A phase 2b, randomized, double-blind, placebo-controlled, clinical trial of atacicept for treatment of IgA nephropathy.

Atacicept is a first-in-class, dual anti-B-cell Activation Factor-A Proliferation-Inducing Ligand fusion protein in clinical evaluation for treatment of IgA nephropathy. To compare efficacy and safety of atacicept versus placebo in patients with IgAN, this randomized, double-blind, placebo-controlled phase 2b clinical trial ORIGIN enrolled 116 individuals with biopsy-proven IgA nephropathy. Participants were randomized to atacicept 150, 75, or 25 mg versus placebo once weekly for up to 36 weeks. Primary and key secondary endpoints were changes in urine protein creatinine ratio based on 24-hour urine collection at weeks 24 and 36, respectively, in the combined atacicept 150 mg and 75 mg group versus placebo. The primary endpoint was met at week 24 as the mean urine protein creatinine ratio was reduced from baseline by 31% in the combined atacicept group versus 8% with placebo, resulting in a significant 25% reduction with atacicept versus placebo. At week 36, the key secondary endpoint was met as the mean urine protein creatinine ratio reduced from baseline by 34% in the combined atacicept group versus a 2% increase with placebo, resulting in a significant 35% reduction with atacicept versus placebo. The reduction in proteinuria was accompanied by stabilization in endpoint eGFR with atacicept compared to a decline with placebo at week 36, resulting in significant between-group geometric mean difference of 11%, approximating an absolute difference of 5.7 mL/min/1.73m2. Endpoint galactose deficient IgA1 levels significantly decreased from baseline by 60% versus placebo. The safety profile of atacicept was like placebo. Thus, our results provide evidence to support a pivotal, phase 3 study of atacicept in IgA nephropathy.

Post-transplant recurrence of focal segmental glomerular sclerosis: consensus statements.

Focal segmental glomerular sclerosis (FSGS) is 1 of the primary causes of nephrotic syndrome in both pediatric and adult patients, which can lead to end-stage kidney disease. Recurrence of FSGS after kidney transplantation significantly increases allograft loss, leading to morbidity and mortality. Currently, there are no consensus guidelines for identifying those patients who are at risk for recurrence or for the management of recurrent FSGS. Our work group performed a literature search on PubMed/Medline, Embase, and Cochrane, and recommendations were proposed and graded for strength of evidence. Of the 614 initially identified studies, 221 were found suitable to formulate consensus guidelines for recurrent FSGS. These guidelines focus on the definition, epidemiology, risk factors, pathogenesis, and management of recurrent FSGS. We conclude that additional studies are required to strengthen the recommendations proposed in this review.

Daprodustat for the Treatment of Anemia in Patients Undergoing Dialysis.

BACKGROUND: Among patients with chronic kidney disease (CKD), the use of recombinant human erythropoietin and its derivatives for the treatment of anemia has been linked to a possibly increased risk of stroke, myocardial infarction, and other adverse events. Several trials have suggested that hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitors (PHIs) are as effective as erythropoiesis-stimulating agents (ESAs) in increasing hemoglobin levels. METHODS: In this randomized, open-label, phase 3 trial, we assigned patients with CKD who were undergoing dialysis and who had a hemoglobin level of 8.0 to 11.5 g per deciliter to receive an oral HIF-PHI (daprodustat) or an injectable ESA (epoetin alfa if they were receiving hemodialysis or darbepoetin alfa if they were receiving peritoneal dialysis). The two primary outcomes were the mean change in the hemoglobin level from baseline to weeks 28 through 52 (noninferiority margin, -0.75 g per deciliter) and the first occurrence of a major adverse cardiovascular event (a composite of death from any cause, nonfatal myocardial infarction, or nonfatal stroke), with a noninferiority margin of 1.25. RESULTS: A total of 2964 patients underwent randomization. The mean (±SD) baseline hemoglobin level was 10.4±1.0 g per deciliter overall. The mean (±SE) change in the hemoglobin level from baseline to weeks 28 through 52 was 0.28±0.02 g per deciliter in the daprodustat group and 0.10±0.02 g per deciliter in the ESA group (difference, 0.18 g per deciliter; 95% confidence interval [CI], 0.12 to 0.24), which met the prespecified noninferiority margin of -0.75 g per deciliter. During a median follow-up of 2.5 years, a major adverse cardiovascular event occurred in 374 of 1487 patients (25.2%) in the daprodustat group and in 394 of 1477 (26.7%) in the ESA group (hazard ratio, 0.93; 95% CI, 0.81 to 1.07), which also met the prespecified noninferiority margin for daprodustat. The percentages of patients with other adverse events were similar in the two groups. CONCLUSIONS: Among patients with CKD undergoing dialysis, daprodustat was noninferior to ESAs regarding the change in the hemoglobin level from baseline and cardiovascular outcomes. (Funded by GlaxoSmithKline; ASCEND-D ClinicalTrials.gov number, NCT02879305.).

Daprodustat for the Treatment of Anemia in Patients Not Undergoing Dialysis.

BACKGROUND: Daprodustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor. In patients with chronic kidney disease (CKD) who are not undergoing dialysis, the efficacy and safety of daprodustat, as compared with the conventional erythropoiesis-stimulating agent darbepoetin alfa, are unknown. METHODS: In this randomized, open-label, phase 3 trial with blinded adjudication of cardiovascular outcomes, we compared daprodustat with darbepoetin alfa for the treatment of anemia in patients with CKD who were not undergoing dialysis. The primary outcomes were the mean change in the hemoglobin level from baseline to weeks 28 through 52 and the first occurrence of a major adverse cardiovascular event (MACE; a composite of death from any cause, nonfatal myocardial infarction, or nonfatal stroke). RESULTS: Overall, 3872 patients were randomly assigned to receive daprodustat or darbepoetin alfa. The mean (±SD) baseline hemoglobin levels were similar in the two groups. The mean (±SE) change in the hemoglobin level from baseline to weeks 28 through 52 was 0.74±0.02 g per deciliter in the daprodustat group and 0.66±0.02 g per deciliter in the darbepoetin alfa group (difference, 0.08 g per deciliter; 95% confidence interval [CI], 0.03 to 0.13), which met the prespecified noninferiority margin of -0.75 g per deciliter. During a median follow-up of 1.9 years, a first MACE occurred in 378 of 1937 patients (19.5%) in the daprodustat group and in 371 of 1935 patients (19.2%) in the darbepoetin alfa group (hazard ratio, 1.03; 95% CI, 0.89 to 1.19), which met the prespecified noninferiority margin of 1.25. The percentages of patients with adverse events were similar in the two groups. CONCLUSIONS: Among patients with CKD and anemia who were not undergoing dialysis, daprodustat was noninferior to darbepoetin alfa with respect to the change in the hemoglobin level from baseline and with respect to cardiovascular outcomes. (Funded by GlaxoSmithKline; ASCEND-ND ClinicalTrials.gov number, NCT02876835.).

Organization and Structures for Detection and Monitoring of CKD Across World Countries and Regions: Observational Data From a Global Survey.

RATIONALE & OBJECTIVE: Established therapeutic interventions effectively mitigate the risk and progression of chronic kidney disease (CKD). Countries and regions have a compelling need for organizational structures that enable early identification of people with CKD who can benefit from these proven interventions. We report the current global status of CKD detection programs. STUDY DESIGN: A multinational cross-sectional survey. SETTING & PARTICIPANTS: Stakeholders, including nephrologist leaders, policymakers, and patient advocates from 167 countries, participating in the International Society of Nephrology (ISN) survey from June to September 2022. OUTCOME: Structures for the detection and monitoring of CKD, including CKD surveillance systems in the form of registries, community-based detection programs, case-finding practices, and availability of measurement tools for risk identification. ANALYTICAL APPROACH: Descriptive statistics. RESULTS: Of all participating countries, 19% (n=31) reported CKD registries, and 25% (n=40) reported implementing CKD detection programs as part of their national policies. There were variations in CKD detection program, with 50% (n=20) using a reactive approach (managing cases as identified) and 50% (n=20) actively pursuing case-finding in at-risk populations. Routine case-finding for CKD in high-risk populations was widespread, particularly for diabetes (n=152; 91%) and hypertension (n=148; 89%). Access to diagnostic tools, estimated glomerular filtration rate (eGFR), and urine albumin-creatinine ratio (UACR) was limited, especially in low-income (LICs) and lower-middle-income (LMICs) countries, at primary (eGFR: LICs 22%, LMICs 39%, UACR: LICs 28%, LMICs 39%) and secondary/tertiary health care levels (eGFR: LICs 39%, LMICs 73%, UACR: LICs 44%, LMICs 70%), potentially hindering CKD detection. LIMITATIONS: A lack of detailed data prevented an in-depth analysis. CONCLUSIONS: This comprehensive survey highlights a global heterogeneity in the organization and structures (surveillance systems and detection programs and tools) for early identification of CKD. Ongoing efforts should be geared toward bridging such disparities to optimally prevent the onset and progression of CKD and its complications. PLAIN-LANGUAGE SUMMARY: Early detection and management of chronic kidney disease (CKD) is crucial to prevent progression to kidney failure. A multinational survey across 167 countries revealed disparities in CKD detection programs. Only 19% reported CKD registries, and 25% implemented detection programs as part of their national policy. Half used a reactive approach while others actively pursued case-finding in at-risk populations. Routine case-finding was common for individuals with diabetes and hypertension. However, limited access to gold standard tools such as estimated glomerular filtration rate (eGFR) and urine albumin-creatinine ratio (UACR), especially in low-income and lower-middle income countries, may hinder CKD detection. A global effort to bridge these disparities is needed to optimally prevent the onset and progression of CKD and its complications.

Acute Kidney Injury in Acute Heart Failure - When to worry and when not to worry?

Acute kidney injury is common in patients with acute decompensated heart failure. It is more common in patients with acute heart failure who suffer from chronic kidney disease. Worsening renal function is often defined as a rise in serum creatinine of more than 0.3 milligrams per deciliter (26.5 µmol/L), which by definition, is acute kidney injury stage one. Perhaps the term acute kidney injury is more appropriate than worsening renal function as it is used universally by nephrologists, internists, and other medical practitioners. In health, the heart and the kidney support each other to maintain body's homeostasis. In disease, the heart and the kidney can adversely affect each other's function causing further clinical deterioration. In patients presenting with acute heart failure and fluid overload, therapy with diuretics for decongestion often causes a rise in serum creatinine and acute kidney injury. However, in the longer term the decongestion improves survival and prevents hospital admissions despite rising serum creatinine and acute kidney injury. It is important to realize that renal venous congestion due to increased right sided heart pressures in acute heart failure is a major cause of kidney dysfunction and hence decongestion therapy improves kidney function in the longer term. This review provides a perspective on the acceptable acute kidney injury with decongestion therapy which is associated with improved survival; as opposed to acute kidney injury due to tubular injury related to sepsis or nephrotoxic drugs, which is associated with poor survival.

Global Kidney Health priorities - Perspectives from the ISN-GKHA.

Kidney diseases have become a global epidemic with significant public health impact. Chronic kidney disease (CKD) is set to become the fifth largest cause of death by 2040, with major impacts on low-resource countries. This review is based on recent report of the International Society of Nephrology Global Kidney Health Atlas (ISN-GKHA) that uncovered gaps in key vehicles of kidney care delivery assessed using World Health Organization building blocks for health systems (financing, services delivery, workforce, access to essential medicines, health information systems, and leadership/governance). High-income countries had more centres for kidney replacement therapies (KRT), higher KRT access, higher allocation of public funds to KRT, larger workforce, more health information systems, and higher government recognition of CKD and KRT as health priorities than low-income nations. Evidence identified from the current ISN-GKHA initiative should serve as template for generating and advancing policies and partnerships to address the global burden of kidney disease. The results provide opportunities for kidney health policymakers, nephrology leaders, and organizations to initiate consultations to identify strategies for improving care delivery and access in equitable, and resource-sensitive manners. Policies to increase use of public funding for kidney care, lower cost of KRT, and increase workforce should be high-priority in low-resource nations, while strategies that expand access to kidney care and maintain current status of care should be prioritized in high-income countries. In all countries, the perspectives of people with CKD should be exhaustively explored to identify core kidney care priorities.

Variation in performing kidney biopsy amongst nephrologists in the Asia-Pacific region: A multinational survey.

AIM: Kidney biopsy (KB) is the gold standard procedure for diagnosing kidney diseases. Globally, nephrologists are trained to perform KB. However, the past few decades have witnessed a transition where interventional radiologists (IRs) are now preferentially performing the procedure. Our survey-based cross-sectional study aimed to investigate the current trends of KB operators in the Asia-Pacific region (APR) in practicing interventional nephrologists. MATERIAL AND METHODS: The Association of Vascular Access and intervenTionAl Renal Physicians (AVATAR) Foundation from India conducted a multinational online survey among interventional nephrologists from the APR to investigate who does KB, if the nephrology training curriculum includes KB, and whether nephrologists have access to ultrasound. RESULTS: Out of 21 countries from the APR that participated in our survey, 10 countries (47.4%) reported that more than 70% of their nephrologists performed KB, whereas in 11 countries (57.6%), KB was most likely done by an IR. The frequency of nephrologists performing KB ranged from 0% in Afghanistan to 100% in countries such as Pakistan, Singapore, and Thailand. Formal training for KB and access to ultrasound was available to nephrologists in 80% of the responding countries. CONCLUSION: Our study shows that despite the availability of training and access to USG, a significant number of nephrologists are not performing KB in the APR. Similar to the trends observed in Western countries, the observed pattern in the APR could be due to lack of time, less incentive, hospital policy, or interest of nephrologists in other aspects of intervention nephrology.

Dexamethasone doses in patients with COVID-19 and hypoxia: A systematic review and meta-analysis.

BACKGROUND: The optimal dose of dexamethasone for severe/critical COVID-19 is uncertain. We compared higher versus standard doses of dexamethasone in adults with COVID-19 and hypoxia. METHODS: We searched PubMed and trial registers until 23 June 2023 for randomised clinical trials comparing higher (>6 mg) versus standard doses (6 mg) of dexamethasone in adults with COVID-19 and hypoxia. The primary outcome was mortality at 1 month. Secondary outcomes were mortality closest to 90 days; days alive without life support; and the occurrence of serious adverse events/reactions (SAEs/SARs) closest to 1 month. We assessed the risk of bias using the Cochrane RoB2 tool, risk of random errors using trial sequential analysis, and certainty of evidence using Grading of Recommendations Assessment, Development and Evaluation (GRADE). RESULTS: We included eight trials (2478 participants), of which four (1293 participants) had low risk of bias. Higher doses of dexamethasone probably resulted in little to no difference in mortality at 1 month (relative risk [RR] 0.97, 95% CI: 0.79-1.19), mortality closest to Day 90 (RR 1.01, 95% CI: 0.86-1.20), and SAEs/SARs (RR 1.00, 95% CI: 0.97-1.02). Higher doses of dexamethasone probably increased the number of days alive without invasive mechanical ventilation and circulatory support but had no effect on days alive without renal replacement therapy. CONCLUSIONS: Based on low to moderate certainty evidence, higher versus standard doses of dexamethasone probably result in little to no difference in mortality, SAEs/SARs, and days alive without renal replacement therapy, but probably increase the number of days alive without invasive mechanical ventilation and circulatory support.

Global variations in funding and use of hemodialysis accesses: an international report using the ISN Global Kidney Health Atlas.

BACKGROUND: There is a lack of contemporary data describing global variations in vascular access for hemodialysis (HD). We used the third iteration of the International Society of Nephrology Global Kidney Health Atlas (ISN-GKHA) to highlight differences in funding and availability of hemodialysis accesses used for initiating HD across world regions. METHODS: Survey questions were directed at understanding the funding modules for obtaining vascular access and types of accesses used to initiate dialysis. An electronic survey was sent to national and regional key stakeholders affiliated with the ISN between June and September 2022. Countries that participated in the survey were categorized based on World Bank Income Classification (low-, lower-middle, upper-middle, and high-income) and by their regional affiliation with the ISN. RESULTS: Data on types of vascular access were available from 160 countries. Respondents from 35 countries (22% of surveyed countries) reported that > 50% of patients started HD with an arteriovenous fistula or graft (AVF or AVG). These rates were higher in Western Europe (n = 14; 64%), North & East Asia (n = 4; 67%), and among high-income countries (n = 24; 38%). The rates of > 50% of patients starting HD with a tunneled dialysis catheter were highest in North America & Caribbean region (n = 7; 58%) and lowest in South Asia and Newly Independent States and Russia (n = 0 in both regions). Respondents from 50% (n = 9) of low-income countries reported that > 75% of patients started HD using a temporary catheter, with the highest rates in Africa (n = 30; 75%) and Latin America (n = 14; 67%). Funding for the creation of vascular access was often through public funding and free at the point of delivery in high-income countries (n = 42; 67% for AVF/AVG, n = 44; 70% for central venous catheters). In low-income countries, private and out of pocket funding was reported as being more common (n = 8; 40% for AVF/AVG, n = 5; 25% for central venous catheters). CONCLUSIONS: High income countries exhibit variation in the use of AVF/AVG and tunneled catheters. In low-income countries, there is a higher use of temporary dialysis catheters and private funding models for access creation.

Prevalence and associated factors of impaired kidney functions among children and adolescents in India: insights from the Comprehensive National Nutrition Survey (CNNS) 2016-18.

BACKGROUND: Chronic kidney disease (CKD) is a significant public health problem. The burden of CKD in children and adolescents in India is not well described. We used data from the recent Comprehensive National Nutrition Survey (CNNS) to estimate the prevalence of impaired kidney function (IKF) and its determinants in children and adolescents between the ages of 5 and 19. METHODS: CNNS 2016-18 adopted a multi-stage sampling design using probability proportional to size sampling procedure after geographical stratification of urban and rural areas. Serum creatinine was tested once in 24,690 children and adolescents aged 5-19 years. The estimated glomerular filtration rate (eGFR) was derived using the revised Schwartz equation. The eGFR value below 60 ml/min/1.73 m2 is defined as IKF. Bivariate analysis was done to depict the weighted prevalence, and multivariable logistic regression examined the predictors of IKF. RESULTS: The mean eGFR in the study population was 113.3 + 41.4 mL/min/1.73 m2. The overall prevalence of IKF was 4.9%. The prevalence in the 5-9, 10-14, and 15-19 year age groups was 5.6%, 3.4% and 5.2%, respectively. Regression analysis showed age, rural residence, non-reserved social caste, less educated mothers, Islam religion, children with severe stunting or being overweight/obese, and residence in Southern India to be predictors of IKF. CONCLUSIONS: The prevalence of IKF among children and adolescents in India is high compared to available global estimates. In the absence of repeated eGFR-based estimates, these nationally representative estimates are intriguing and call for further assessment of socio-demographic disparities, genetics, and risk behaviours to have better clinical insights and public health preparedness.

Multi-model exploration of groundwater quality and potential health risk assessment in Jajpur district, Eastern India.

The presence of fluoride and nitrate is a serious groundwater quality issue in India impacting human health. In the present study, 14 different hydrochemical parameters for 76 groundwater samples collected from the Jajpur district of Odisha, India, were evaluated. Entropy-weighted water quality index (EWQI), fixed-weight groundwater quality index (GWQI), principal component analysis (PCA), and rotated factor loading-based water quality index (PCWQI) were employed to assess groundwater quality. About 65.79 ± 4.68%, 33.55 ± 3.95%, and 0.66 ± 0.76% of the samples were rated as "excellent," "good," or "medium" quality, respectively, across the four different water quality indices, with a nominal rating discrepancy of 13.15%. Though 86% of samples consistently received excellent or good ratings across all WQI frameworks, concentrations of F- and NO3- in 36.8% and 11.84% of the samples exceeded the WHO permissible limit. In health risk assessment, about 38.15% of samples surpassed the F- hazard quotient (HQ > 1) posing non-carcinogenic health risks for children. The non-carcinogenic health risks due to NO3- were evident in 55.26% and 11.84% of samples for children and adults, respectively. The higher concentration of NO3- in some of the water samples, together with its positive correlation with HCO3-, may worsen groundwater pollution. The moderate correlation between Ca2+ and HCO3- (r = 0.410) and the insignificant correlation between Mg2+ and HCO3- (r = 0.234) suggests calcite dissolution is far more common than dolomite.

Our shared responsibility: the urgent necessity of global environmentally sustainable kidney care.

In response to Earth's accelerating climate crisis, we, an international group of nephrologists, call on our global community to unite and align kidney care in accordance with United Nation's 26th Conference of the Parties health sector principles. We announce a global and inclusive initiative, "GREEN-K": Global Environmental Evolution in Nephrology and Kidney Care, with a vision of "sustainable kidney care for a healthy planet and healthy kidneys" and mission to "promote and support environmentally sustainable and resilient kidney care globally through advocacy, education, and collaboration." A patient-centric approach that permits climate change mitigation and adaptation is proposed. Multi-stakeholder GREEN-K action and focus areas will include education, sustainable clinical care, and advances toward environmentally sustainable innovations, procurement, and infrastructure. Mindful of the disproportionately high climate impact of kidney therapies, we welcome the opportunity to work together in shared accountability to patients and Earth's natural systems.

The ASCEND-NHQ randomized trial found positive effects of daprodustat on hemoglobin and quality of life in patients with non-dialysis chronic kidney disease.

The ASCEND-NHQ trial evaluated the effects of daprodustat on hemoglobin and the Medical Outcomes Study 36-item Short Form Survey (SF-36) Vitality score (fatigue) in a multicenter, randomized, double-blind, placebo-controlled trial. Adults with chronic kidney disease (CKD) stages 3-5, hemoglobin 8.5-10.0 g/dl, transferrin saturation 15% or more, and ferritin 50 ng/ml or more without recent erythropoiesis-stimulating agent use were randomized (1:1) to oral daprodustat or placebo to achieve and maintain target hemoglobin of 11-12 g/dl over 28 weeks. The primary endpoint was the mean change in hemoglobin between baseline and the evaluation period (Weeks 24-28). Principal secondary endpoints were proportion of participants with a 1 g/dl or more increase in hemoglobin and mean change in the Vitality score between baseline and Week 28. Outcome superiority was tested (1-sided alpha level of 0.025). Overall, 614 participants with non-dialysis-dependent CKD were randomized. The adjusted mean change in hemoglobin from baseline to the evaluation period was greater with daprodustat (1.58 vs 0.19 g/dl). The adjusted mean treatment difference (AMD) was significant at 1.40 g/dl (95% confidence interval 1.23, 1.56). A significantly greater proportion of participants receiving daprodustat showed a 1 g/dl or greater increase in hemoglobin from baseline (77% vs 18%). The mean SF-36 Vitality score increased by 7.3 and 1.9 points with daprodustat and placebo, respectively; a clinically and statistically significant 5.4 point Week 28 AMD increase. Adverse event rates were similar (69% vs 71%); relative risk 0.98, (95% confidence interval 0.88, 1.09). Thus, in participants with CKD stages 3-5, daprodustat resulted in a significant increase in hemoglobin and improvement in fatigue without an increase in the overall frequency of adverse events.

Defining myocardial infarction in trials of people receiving hemodialysis: consensus report from the SONG-HD MI Expert Working group.

Cardiovascular disease is the leading cause of death in patients receiving hemodialysis. Currently, there is no standardized definition of myocardial infarction (MI) for patients receiving hemodialysis. Through an international consensus process MI was established as the core CVD measure for this population in clinical trials. The Standardised Outcomes in Nephrology Group-Hemodialysis (SONG-HD) initiative convened a multidisciplinary, international working group to address the definition of MI in this population. On the basis of current evidence, the working group recommends using the Fourth Universal Definition of Myocardial Infarction with specific caveats with regard to the interpretation of "ischemic symptoms" and performing a baseline 12-lead electrocardiogram to facilitate interpretation of acute changes on subsequent tracings. The working group does not recommend obtaining baseline cardiac troponin values, though does recommend obtaining serial cardiac biomarkers in settings where ischemia is suspected. The application of an evidence-based uniform definition should increase the reliability and accuracy of trial results.

Community acquired and hospital acquired AKI - two diseases divided by a common definition.

PURPOSE OF REVIEW: Acute kidney injury (AKI) is common across the world. AKI that is acquired in the community (community acquired AKI, CA-AKI) has different risk factors, epidemiological profile, presentation and impact as compared to hospital acquired AKI (HA-AKI). Hence, similar approaches to tackle CA-AKI and HA-AKI might not work. This review highlights the important differences between the two entities that have a bearing on the overall approach to the conditions and how CA-AKI has been overshadowed by HA-AKI in research, diagnosis and treatment recommendations and clinical practice guidelines. RECENT FINDINGS: The overall burden of AKI is disproportionately more in low and low-middle income countries. The Global Snapshot study of International Society of Nephrology's (ISN) AKI 0by25 program has shown that CA-AKI is the dominant form in these settings. Its profile and outcomes vary with geographical and socio-economic characteristics of the regions where it develops. The current clinical practice guidelines for AKI align more with HA-AKI than CA-AKI, and fail to capture the complete spectrum of CA-AKI as well as its impact. The ISN AKI 0by25 studies have uncovered the circumstantial compulsions in defining and assessing AKI in these settings and shown feasibility of community-based interventions. SUMMARY: Efforts are needed to better understand CA-AKI in low-resource settings and develop context specific guidance and interventions. A multidisciplinary, collaborative approach with representation from community would be required.

Regional Variation of Erythropoiesis-Stimulating Agent Hyporesponsiveness in the Global Daprodustat Dialysis Study (ASCEND-D).

INTRODUCTION: Hyporesponsiveness to erythropoiesis-stimulating agents (ESAs) affects 10-15% of the chronic dialysis population. We explored baseline characteristics and predictors of ESA hyporesponsiveness in a global randomized cardiovascular outcomes study comparing an investigational hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI), daprodustat, with conventional ESA treatment. METHODS: ASCEND-D (NCT02879305) recruited 2,964 chronic dialysis patients receiving ESA treatment (standardized to weekly intravenous [IV] epoetin) who were iron replete at baseline. The primary ESA hyporesponsiveness definition was an ESA Resistance Index (ERI, ESA units/kg/week/hemoglobin g/L) ≥2 or IV standardized ESA dose ≥450 units/kg/week. Predictors of ESA hyporesponsiveness were determined using a multivariable regression model. Alternative hyporesponder definitions were explored. RESULTS: Using the primary definition, 354 (12%) patients were ESA hyporesponsive. Geographic region, notably Latin America, lower baseline body mass index and transferrin saturation, younger age, lower albumin concentration, and a higher baseline IV iron dose were identified as strongly associated (p < 0.001) with ESA hyporesponsiveness. Additional predictors of ESA hyporesponsiveness included female sex (p = 0.010), history of heart failure (p = 0.035), longer dialysis vintage (p = 0.077), smoking status (p = 0.247), aspirin use (p = 0.121), and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use (p = 0.214). CONCLUSION: This is the first global HIF-PHI study to report prespecified definitions and predictors of ESA hyporesponsiveness. While most of the predictors identified in our study have been previously reported, geographic region stands out as an unexpected finding, meriting further investigation.

Heterogeneous treatment effects of dexamethasone 12 mg versus 6 mg in patients with COVID-19 and severe hypoxaemia-Post hoc exploratory analyses of the COVID STEROID 2 trial.

BACKGROUND: Corticosteroids improve outcomes in patients with severe COVID-19. In the COVID STEROID 2 randomised clinical trial, we found high probabilities of benefit with dexamethasone 12 versus 6 mg daily. While no statistically significant heterogeneity in treatment effects (HTE) was found in the conventional, dichotomous subgroup analyses, these analyses have limitations, and HTE could still exist. METHODS: We assessed whether HTE was present for days alive without life support and mortality at Day 90 in the trial according to baseline age, weight, number of comorbidities, category of respiratory failure (type of respiratory support system and oxygen requirements) and predicted risk of mortality using an internal prediction model. We used flexible models for continuous variables and logistic regressions for categorical variables without dichotomisation of the baseline variables of interest. HTE was assessed both visually and with p and S values from likelihood ratio tests. RESULTS: There was no strong evidence for substantial HTE on either outcome according to any of the baseline variables assessed with all p values >.37 (and all S values <1.43) in the planned analyses and no convincingly strong visual indications of HTE. CONCLUSIONS: We found no strong evidence for HTE with 12 versus 6 mg dexamethasone daily on days alive without life support or mortality at Day 90 in patients with COVID-19 and severe hypoxaemia, although these results cannot rule out HTE either.

Practice of dialysis access interventional nephrology procedures in the Asia-Pacific region: Getting lay of the land.

AIM: This cross-sectional survey aimed to determine the prevalence of Interventional Nephrology (IN) practice amongst nephrologists in the Asia-Pacific Region (APR), specifically related to dialysis access (DA). METHODS: The Association of VA and intervenTionAl Renal physicians (AVATAR) Foundation from India conducted a multinational online survey amongst nephrologists from the Asia-Pacific to determine the practice of IN in the planning, creation, and management of dialysis access. The treatment modalities, manpower and equipment availability, monthly cost of treatment, specifics of dialysis access interventions, and challenges in the training and practice of IN by nephrologists were included in the survey. RESULTS: Twenty-one countries from the APR participated in the survey. Nephrologists from 18 (85.7%) countries reported performing at least one of the basic dialysis access-related IN procedures, primarily the placement of non-tunnelled central catheters (n-TCC; 71.5%). Only 10 countries (47.6%) reported having an average of <4% of nephrologists performing any of the advanced IN access procedures, the most common being the placement of a peritoneal dialysis (PD) catheter (20%). Lack of formal training (57.14%), time (42.8%), incentive (38%), institutional support (38%), medico-legal protection (28.6%), and prohibitive cost (23.8%) were the main challenges to practice IN. The primary obstacles to implementing the IN training were a lack of funding and skilled personnel. CONCLUSION: The practice of dialysis access-related IN in APR is inadequate, mostly due to a lack of training, backup support, and economic constraints, whereas training in access-related IN is constrained by a lack of a skilled workforce and finances.

Estimated Glomerular Filtration Rate, Albuminuria, and Adverse Outcomes: An Individual-Participant Data Meta-Analysis.

Importance: Chronic kidney disease (low estimated glomerular filtration rate [eGFR] or albuminuria) affects approximately 14% of adults in the US. Objective: To evaluate associations of lower eGFR based on creatinine alone, lower eGFR based on creatinine combined with cystatin C, and more severe albuminuria with adverse kidney outcomes, cardiovascular outcomes, and other health outcomes. Design, Setting, and Participants: Individual-participant data meta-analysis of 27 503 140 individuals from 114 global cohorts (eGFR based on creatinine alone) and 720 736 individuals from 20 cohorts (eGFR based on creatinine and cystatin C) and 9 067 753 individuals from 114 cohorts (albuminuria) from 1980 to 2021. Exposures: The Chronic Kidney Disease Epidemiology Collaboration 2021 equations for eGFR based on creatinine alone and eGFR based on creatinine and cystatin C; and albuminuria estimated as urine albumin to creatinine ratio (UACR). Main Outcomes and Measures: The risk of kidney failure requiring replacement therapy, all-cause mortality, cardiovascular mortality, acute kidney injury, any hospitalization, coronary heart disease, stroke, heart failure, atrial fibrillation, and peripheral artery disease. The analyses were performed within each cohort and summarized with random-effects meta-analyses. Results: Within the population using eGFR based on creatinine alone (mean age, 54 years [SD, 17 years]; 51% were women; mean follow-up time, 4.8 years [SD, 3.3 years]), the mean eGFR was 90 mL/min/1.73 m2 (SD, 22 mL/min/1.73 m2) and the median UACR was 11 mg/g (IQR, 8-16 mg/g). Within the population using eGFR based on creatinine and cystatin C (mean age, 59 years [SD, 12 years]; 53% were women; mean follow-up time, 10.8 years [SD, 4.1 years]), the mean eGFR was 88 mL/min/1.73 m2 (SD, 22 mL/min/1.73 m2) and the median UACR was 9 mg/g (IQR, 6-18 mg/g). Lower eGFR (whether based on creatinine alone or based on creatinine and cystatin C) and higher UACR were each significantly associated with higher risk for each of the 10 adverse outcomes, including those in the mildest categories of chronic kidney disease. For example, among people with a UACR less than 10 mg/g, an eGFR of 45 to 59 mL/min/1.73 m2 based on creatinine alone was associated with significantly higher hospitalization rates compared with an eGFR of 90 to 104 mL/min/1.73 m2 (adjusted hazard ratio, 1.3 [95% CI, 1.2-1.3]; 161 vs 79 events per 1000 person-years; excess absolute risk, 22 events per 1000 person-years [95% CI, 19-25 events per 1000 person-years]). Conclusions and Relevance: In this retrospective analysis of 114 cohorts, lower eGFR based on creatinine alone, lower eGFR based on creatinine and cystatin C, and more severe UACR were each associated with increased rates of 10 adverse outcomes, including adverse kidney outcomes, cardiovascular diseases, and hospitalizations.