A prospective observational study for justification, safety, and efficacy of a third dose of mRNA vaccine in patients receiving maintenance hemodialysis.

The level of protection achieved by the standard two doses of COVID-19 mRNA vaccines in patients receiving maintenance hemodialysis (MHD) remains unclear. To study this we used the French Renal Epidemiology and Information Network (REIN) Registry to compare the incidence and severity of 1474 cases of COVID-19 diagnosed in patients receiving MHD after none, one or two doses of vaccine. Vaccination significantly reduce COVID-19 incidence and severity, but 11% of patients infected after two doses still died. Lack of vaccinal protection in patients naïve for SARS-CoV-2 could be due to defective Tfh response [38% of patients with negative spike-specific CD4+ T-cell interferon gamma release assay] and failure to generate viral neutralizing titers of anti-spike receptor binding domain (RBD) IgGs (63% of patients with titer at or under 997 BAU/ml, defining low/no responders) after two doses of vaccine. To improve protection, a third dose of vaccine was administered to 75 patients [57 low/no responders, 18 high responders after two doses] from the ROMANOV cohort that prospectively enrolled patients receiving MHD vaccinated with BNT162b2 (Pfizer). Tolerance to the third dose was excellent. High responders to two doses did not generate more anti-RBD IgGs after three doses but had more side effects. Importantly, 31 (54%) of low/no responders to two doses reached neutralizing titers of anti-RBD IgGs after three doses. A positive interferon gamma release assay and/or suboptimal titer of anti-RBD IgGs after two doses were the only predictive variables for response to three doses in multivariate analysis. Thus, the standard scheme of vaccination insufficiently protects patients receiving MHD. Anti-RBD IgG and specific CD4+ T-cell response after two doses can guide personalized administration of the third dose, which improves the humoral response of SARS-CoV-2-naïve patients receiving MHD.

The ROMANOV study found impaired humoral and cellular immune responses to SARS-CoV-2 mRNA vaccine in virus-unexposed patients receiving maintenance hemodialysis.

Patients on maintenance hemodialysis (MHD), which are at high risk of infection by SARS-CoV-2 virus and death due to COVID-19, have been prioritized for vaccination. However, because they were excluded from pivotal studies and have weakened immune responses, it is not known whether these patients are protected after the "standard" two doses of mRNA vaccines. To answer this, anti-spike receptor binding domain (RBD) IgG and interferon gamma-producing CD4+ and CD8+ specific-T cells were measured in the circulation 10-14 days after the second injection of BNT162b2 vaccine in 106 patients receiving MHD (14 with history of COVID-19) and compared to 30 healthy volunteers (four with history of COVID-19). After vaccination, most (72/80, 90%) patients receiving MHD naïve for the virus generated at least one type of immune effector, but their response was weaker and less complete than that of healthy volunteers. In multivariate analysis, hemodialysis and immunosuppressive therapy were significantly associated with absence of both anti-RBD IgGs and anti-spike CD8+ T cells. In contrast, previous history of COVID-19 in patients receiving MHD correlated with the generation of both types of immune effectors anti-RBD IgG and anti-spike CD8+ T cells at levels similar to healthy volunteers. Patients receiving MHD naïve for SARS-Cov-2 generate mitigated immune responses after two doses of mRNA vaccine. Thus, the good response to vaccine of patients receiving MHD with a history of COVID-19 suggest that these patients may benefit from a third vaccine injection.

Cystatin C-Creatinine Based Glomerular Filtration Rate Equation in Obese Chronic Kidney Disease Patients: Impact of Deindexation and Gender.

BACKGROUND: Cystatin C is considered an alternative to creatinine to estimate glomerular filtration rate (GFR). However, studies have reported that increased adiposity is associated with a higher level of circulating cystatin C questioning the performance of estimation of GFR using cystatin C in obese subjects. METHODS: We prospectively included 166 obese stages 1-5 chronic kidney disease (CKD) patients between 2013 and 2015. GFR was measured with a reference method without (measured GFR [mGFR]) and with adjustment to body surface area (mGFRr) and estimated (eGFR) or de-indexed eGFR using the Chronic Kidney Disease and Epidemiology (CKD-EPI) equation using creatinine (CKD-EPIcreat), cystatin (CKD-EPIcyst) and the combination of cystatin and creatinine (CKD-EPIcyst-creat). RESULTS: The biases between mGFR and de-indexed CKD-EPIcyst-creat were significantly lower than de-indexed CKD-EPIcreat (p = 0.001). Accuracies were significantly better with de-indexed CKD-EPIcyst-creat compared to CKD-EPIcreat and CKD-EPIcyst, respectively (p = 0.04 and 0.03). Bland and Altman plot showed a great dispersion of all formulae when patients had a GFR >60 ml/min. Interestingly, there is a gender difference; biases, precisions and accuracies of de-indexed CKD-EPIcyst-creat were significantly lower in obese women. These results may be related to a difference in the change of body composition during obesity in men versus women and in fact only waist circumference (WC) was positively and significantly correlated with cystatin C (p < 0.0001) whereas body mass index (BMI; p = 0.3) was not; bias for CKD-EPIcyst-creat was related with WC. CONCLUSION: Cystatin C-creatinine-based GFR equations outperform creatinine-based formula in obese CKD patients especially those with BMI ≥35 and in obese women.

Reconsidering 'ethics' and 'quality' in healthcare research: the case for an iterative ethical paradigm.

BACKGROUND: UK-based research conducted within a healthcare setting generally requires approval from the National Research Ethics Service. Research ethics committees are required to assess a vast range of proposals, differing in both their topic and methodology. We argue the methodological benchmarks with which research ethics committees are generally familiar and which form the basis of assessments of quality do not fit with the aims and objectives of many forms of qualitative inquiry and their more iterative goals of describing social processes/mechanisms and making visible the complexities of social practices. We review current debates in the literature related to ethical review and social research, and illustrate the importance of re-visiting the notion of ethics in healthcare research. DISCUSSION: We present an analysis of two contrasting paradigms of ethics. We argue that the first of these is characteristic of the ways that NHS ethics boards currently tend to operate, and the second is an alternative paradigm, that we have labelled the 'iterative' paradigm, which draws explicitly on methodological issues in qualitative research to produce an alternative vision of ethics. We suggest that there is an urgent need to re-think the ways that ethical issues are conceptualised in NHS ethical procedures. In particular, we argue that embedded in the current paradigm is a restricted notion of 'quality', which frames how ethics are developed and worked through. Specific, pre-defined outcome measures are generally seen as the traditional marker of quality, which means that research questions that focus on processes rather than on 'outcomes' may be regarded as problematic. We show that the alternative 'iterative' paradigm offers a useful starting point for moving beyond these limited views. SUMMARY: We conclude that a 'one size fits all' standardisation of ethical procedures and approach to ethical review acts against the production of knowledge about healthcare and dramatically restricts what can be known about the social practices and conditions of healthcare. Our central argument is that assessment of ethical implications is important, but that the current paradigm does not facilitate an adequate understanding of the very issues it aims to invigilate.

Insulin resistance in chronic kidney disease: new lessons from experimental models.

Insulin resistance (IR) is a common feature of chronic kidney disease (CKD), but the underlying mechanisms still remain unclear. A growing body of evidence suggests that IR and its associated metabolic disorders are important contributors for the cardiovascular burden of these patients. In recent years, the modification of the intestinal flora and activation of inflammation pathways have been implicated in the pathogenesis of IR in obese and diabetic patients. All these pathways ultimately lead to lipid accumulation in ectopic sites and impair insulin signalling. These important discoveries have led to major advances in understanding the mechanisms of uraemia-induced IR. Indeed, recent studies show impairment of the intestinal barrier function and changes in the composition of the gut microbiome during CKD that can contribute to the prevailing inflammation, and the production and absorption of toxins generated from bacterial metabolism. The specific role of individual uraemic toxins in the pathogenesis of IR has been highlighted in rodents. Moreover, correcting some uraemia-associated factors by modulating the intestinal flora improves insulin sensitivity. This review outlines potential mechanisms by which important modifications of body homeostasis induced by the decline in kidney function can affect insulin sensitivity, and the relevance of recent advances in the field to provide novel therapeutic approaches to reduce IR associated cardiovascular mortality.

p-Cresyl sulfate promotes insulin resistance associated with CKD.

The mechanisms underlying the insulin resistance that frequently accompanies CKD are poorly understood, but the retention of renally excreted compounds may play a role. One such compound is p-cresyl sulfate (PCS), a protein-bound uremic toxin that originates from tyrosine metabolism by intestinal microbes. Here, we sought to determine whether PCS contributes to CKD-associated insulin resistance. Administering PCS to mice with normal kidney function for 4 weeks triggered insulin resistance, loss of fat mass, and ectopic redistribution of lipid in muscle and liver, mimicking features associated with CKD. Mice treated with PCS exhibited altered insulin signaling in skeletal muscle through ERK1/2 activation. In addition, exposing C2C12 myotubes to concentrations of PCS observed in CKD caused insulin resistance through direct activation of ERK1/2. Subtotal nephrectomy led to insulin resistance and dyslipidemia in mice, and treatment with the prebiotic arabino-xylo-oligosaccharide, which reduced serum PCS by decreasing intestinal production of p-cresol, prevented these metabolic derangements. Taken together, these data suggest that PCS contributes to insulin resistance and that targeting PCS may be a therapeutic strategy in CKD.

Fibromuscular dysplasia of the renal arteries: what do we know in 2024? / Dysplasie fibromusculaire des artères rénales : que savons-nous en 2024 ?

Fibromuscular dysplasia (FMD) is a rare nonatherosclerotic, noninflammatory vascular disease affecting mostly renal and carotid arteries and is the second most frequent cause of renal artery stenosis. The symptomatology is dominated by arterial hypertension due to the frequent involvement of the renal arteries and depends on the location of the lesions. Most of the cases are middle-aged women of Caucasian origin. There are two subtypes based on angiographic aspect: multifocal FMD (80% of the cases) and focal FMD (rarer with a more balanced sex ratio). Angioplasty of the renal arteries is generally disappointing with less than 50% cure of hypertension. It appears necessary to improve our knowledge of the FMD and to optimize the selection of eligible patients for revascularization with transdisciplinary collegial therapeutic decision.

La dysplasie fibromusculaire (DFM) est une maladie rare caractérisée par des sténoses segmentaires non artérioscléreuses, non inflammatoires, des artères de moyens calibres, touchant surtout les artères rénales et les carotides. Elle constitue la seconde cause de sténoses des artères rénales. La symptomatologie dépend de la localisation des lésions et est dominée par l'hypertension artérielle (HTA) en raison de l'atteinte fréquente des artères rénales. Cette pathologie touche majoritairement les femmes caucasiennes d'âge moyen. Il en existe deux sous-types, basés sur l'aspect angiographique : la DFM multifocale (80 % des cas) et la DFM focale (plus rare, sex ratio plus équilibré). Les résultats des prises en charge interventionnelles s'avèrent globalement décevants avec moins de 50 % de guérison de l'HTA. Il est nécessaire d'améliorer nos connaissances sur la physiopathologie de la DFM et d'optimiser la sélection des patients éligibles à une revascularisation par une prise de décision thérapeutique collégiale, en réunion de concertation pluridisciplinaire.

White adipose tissue overproduces the lipid-mobilizing factor zinc α2-glycoprotein in chronic kidney disease.

Chronic kidney disease (CKD) is frequently associated with protein-energy wasting, a recognized strong predictive factor of mortality. Zinc α2-glycoprotein (ZAG) is a new adipokine involved in body weight control through its lipid-mobilizing activity. Here we tested whether the uremic environment in CKD could alter ZAG production by white adipose tissue and contribute to CKD-associated metabolic disturbances. Compared with normal plasma, uremic plasma induced a significant increase in ZAG synthesis (124%), was associated with a significant increase in basal lipolysis (31%), and significantly blunted lipogenesis (-53%) in 3T3-L1 adipocytes in vitro. In 5/6 nephrectomized rats and mice in vivo, there was a significant decrease in white adipose tissue accretion (-44% and -43%, respectively) and a significantly higher white adipose tissue content of ZAG protein than in sham-operated, pair-fed control animals (498% and 106%, respectively). Subcutaneous white adipose tissue biopsies from patients with end-stage renal disease exhibited a higher content of ZAG (573%) than age-matched controls. Thus, the ZAG content is increased in white adipose tissue from patients or animal models with CKD. Overproduction of ZAG in CKD could be a major contributor to metabolic disturbances associated with CKD.

Prediction Tool to Estimate Potassium Diet in Chronic Kidney Disease Patients Developed Using a Machine Learning Tool: The UniverSel Study.

There is a need for a reliable and validated method to estimate dietary potassium intake in chronic kidney disease (CKD) patients to improve prevention of cardiovascular complications. This study aimed to develop a clinical tool to estimate potassium intake using 24-h urinary potassium excretion as a surrogate of dietary potassium intake in this high-risk population. Data of 375 adult CKD-patients routinely collecting their 24-h urine were included to develop a prediction tool to estimate potassium diet. The prediction tool was built from a random sample of 80% of patients and validated on the remaining 20%. The accuracy of the prediction tool to classify potassium diet in the three classes of potassium excretion was 74%. Surprisingly, the variables related to potassium consumption were more related to clinical characteristics and renal pathology than to the potassium content of the ingested food. Artificial intelligence allowed to develop an easy-to-use tool for estimating patients' diets in clinical practice. After external validation, this tool could be extended to all CKD-patients for a better clinical and therapeutic management for the prevention of cardiovascular complications.

Two Toxic Lipid Aldehydes, 4-hydroxy-2-hexenal (4-HHE) and 4-hydroxy-2-nonenal (4-HNE), Accumulate in Patients with Chronic Kidney Disease.

Lipid aldehydes originating from the peroxidation of n-3 and n-6 polyunsaturated fatty acids are increased in hemodialysis (HD) patients, a process already known to promote oxidative stress. However, data are lacking for patients with chronic kidney disease (CKD) before the initiation of HD. We prospectively evaluated the changes of plasma concentrations of two major lipid aldehydes, 4-HHE and 4-HNE, according to the decrease of glomerular filtration rate (GFR) in 40 CKD and 13 non-CKD participants. GFR was measured by inulin or iohexol clearance. Thus, 4-hydroxy-2-nonenal (4-HNE) and 4-hydroxy-2-hexenal (4-HHE) were quantitated in plasma by gas chromatography coupled with mass spectrometry and their covalent adducts on proteins were quantified by immunoblotting. On the one hand, 4-HHE plasma concentration increased from CKD stage I-II to CKD stage IV-V compared to non-CKD patients (4.5-fold higher in CKD IV-V, p < 0.005). On the other hand, 4-HNE concentration only increased in CKD stage IV-V patients (6.2-fold, p < 0.005). The amount of covalent adducts of 4-HHE on plasma protein was 9.5-fold higher in CKD patients than in controls (p < 0.005), while no difference was observed for 4-HNE protein adducts. Plasma concentrations of 4-HNE and 4-HHE are increased in CKD IV-V patients before the initiation of hemodialysis.

Estimated Glomerular Filtration Rate Bias in Participants with Severe Obesity Regardless of Deindexation.

OBJECTIVE: Morbid obesity is associated with a higher independent risk of chronic kidney disease (CKD). Estimated glomerular filtration rate (eGFR) has been evaluated in a limited number of study participants with severe obesity. METHODS: A total of 706 measured GFR (mGFR) results from 598 participants with obesity (BMI ≥ 35 kg/m2 ) were retrospectively collected. The performance of the Modification of Diet in Renal Disease (MDRD) equation, Chronic Kidney Disease-Epidemiology (CKD-EPI) equation, and deindexed eGFR were compared with mGFR from the gold standard technique (inuline or iohexol), adjusted (mGFRr) or nonadjusted (mGFR) to body surface area. Absolute bias, precision, and accuracy were calculated. RESULTS: Mean mGFRr (58 ± 31 mL/min/1.73 m2 ) was significantly different from CKD-EPI and MDRD (P < 0.001). Mean mGFR (nonindexed) (70 ± 40 mL/min) was significantly higher than mGFRr (P < 0.001). eGFR showed important biases and low accuracies for CKD-EPI and MDRD (10.7 ± 10.7 and 12.2 ± 13.7 mL/min/1.73 m2 ; 78% vs. 75% respectively). Deindexation worsened bias and accuracy 30% (percentage of GFR estimates within 30% of mGFRr or mGFR) between eGFR and mGFR. CONCLUSIONS: eGFR overestimates mGFR and is associated with important biases and inaccuracies in patients with severe obesity, and deindexing eGFR worsens the overestimation. These findings may have important implications in examining kidney function in patients with obesity.

Elevation of Trimethylamine-N-Oxide in Chronic Kidney Disease: Contribution of Decreased Glomerular Filtration Rate.

Gut microbiota-dependent Trimethylamine-N-oxide (TMAO) has been reported to be strongly linked to renal function and to increased cardiovascular events in the general population and in Chronic Kidney Disease (CKD) patients. Considering the lack of data assessing renal handling of TMAO, we conducted this study to explore renal excretion and mechanisms of accumulation of TMAO during CKD. We prospectively measured glomerular filtration rate (mGFR) with gold standard methods and plasma concentrations of trimethylamine (TMA), TMAO, choline, betaine, and carnitine by LC-MS/MS in 124 controls, CKD, and hemodialysis (HD) patients. Renal clearance of each metabolite was assessed in a sub-group of 32 patients. Plasma TMAO was inversely correlated with mGFR (r2 = 0.388, p < 0.001), confirming elevation of TMAO plasma levels in CKD. TMAO clearances were not significantly different from mGFR, with a mean ± SD TMAO fractional excretion of 105% ± 32%. This suggests a complete renal excretion of TMAO by glomerular filtration with a negligible participation of tubular secretion or reabsorption, during all stages of CKD. Moreover, TMAO was effectively removed within 4 h of hemodiafiltration, showing a higher fractional reduction value than that of urea (84.9% ± 6.5% vs. 79.2% ± 5.7%, p = 0.04). This study reports a strong correlation between plasma TMAO levels and mGFR, in CKD, that can be mainly related to a decrease in TMAO glomerular filtration. Clearance data did not support a significant role for tubular secretion in TMAO renal elimination.

Blood pressure decreases after revascularization in atherosclerotic renal artery disease: A cohort study based on a multidisciplinary meeting.

BACKGROUND: In atherosclerotic renal artery disease, the benefit of revascularization is controversial. A clinical decision-making process based on a multidisciplinary meeting was formalized in the Lyon university hospital. OBJECTIVES: To investigate whether this decisional process ensured a clinical benefit to patients assigned to renal revascularization. METHODS: Single-centre retrospective cohort study, including patients diagnosed from April 2013 to February 2015 with an atherosclerotic renal artery disease with a peak systolic velocity >180cm/s. For each patient, the decision taken in multidisciplinary meeting (medical treatment or revacularization) was compared to the one guided by international guidelines. Blood pressure values, number of antihypertensive medications, presence of an uncontrolled or resistant hypertension, and glomerular filtration rate at one-year follow-up were compared to baseline values. Safety data were collected. RESULTS: Forty-nine patients were included: 26 (53%) were assigned to a medical treatment and 23 (47%) to a renal revascularization. Therapeutic decision was in accordance with the 2013 American Health Association guidelines and with the 2017 European Society of Cardiology guidelines for 78% and 22% of patients who underwent revascularization, respectively. Patients assigned to revascularization presented a significant decrease in systolic blood pressure (-23±34mmHg, p = 0.007), diastolic blood pressure (-12±18mmHg, p = 0.007), number of antihypertensive medications (-1.00±1.03, p = 0.001), and number of uncontrolled or resistant hypertension (p = 0.022 and 0.031) at one-year follow-up. Those parameters were not modified among patients assigned to medical treatment alone. There was no grade 3 adverse event. CONCLUSION: Based on a multidisciplinary selection of revascularization indications, patients on whom a renal revascularization was performed exhibited a significant improvement of blood pressure control parameters with no severe adverse events.

The co-construction of medical disposals in emergency medicine consultations.

Waiting times in Accident and Emergency (A&E) Departments are a key performance indicator for the UK National Health Service (NHS) and are linked to medical decision making. We use the concept of medical disposal to consider the ways in which patients' medical problems are remoulded and transformed into a solvable problem enabling what he refers to as 'medical disposal'. Drawing on a study of 16 video-recorded cases from a single A&E Department in the UK, collected in 2014 and 2015, conversation analysis is used to explore how options for disposal (referral and discharge) are constructed and received in interactions between junior doctors and consultants. We consider the potential impact of information imbalances between junior doctors and consultants, as well as orientation to organisation goals in the form of standardised procedures and guidelines and constraints on time. In this way we demonstrate the interactional delicacy of discussions between junior doctors and consultants concerning moving patients on from A&E. We show how when juniors discuss cases with consultants the resultant decision making may be viewed as co-constructed. We make a case for detailed and nuanced understanding of interactions in A&E departments in order to understand the complexity of decision-making in this highly politically visible setting.

Adenine Rich Diet Is Not a Surrogate of 5/6 Nephrectomy in Rabbits.

BACKGROUND: Animal models are important tools needed to understand the mechanisms underlying the progression of renal disease and to implement new therapeutic approaches. A non-surgical model of chronic kidney disease (CKD) developed by chemical nephrectomy using an adenine-enriched diet has been shown to be a robust model to induce kidney failure in mice and rats. The purpose of this study was to implement an adenine diet to induce CKD in rabbits. METHODS: Male New Zealand rabbits were fed for 4 weeks with a diet containing 0.75% (w/w) adenine, and renal function was assessed by measuring plasma urea and creatinine concentrations. The glomerular filtration rate (GFR) was measured using the plasmatic clearance of Iohexol. Kidney histology was performed with haematoxylin erythrosine saffron and Sirius red staining. RESULTS: In contrast to what was observed in rodents, adenine diet failed to induce kidney failure in rabbits as is evident in the plasma concentrations of creatinine and urea and the direct measurement of GFR or histopathological studies. CONCLUSION: Adenine diet is not a surrogate of subtotal nephrectomy to induce kidney failure in rabbits. Several interspecies differences in metabolism and renal physiology could account for this observation.

The relationship between renal function and plasma concentration of the cachectic factor zinc-alpha2-glycoprotein (ZAG) in adult patients with chronic kidney disease.

Zinc-α2-glycoprotein (ZAG), a potent cachectic factor, is increased in patients undergoing maintenance dialysis. However, there is no data for patients before initiation of renal replacement therapy. The purpose of the present study was to assess the relationship between plasma ZAG concentration and renal function in patients with a large range of glomerular filtration rate (GFR). Plasma ZAG concentration and its relationship to GFR were investigated in 71 patients with a chronic kidney disease (CKD) stage 1 to 5, 17 chronic hemodialysis (HD), 8 peritoneal dialysis (PD) and 18 non-CKD patients. Plasma ZAG concentration was 2.3-fold higher in CKD stage 5 patients and 3-fold higher in HD and PD patients compared to non-CKD controls (P<0.01). The hemodialysis session further increased plasma ZAG concentration (+39%, P<0.01). An inverse relationship was found between ZAG levels and plasma protein (rs = -0.284; P<0.01), albumin (rs = -0.282, P<0.05), hemoglobin (rs = -0.267, P<0.05) and HDL-cholesterol (rs = -0.264, P<0.05) and a positive correlation were seen with plasma urea (rs = 0.283; P<0.01). In multiple regression analyses, plasma urea and HDL-cholesterol were the only variables associated with plasma ZAG (r2 = 0.406, P<0.001). In CKD-5 patients, plasma accumulation of ZAG was not correlated with protein energy wasting. Further prospective studies are however needed to better elucidate the potential role of ZAG in end-stage renal disease.

Ectopic lipid accumulation: A potential cause for metabolic disturbances and a contributor to the alteration of kidney function.

Ectopic lipid accumulation is now known to be a mechanism that contributes to organ injury in the context of metabolic diseases. In muscle and liver, accumulation of lipids impairs insulin signaling. This hypothesis accounts for the mechanism of insulin resistance in obesity, type 2 diabetes, aging and lipodystrophy. Increasing data suggest that lipid accumulation in the kidneys could also contribute to the alteration of kidney function in the context of metabolic syndrome and obesity. Furthermore and more unexpectedly, animal models of kidney disease exhibit a decreased adiposity and ectopic lipid redistribution suggesting that kidney disease may be a state of lipodystrophy. However, whether this abnormal lipid partitioning during chronic kidney disease (CKD) may have any functional impact in these tissues needs to be investigated. Here, we provide a perspective by defining the problem and analyzing the possible causes and consequences. Further human studies are required to strengthen these observations, and provide novel therapeutic approaches.