries. CONCLUSION: The availability, access and affordability of KT services, especially in low-income countries, remain limited. There is an exigent need to identify strategies to ensure equitable access to KT services for people with kidney failure worldwide, especially in the low-income countries.

Dialysis Outcomes Across Countries and Regions: A Global Perspective From the International Society of Nephrology Global Kidney Health Atlas Study.

Introduction: Kidney failure treated with hemodialysis (HD), or peritoneal dialysis (PD) is a major global health problem that is associated with increased risks of death and hospitalization. This study aimed to compare the incidence and causes of death and hospitalization during the first year of HD or PD among countries. Methods: The third iteration of the International Society of Nephrology Global Kidney Health Atlas (ISN-GKHA) was conducted between June and September 2022. For this analysis, data were obtained from the cross-sectional survey of key stakeholders from ISN-affiliated countries. Results: A total of 167 countries participated in the survey (response rate 87.4%). In 48% and 58% of countries, 1% to 10% of people treated with HD and PD died within the first year, respectively, with cardiovascular disease being the main cause. Access-related infections or treatment withdrawal owing to cost were important causes of death in low-income countries (LICs). In most countries, <30% and <20% of patients with HD and PD, respectively, required hospitalization during the first year. A greater proportion of patients with HD and PD in LICs were hospitalized in the first year than those in high-income countries (HICs). Access-related infection and cardiovascular disease were the commonest causes of hospitalization among patients with HD, whereas PD-related infection was the commonest cause in patients with PD. Conclusion: There is significant heterogeneity in the incidence and causes of death and hospitalization in patients with kidney failure treated with dialysis. These findings highlight opportunities to improve care, especially in LICs where infectious and social factors are strong contributors to adverse outcomes.