A Randomized Trial of Intravenous Iron Supplementation and Exercise on Exercise Capacity in Iron-Deficient Nonanemic Patients With CKD.

Introduction: Patients with chronic kidney disease (CKD) are often iron deficient, even when not anemic. This trial evaluated whether iron supplementation enhances exercise capacity of nonanemic patients with CKD who have iron-deficiency. Methods: Prospective, multicenter double-blind randomized controlled trial of nondialysis patients with CKD and iron-deficiency but without anemia (Hemoglobin [Hb] >110 g/l). Patients were assigned 1:1 to intravenous (IV) iron therapy, or placebo. An 8-week exercise program commenced at week 4. The primary outcome was the mean between-group difference in 6-minute walk test (6MWT) at 4 weeks. Secondary outcomes included 6MWT at 12 weeks, transferrin saturation (TSAT), serum ferritin (SF), Hb, renal function, muscle strength, functional capacity, quality of life, and adverse events at baseline, 4 weeks, and at 12 weeks. Mean between-group differences were analyzed using analysis of covariance models. Results: Among 75 randomized patients, mean (SD) age for iron therapy (n = 37) versus placebo (n = 38) was 54 (16) versus 61 (12) years; estimated glomerular filtration rate (eGFR) (34 [12] vs. 35 [11] ml/min per 1.73 m2], TSAT (23 [12] vs. 21 [6])%; SF (57 [64] vs. 62 [33]) µg/l; Hb (122.4 [9.2] vs. 127 [13.2] g/l); 6MWT (384 [95] vs. 469 [142] meters) at baseline, respectively. No significant mean between-group difference was observed in 6MWT distance at 4 weeks. There were significant increases in SF and TSAT at 4 and 12 weeks (P < 0.02), and Hb at 12 weeks (P = 0.009). There were no between-group differences in other secondary outcomes and no adverse events attributable to iron therapy. Conclusion: This trial did not demonstrate beneficial effects of IV iron therapy on exercise capacity at 4 weeks. A larger study is needed to confirm if IV iron is beneficial in nondialysis patients with CKD who are iron-deficient.

Assessment and management of chronic kidney disease in people living with obesity.

Obesity and chronic kidney disease (CKD) are common and frequently coexisting medical conditions. Already well known to be a risk factor for type 2 diabetes mellitus (T2DM), ischaemic heart disease, stroke, hypertension, malignancy and premature death, obesity also predisposes to CKD. Elevated weight leads to declining renal function through several mechanisms, including established pathways via metabolic syndrome, hypertension and T2DM, but also through relatively recently understood glomerulosclerosis, directly related to obesity. Compared with non-obese comparators, people living with obesity and established CKD develop faster decline in glomerular filtration, progression to end-stage renal disease (ESRD) and death. Importantly, treatment of obesity can influence these crucial renal outcomes and significantly improve quality of life. Declining renal function also impacts the medical and surgical treatment options available to treat patients with overweight and obesity. In this article, we briefly outline the epidemiology of obesity and renal disease and review the pathological interactions between these diseases before focusing on considerations for assessment and evidence-based treatments for obesity and renal disease.

Gut Dysbiosis in Experimental Kidney Disease: A Meta-Analysis of Rodent Repository Data.

SIGNIFICANCE STATEMENT: Alterations in gut microbiota contribute to the pathophysiology of a diverse range of diseases, leading to suggestions that chronic uremia may cause intestinal dysbiosis that contributes to the pathophysiology of CKD. Various small, single-cohort rodent studies have supported this hypothesis. In this meta-analysis of publicly available repository data from studies of models of kidney disease in rodents, cohort variation far outweighed any effect of experimental kidney disease on the gut microbiota. No reproducible changes in animals with kidney disease were seen across all cohorts, although a few trends observed in most experiments may be attributable to kidney disease. The findings suggest that rodent studies do not provide evidence for the existence of "uremic dysbiosis" and that single-cohort studies are unsuitable for producing generalizable results in microbiome research. BACKGROUND: Rodent studies have popularized the notion that uremia may induce pathological changes in the gut microbiota that contribute to kidney disease progression. Although single-cohort rodent studies have yielded insights into host-microbiota relationships in various disease processes, their relevance is limited by cohort and other effects. We previously reported finding metabolomic evidence that batch-to-batch variations in the microbiome of experimental animals are significant confounders in an experimental study. METHODS: To attempt to identify common microbial signatures that transcend batch variability and that may be attributed to the effect of kidney disease, we downloaded all data describing the molecular characterization of the gut microbiota in rodents with and without experimental kidney disease from two online repositories comprising 127 rodents across ten experimental cohorts. We reanalyzed these data using the DADA2 and Phyloseq packages in R, a statistical computing and graphics system, and analyzed data both in a combined dataset of all samples and at the level of individual experimental cohorts. RESULTS: Cohort effects accounted for 69% of total sample variance ( P <0.001), substantially outweighing the effect of kidney disease (1.9% of variance, P =0.026). We found no universal trends in microbial population dynamics in animals with kidney disease, but observed some differences (increased alpha diversity, a measure of within-sample bacterial diversity; relative decreases in Lachnospiraceae and Lactobacillus ; and increases in some Clostridia and opportunistic taxa) in many cohorts that might represent effects of kidney disease on the gut microbiota . CONCLUSIONS: These findings suggest that current evidence that kidney disease causes reproducible patterns of dysbiosis is inadequate. We advocate meta-analysis of repository data as a way of identifying broad themes that transcend experimental variation.

The management of dialysis access thrombosis during the COVID-19 pandemic.

BACKGROUND: Maintaining patent access is essential for haemodialysis dependent end stage renal failure patients. The COVID-19 pandemic has significantly affected surgical and interventional radiology services worldwide. We aimed to review the impact COVID-19 has caused to the management of acute dialysis access thrombosis. METHODS: We conducted a single centre retrospective review of outcomes of patients with arteriovenous fistula and arteriovenous graft thrombosis between March and May 2020, which coincided with the first peak of the COVID-19 pandemic in London, and a similar period in the previous year, March-May 2019. Outcomes in both cohorts of patients were compared, including attempts at salvage, salvage success, 1-month patency rates after salvage and subsequent surgery on the same access. We also analysed the use of tunnelled haemodialysis lines (THL), either due to failed salvage attempts or when salvage was not attempted. RESULTS: There was a similar incidence of access thrombosis in both periods (26 cases in 2019, 38 in 2020). There were 601 patients dialysing via an arteriovenous fistula or graft in 2019, and 568 patients in 2020. Access salvage, when attempted, had similar success rates and 1-month patency (salvage success 74% vs 80%, p = 0.39; 1-month patency 55% vs 62%, p = 0.69). The proportion of patients where access salvage was not attempted and a THL inserted was significantly higher in 2020 compared to 2019 (32% vs 4%, p = 0.007). There were more patients who subsequently had surgery to salvage or revise the same access in 2019 compared to 2020 (62% vs 13%, p < 0.001). CONCLUSIONS: During the peak of the COVID-19 pandemic, there were fewer attempts at access salvage. This was a conscious decision due to increased pressure on the healthcare system, access to emergency interventional radiology or operative theatres and the perceived risk/benefit ratio of access salvage. The long-term effects of this change in practice remain unknown.

The effect of intravenous iron supplementation on exercise capacity in iron-deficient but not anaemic patients with chronic kidney disease: study design and baseline data for a multicentre prospective double-blind randomised controlled trial.

BACKGROUND: Many people living with chronic kidney disease (CKD) are iron deficient, even though they may not be anaemic. The Iron and Muscle study aims to evaluate whether iron supplementation reduces symptoms of fatigue, improves muscle metabolism, and leads to enhanced exercise capacity and physical function. We report here the trial design and baseline characteristics. METHODS: This is a prospective, double-blind multicentre randomised controlled trial (RCT) including 75 non-dialysis stage 3-4 CKD patients with iron deficiency but without anaemia. Patients were randomly (1:1) assigned to either: i) intravenous iron therapy, or ii) placebo, with concurrent recruitment of eight CKD non-iron deficient participants and six healthy volunteers. The primary outcome of the study is the six-minute walk test (6MWT) distance between baseline and four-weeks. An additional exercise training programme for patients in both groups was initiated and completed between 4 and 12 weeks, to determine the effect of iron repletion compared to placebo treatment in the context of patients undertaking an exercise programme. Additional secondary outcomes include fatigue, physical function, muscle strength, muscle metabolism, quality of life, resting blood pressure, clinical chemistry, safety and harms associated with the iron therapy intervention and the exercise training intervention, and hospitalisations. All outcomes were conducted at baseline, 4, and 12 weeks, with a nested qualitative study, to investigate the experience of living with iron deficiency and intervention acceptability. The cohort have been recruited and baseline assessments undertaken. RESULTS: Seventy-five individuals were recruited. 44% of the randomised cohort were male, the mean (SD) age was 58 (14) years, and 56% were White. Body mass index was 31 (7) kg/m2; serum ferritin was 59 (45) µg/L, transferrin saturation was 22 (10) %, and haemoglobin was 125 (12) g/L at randomisation for the whole group. Estimated glomerular filtration rate was 35 (12) mL/min/1.73 m2 and the baseline 6MWT distance was 429 (174) m. CONCLUSION: The results from this study will address a substantial knowledge gap in the effects of intravenous iron therapy, and offer potential clinical treatment options, to improve exercise capacity, physical function, fatigue, and muscle metabolism, for non-dialysis patients with CKD who are iron-deficient but not anaemic. It will also offer insight into the potential novel effects of an 8-week exercise training programme. TRIAL REGISTRATION: EudraCT: 2018-000,144-25 Registered 28/01/2019.

Uninephrectomy and class II PI3K-C2ß inactivation synergistically protect against obesity, insulin resistance and liver steatosis in mice.

Uninephrectomy (UNx) in living kidney donors for transplantation is now routine clinical practice. While chronic kidney disease, due to bilateral kidney dysfunction, is associated with insulin resistance, liver steatosis, and type 2 diabetes, the metabolic impact of UNx remains unclear. To better understand the crosstalk between the kidney and insulin target tissues, we studied the metabolic consequences of UNx and the potential involvement of class II PI3K-C2ß, the inactivation of which has been reported to result in insulin sensitization. Mice underwent UNx or sham operation followed by either normal chow or high-fat diet (HFD). Seventeen weeks post-UNx, mice showed improved glucose tolerance, insulin sensitivity, and decreased HFD-induced liver steatosis. This was associated with an enhanced serum FGF21 and insulin-stimulated Akt signaling in the liver and muscle of both lean and obese mice. Remarkably, the combination of UNx and PI3K-C2ß inactivation protected against HFD-induced obesity and further potentiated the metabolic improvement observed in WT UNx mice correlating with a synergistic increase in metabolic tissues of (1) insulin-stimulated Akt signaling (2) FGFR1 and ßKlotho expression. We demonstrated a potential beneficial effect of kidney donation and more effectively with PI3K-C2ß inactivation to protect against metabolic disorders through a mutual insulin/FGF21 sensitization.

NIMO-CKD-UK: a real-world, observational study of iron isomaltoside in patients with iron deficiency anaemia and chronic kidney disease.

BACKGROUND: Intravenous iron is often used to treat iron deficiency anaemia in non-dialysis chronic kidney disease (ND-CKD), but the optimal dosing regimen remains unclear. We evaluated the impact of high- versus low-dose intravenous iron isomaltoside on the probability of retreatment with intravenous iron in iron-deficient ND-CKD patients. METHODS: This real-world, prospective, observational study collected data from 256 ND-CKD patients treated for anaemia in the UK. Following an initial course of iron isomaltoside, patients were followed for ≥12 months. Iron dose and the need for retreatment were determined at the investigators' discretion. The primary study outcome was the need for retreatment at 52 weeks compared between patients who received >1000 mg of iron during Course 1 and those who received ≤1000 mg. Safety was evaluated through adverse drug reactions. RESULTS: The probability of retreatment at Week 52 was significantly lower in the >1000 mg iron group (n = 58) versus the ≤1000 mg group (n = 198); hazard ratio (95% confidence interval [CI]): 0.46 (0.20, 0.91); p = 0.012. Mean (95% CI) haemoglobin increased by 6.58 (4.94, 8.21) g/L in the ≤1000 mg group and by 10.59 (7.52, 13.66) g/L in the >1000 mg group (p = 0.024). Changes in other blood and iron parameters were not significantly different between the two groups. Administering >1000 mg of iron isomaltoside saved 8.6 appointments per 100 patients compared to ≤1000 mg. No serious adverse drug reactions were reported. Of the patients who received ≤1000 mg of iron in this study, 82.3% were eligible for a dose >1000 mg. CONCLUSIONS: The >1000 mg iron isomaltoside regimen reduced the probability of retreatment, achieved a greater haemoglobin response irrespective of erythropoiesis-stimulating agent treatment, and reduced the total number of appointments required, compared to the ≤1000 mg regimen. Many of the patients who received ≤1000 mg of iron were eligible for >1000 mg, indicating that there was considerable underdosing in this study. TRIAL REGISTRATION: ClinicalTrials.gov NCT02546154 , 10 September 2015.

HEROIC: a 5-year observational cohort study aimed at identifying novel factors that drive diabetic kidney disease: rationale and study protocol.

INTRODUCTION: Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease worldwide and a major cause of premature mortality in diabetes mellitus (DM). While improvements in care have reduced the incidence of kidney disease among those with DM, the increasing prevalence of DM means that the number of patients worldwide with DKD is increasing. Improved understanding of the biology of DKD and identification of novel therapeutic targets may lead to new treatments. A major challenge to progress has been the heterogeneity of the DKD phenotype and renal progression. To investigate the heterogeneity of DKD we have set up The East and North London Diabetes Cohort (HEROIC) Study, a secondary care-based, multiethnic observational study of patients with biopsy-proven DKD. Our primary objective is to identify histological features of DKD associated with kidney endpoints in a cohort of patients diagnosed with type 1 and type 2 DM, proteinuria and kidney impairment. METHODS AND ANALYSIS: HEROIC is a longitudinal observational study that aims to recruit 500 patients with DKD at high-risk of renal and cardiovascular events. Demographic, clinical and laboratory data will be collected and assessed annually for 5 years. Renal biopsy tissue will be collected and archived at recruitment. Blood and urine samples will be collected at baseline and during annual follow-up visits. Measured glomerular filtration rate (GFR), echocardiography, retinal optical coherence tomography angiography and kidney and cardiac MRI will be performed at baseline and twice more during follow-up. The study is 90% powered to detect an association between key histological and imaging parameters and a composite of death, renal replacement therapy or a 30% decline in estimated GFR. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the Bloomsbury Research Ethics Committee (REC 18-LO-1921). Any patient identifiable data will be stored on a password-protected National Health Services N3 network with full audit trail. Anonymised imaging data will be stored in a ISO27001-certificated data warehouse.Results will be reported through peer-reviewed manuscripts and conferences and disseminated to participants, patients and the public using web-based and social media engagement tools as well as through public events.

Ischemic conditioning in solid organ transplantation: is it worth giving your right arm for?

PURPOSE OF REVIEW: Ischemia reperfusion injury (IRI) is an inevitable complication in solid organ transplantation. Limiting this injury can increase patient and graft survival and can decrease complications associated with transplantation. We provide an extensive literature review analyzing the available evidence for ischemic conditioning in solid organ transplantation, including kidney, liver, heart, and lung. RECENT FINDINGS: Ischemic conditioning strategies are a group of interventions, characterized by episodes of ischemia and reperfusion to an organ which confirm tissue protection. Arguably, transplantation is the ideal setting to use this novel strategy due to the predictable timing and duration of the ischemic insult. Liver transplantation has provided us with the most number of clinical trials, followed by kidney transplantation. Most of these trials have been negative but the methodology has been variable, making comparison difficult. SUMMARY: Despite the promising results seen in animal models, translating these results in clinical trials has proved to be difficult. The promising effects of ischemic conditioning are present in some trials with weaker positive signals existing in other trials. We believe that tailoring trials to allow better comparison will provide positive results in the future.

The challenge of translating ischemic conditioning from animal models to humans: the role of comorbidities.

Following a period of ischemia (local restriction of blood supply to a tissue), the restoration of blood supply to the affected area causes significant tissue damage. This is known as ischemia-reperfusion injury (IRI) and is a central pathological mechanism contributing to many common disease states. The medical complications caused by IRI in individuals with cerebrovascular or heart disease are a leading cause of death in developed countries. IRI is also of crucial importance in fields as diverse as solid organ transplantation, acute kidney injury and following major surgery, where post-operative organ dysfunction is a major cause of morbidity and mortality. Given its clinical impact, novel interventions are urgently needed to minimize the effects of IRI, not least to save lives but also to reduce healthcare costs. In this Review, we examine the experimental technique of ischemic conditioning, which entails exposing organs or tissues to brief sub-lethal episodes of ischemia and reperfusion, before, during or after a lethal ischemic insult. This approach has been found to confer profound tissue protection against IRI. We discuss the translation of ischemic conditioning strategies from bench to bedside, and highlight where transition into human clinical studies has been less successful than in animal models, reviewing potential reasons for this. We explore the challenges that preclude more extensive clinical translation of these strategies and emphasize the role that underlying comorbidities have in altering the efficacy of these strategies in improving patient outcomes.

Ischaemic conditioning strategies for the nephrologist: a promise lost in translation?

Over the last quarter of a century, a huge effort has been made to develop interventions that can minimise ischaemia reperfusion injury. The most potent of these are the ischaemic conditioning strategies, which comprise ischaemic preconditioning, remote ischaemic preconditioning and ischaemic postconditioning. While much of the focus for these interventions has been on protecting the myocardium, other organs including the kidney can be similarly protected. However, translation of these beneficial effects from animal models into routine clinical practice has been less straightforward than expected. In this review, we examine the role of ischaemic conditioning strategies in reducing tissue injury from the 'bench to the bedside' and discuss the barriers to their greater translation.