Prescribing off-label medications for patients undergoing dialysis presents significant clinical challenges that require careful judgement to optimize the risk-benefit ratio. The altered pharmacokinetic profile in this population, characterized by impaired renal elimination, modified non-renal clearance pathways, and complex polypharmacy, has traditionally led to numerous contraindications, not solely due to concerns about drug accumulation but also to prevent serious adverse events. While established dosing protocols exist for certain drug classes, robust pharmacological data remain insufficient for many contemporary medications, leaving clinicians without evidence-based guidance for commonly prescribed authorized therapies in participants without significant chronic renal disease. The categorical off-label medication contraindications in haemodialysis warrants new reconsideration in the light of emerging evidence that has successfully challenged these constraints through well-designed clinical studies and real-world experiences. In this review, we aim to examine the evidence on selected examples of off-label medications previously deemed contraindicated that have been successfully evaluated in patients treated by dialysis, and explore emerging therapeutic agents. Finally, we discuss the clinical, research, methodological, and regulatory barriers that must be addressed to improve evidence-based prescribing in patients on dialysis.

10.1093/ndt/gfaf081 Video Abstract Watch the video abstract of this contribution at https://academic.oup.com/ndt/pages/author_videos gfaf081Media1 6373021127112

Uremic secondary hyperparathyroidism (SHP) refers to the biochemical abnormalities that characterize CKD-MBD. However, historically parathyroid hormone (PTH) is identified as the key culprit hormone and the essential biomarker of secondary hyperparathyroidism. SHP represents the adaptive response to several mineral abnormalities that initiate and maintain increased PTH secretion through classical mineral derangements and more recently elucidated hormonal dysregulations. Among classic factors involved in the pathogenesis of SHP, phosphate, calcium, and calcitriol have a prominent role. The discovery of new pathogenetic factors involved in the development of SHP (and the eventual CKD-MBD) including fibroblast growth factor-23 (FGF23) and klotho provides new hypothesis and perspectives to our understanding of this complex metabolic disturbance. Recently more than serum phosphate a critical role in regulating FGF23 synthesis and the progression of CKD is ascribed to phosphate pool, reflected by production of glycerol-3-phosphate and the formation of excessive CPP-2. Finally, also skeletal resistance to PTH action, due to dysregulation of the Wnt-β-catenin system and intestinal dysbiosis, affecting the PTH actions on bone are causal factor of SHP. Identifying all the actors at play is mandatory to allow the most precise therapeutic prescription in the individual patient. This paper aims to review, in particular, the pathophysiology of SHP, which is essential to envisage the eventual therapeutic options for the associated MBD.

Rationale & Objective:Patients with kidney failure requiring maintenance dialysis have a high risk of cardiovascular events warranting antithrombotic therapies, including oral anticoagulant (OAC) or antiplatelet therapy (APT). However, chronic use of antithrombotic therapy can increase the bleeding risk in patients receiving dialysis. However, little is known about medication use patterns and risk of bleeding events in real-world clinical practice. Study Design:Retrospective analysis of data from 2 prospective cohort studies. Setting & Participants:We included 27,612 patients from the Dialysis Outcomes and Practice Patterns Study (DOPPS) and 5,289 patients from the Peritoneal DOPPS (PDOPPS), international cohorts of hemodialysis (HD) and peritoneal dialysis (PD) patients. Exposures:Patient demographics and comorbid conditions; OAC and APT use. Outcomes:OAC and APT use; a bleeding composite outcome including a hospitalization or death because of a major bleeding event. Analytical Approach:Descriptive analyses to explore OAC and APT utilization and crude rates of the bleeding composite outcome and Kaplan-Meier analyses to estimate medication discontinuation. Results:Baseline OAC and APT use was 9% and 10% in HD patients and 4% and 7% in PD patients, respectively. Patients prescribed antithrombotic drugs were older and more likely to have a history of cardiovascular disease. After 36 months, the Kaplan-Meier estimated proportions of baseline users who remained on therapy were 57% for OAC and 53% for APT. The composite bleeding rates per 100 patient-years among patients with baseline OAC use versus baseline APT use versus neither were 8.6, 5.6, and 4.1 in HD patients and 12.0, 6.1, and 3.9 in PD patients, respectively. Limitations:Potential for event misclassification; no over-the-counter medication data; rates unadjusted. Conclusions:Antithrombotic drugs are infrequently prescribed and often discontinued in patients receiving HD or PD. With major bleeding event rates high among antithrombotic users, new strategies are needed to optimize the risks and benefits of antithrombotic agents in the dialysis setting.

Background The serum calcification propensity test (or T50 test) might become a standard tool for the assessment of vascular calcification risk and T50 might be a valuable biomarker in clinical trials of treatments intended to slow the progression of vascular calcification. Literature data suggest that non-calcium-containing phosphate binders can influence T50 in chronic dialysed patients. However, it is not clear whether similar interventions are effective in patients at earlier stages of chronic kidney disease (CKD).Methods The FGF23 Reduction: Efficacy of a New phosphate binder in CHronic kidney disease (FRENCH) trial was a multicentre, double-blind, placebo-controlled, randomized trial of sevelamer carbonate in participants with stage 3b/4 CKD. In this subanalysis of the FRENCH data, T50 and other laboratory variables (including fetuin-A and ionized and total magnesium) were measured centrally at baseline and after 12 weeks of treatment.Results A total of 96 patients were screened and 78 (55 men and 23 women) met the inclusion criteria and were randomized to receive placebo (n = 39) or sevelamer carbonate (n = 39). The median patient age was 66 years [interquartile range (IQR) 56-72], the median eGFR was 25 ml/min/1.73 m2 (IQR 21-30) and the mean T50 was 335 minutes (standard deviation 82). In a linear regression model, T50 was independently associated with serum ionized magnesium, fetuin-A and bicarbonate levels and inversely associated with phosphate concentration. The within-group changes in the mean T50 between week 0 and week 12 were not significant in the sevelamer group or the placebo group {4.6 minutes [95% confidence interval (CI) -13.6-22.8; P = .61] and 7.8 minutes [95% CI -16.4-32.1; P = .51], respectively}. Furthermore, we did not observe significant changes in fetuin-A and magnesium levels.Conclusion A 12-week course of the non-calcium-containing phosphate binder sevelamer carbonate was not associated with a significant change in T50 in patients with stage 3b/4 CKD. Phosphate binders might not be an effective strategy for modifying serum calcification propensity in non-dialysis-dependent patients with CKD.

Abstract Background and Aims Anemia and iron deficiencies are frequent in hemodialysis (HD) patients and in patients with cancer. If specific guidelines on the management of erythropoiesis-stimulating agent (ESA) in HD patients with cancer have been published, the association between the iron status and the risk of morbidity and mortality in this population remains elusive. Method This retrospective, observational study include HD patients who had been diagnosed with cancer after the start of HD, between September 2009 and March 2021. Demographics, lab test, iron status and cumulative dose of iron and ESA were collected quarterly, from one year before cancer diagnosis to one year after. Univariate analyses were performed to assess the impact of iron or ESA exposure on mortality, after modelling exposure before and after diagnosis of cancer. Then, each model was adjusted, using the baseline variables that were found to be independently associated with mortality. Cox proportional-hazards modelling was used for all regression analyses. P-value < .05 is considered significant. Results Seventy-nine patients were included, with a median follow-up of 2.2 years (IQR: 0.9–5.3). At baseline, the median age was 72 years (IQR 63–79), 30.4% were women. The median dialysis vintage before the diagnosis of cancer was 3 years (IQR 2-7). The main cancers found were prostate (14%), colorectal (13%), bronchopulmonary (11%), urothelial (10%) and skin (10%). Lymph node involvement were observed in 18% and metastasis in 16% patients. The median hemoglobin level was 10.4 g/dL (IQR 9.9–11.7), the median ferritin level was 412 ng/mL (IQR 213–626). The median cumulative quarterly dose of iron was 600 (215–900) mg and the cumulative dose of ESA was 71 (IQR 40–148) UI/kg/week of darbopoetin alfa or equivalent. The year following the cancer diagnosis, the median dose of iron administered remained stable, but with significant variations between patients. There was an increase in the median dose of ESA, particularly after the 6th month, up to 134 (35–314) UI/kg/week. The median hemoglobin remained between 10 and 12 g/dL. The median ferritin level rises moderately during the first 6 months, then returns to values equivalent to those preceding the diagnosis of cancer. Mortality after 12 months of follow-up was high (mortality rate of 47.4%). Age, the presence of a atrial fibrillation, lymphatic invasion, metastatic invasion, or the need for more than one antitumor treatment were independently associated with mortality. In adjusted analysis (using baseline characteristics associated with death), an association with all-cause mortality was only observed with the cumulative dose of ESA in the year preceding the diagnosis of cancer (HR 1.41 [1.06–1.88], P = .017). In multivariate analysis, an association was observed between all-cause mortality and the cumulative dose of ESA in the year preceding the diagnosis of cancer, with an HR of 1.37 (1.03-1.83, P = .031). This association between all-cause mortality and cumulative dose of ESA was also found in the year following cancer diagnosis, but without reaching significance (HR 1.37 [0.95-1.98], P = .092). However, there was no association between mortality and the cumulative dose of iron administered before or after the diagnosis of cancer in multivariate analyses. Conclusion In HD patients diagnosed with cancer, the amount of iron administered was not associated with an increased risk of mortality, probably making it possible to increase the doses administered, if necessary, without any additional risk. However, it was not possible to guarantee the safety of increasing the dose of ESA in these patients. These findings should be confirmed in a larger population in order to define guideline for iron and ESA supplementation in this population.

Vertebral fractures (VFs) are the most common osteoporotic fractures in the general population, and they have been associated with high mortality, decreased quality of life, and high risk of subsequent fractures, especially when recent, multiple, or severe. Currently, VF diagnosis and classification determine fracture risk and the most appropriate anti-osteoporotic treatment. However, VFs are clearly underdiagnosed, especially in patients with chronic kidney disease (CKD), and CKD-associated osteoporosis has been disregarded until recently. VFs are associated with higher morbidity and mortality, and their prevalence and incidence differ depending on the grade of renal dysfunction (CKD G1-G5) and/or the type of renal replacement therapy (dialysis or transplantation). In addition to classical risk factors [such as higher age, female sex, reduced bone mineral density, diabetes and steroid use], various other factors have been associated with an increased risk of VFs in CKD, including CKD grade, haemodialysis vintage, time since renal transplantation, low or high intact parathyroid hormone and phosphate levels, and/or vitamin D and K1 deficiencies. Importantly, several clinical societies have recently modified their algorithms according to the fracture risk classification (including the presence of VFs) and determined the most appropriate anti-osteoporotic treatment for the general population. However, there are no specific guidelines addressing this topic in patients with CKD despite an important paradigm shift regarding the prognostic value of bone mineral density in 2017 after the publication of the CKD-Mineral and Bone Disorder Kidney Disease: Improving Global Outcomes guidelines. A proactive attitude towards diagnosis, treatment, and research is proposed to avoid therapeutic nihilism.

Sarcopenia and dynapenia are two terms associated with ageing that respectively define the loss of muscle mass and strength. In 2018, the European Working Group on Sarcopenia in Older People (EWGSOP) introduced the EWGSOP2 diagnostic algorithm for sarcopenia, which integrates both concepts. It consists of 4 sequential steps: screening for sarcopenia, examination of muscle strength, assessment of muscle mass and physical performance; depending on these last 3 aspects sarcopenia is categorised as probable, confirmed, and severe respectively. In the absence of validation of the EWGSOP2 algorithm in various clinical contexts, its use in haemodialysis poses several limitations: (a) low sensitivity of the screening, (b) the techniques that assess muscle mass are not very accessible, reliable, or safe in routine clinical care, (c) the sequential use of the magnitudes that assess dynapenia and muscle mass do not seem to adequately reflect the muscular pathology of the elderly person on dialysis. We reflect on the definition of sarcopenia and the use of more precise terms such as “myopenia” (replacing the classic concept of sarcopenia to designate loss of muscle mass), dynapenia and kratopenia. Prospective evaluation of EWGSOP2 and its comparison with alternatives (i.e. assessment of kratopenia and dynapenia only; steps 2 and 4) is proposed in terms of its applicability in clinical routine, resource consumption, identification of at-risk individuals and impact on events.

Anaemia is common in chronic kidney disease (CKD) and has a significant impact on quality of life (QoL), work productivity and outcomes. Current management includes oral or intravenous iron and erythropoiesis-stimulating agents (ESAs), to which hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) have been recently added, increasing the available therapeutic options. In randomised controlled trials, only intravenous iron improved cardiovascular outcome, while some ESAs were associated with increased adverse cardiovascular events. Despite therapeutic advances, several challenges and unmet needs remain in the current management of anaemia of CKD. In particular, clinical practice does not include an assessment of QoL, which prompted a group of European nephrologists and representatives of patient advocacy groups to revisit the current approach. In this consensus document, the authors propose a move towards a more holistic, personalised and long-term approach, based on existing evidence. The focus of treatment should be on improving QoL without increasing the risk of adverse cardiovascular events, and tailoring management strategies to the needs of the individual. In addition, the authors discuss the suitability of a currently available anaemia of CKD-specific health-related QoL measure for inclusion in the routine clinical management of anaemia of CKD. The authors also outline the logistics and challenges of incorporating such a measure into electronic health records and how it may be used to improve QoL for people with anaemia of CKD.

Background:The use of diuretics in patients on haemodialysis (HD) is thought to maintain diuresis. However, this assumption and the optimal dose are based on little scientific evidence, and associations with clinical outcomes are unclear. Methods:We reported international variations in diuretic use and loop diuretic dose across 27 759 HD patients with dialysis vintage <1 year in the Dialysis Outcomes and Practice Patterns Study phases 2-5 (2002-2015), a prospective cohort study. Doses of torsemide (4:1) and bumetanide (80:1) were converted to oral furosemide-equivalent doses. Adjusted Cox, logistic and linear regressions were used to investigate the association of diuretic use and dose with outcomes. Results:Diuretic utilization varied widely by country at vintage <3 months, ranging from >80% in Germany and Sweden to <35% in the USA, at a median dose ranging from 400-500 mg/day in Germany and Sweden to <100 mg/day in Japan and the USA. Neither diuretic use nor higher doses were associated with a lower risk of all-cause mortality, a higher risk of hospitalization for fracture or elevated parathyroid hormone levels, but the prescription of higher doses (>200 mg/day) was associated with a higher risk of all-cause hospitalization. Conclusions:Substantial international differences exist in diuretic prescriptions, with use and doses much higher in some European countries than the USA. The prescription and higher doses of loop diuretics was not associated with improved outcomes.

Patients with advanced chronic kidney disease and those already on dialysis have an increased prevalence of cardiovascular calcifications. They are the cause of severe complications and are associated with a reduced life expectancy in these patients. Recommendations and imaging scores have been developed to detect and assess their importance, to guide and improve the management of cardiovascular risk. However, despite these recommendations, current practice teaches us that they are only partially applied. The prevention and treatment of cardiovascular calcifications go through the correction of classic risk factors associated with atherosclerosis, mineral and bone metabolism disorders and by optimizing the dose and the efficiency of dialysis. New therapeutic strategies are beginning to emerge, others are being evaluated, such as sodium thiosulfate, rheopheresis, vitamin K, magnesium supplementation, and SNF-472.Les patients atteints de maladie rénale chronique (MRC) avancée et ceux déjà traités par dialyse présentent une prévalence accrue de calcifications cardiovasculaires. Elles sont à l’origine des complications sévères et s’associent à une diminution de l’espérance de vie chez ces patients. Des recommandations et des scores radiographiques ont été développés pour dépister et évaluer leur importance, afin d’orienter et améliorer la prise en charge du risque cardiovasculaire. Cependant, en dépit de ces recommandations, la pratique courante nous enseigne qu’elles ne sont que partiellement appliquées. La prévention et le traitement de calcifications cardiovasculaires passent par la correction des facteurs de risque classiques associés à l’athérosclérose, des troubles du métabolisme minéral et osseux et en optimisant la dose et l’efficacité de la dialyse. Des nouvelles stratégies thérapeutiques commencent à voir le jour, d’autres sont en cours d’évaluation, comme le thiosulfate de sodium, la rhéophérèse, la vitamine K, la supplémentation en magnésium et le SNF-472.

Abstract Background and Aims Apolipoprotein L1 (APOL1) toxic gain-of-function variants (G1 or G2) are genetic factors driving a broad spectrum of progressive, proteinuric nephropathies referred to as APOL1-mediated kidney disease (AMKD). APOL1 genotyping is not routinely performed in kidney disease care, and prevalence of APOL1 variants among persons with chronic kidney disease (CKD) in Europe is not well known. These variants are common in persons of recent African ancestry. We report interim data of a global study estimating the prevalence of APOL1 genotypes in participants of recent African ancestry and proteinuric CKD, with a focus on data from Europe. Method Enrollment in this ongoing study will include up to 2,500 participants across different geographies who are of recent African ancestry and have focal segmental glomerulosclerosis (FSGS) or other proteinuric nondiabetic kidney disease (NDKD). The study includes a single visit during which blood samples are collected from participants to determine their APOL1 genotype using a validated polymerase chain reaction (PCR)-based assay. The percent of participants with two APOL1 variants and percent of participants in each genotype category (e.g., G1/G1, G1/G2, G2/G2) are assessed; genetic counseling services are available to participants, if desired. Results This interim analysis included 1,256 participants of whom 174 (13.9%) were from Europe. As shown in the table, among the 88 participants with FSGS and 86 participants with proteinuric NDKD, 54 (61.4%) and 32 (37.2%) have two APOL1 variants, respectively. Conclusion Our study will generate one of the largest global APOL1 genotyping data sets in participants with proteinuric kidney disease. These data begin to address a critical knowledge gap and highlight the importance of APOL1 genotyping in kidney disease care to identify AMKD, potentially optimize disease management, and enable referral for interventional clinical trials evaluating targeted therapies for AMKD.

Torres, Pablo A. Urena; Seris, Pascal; Kolko-Labadens, Anne; Chazot, Charles Author Information

Patients with advanced chronic kidney disease and those already on dialysis have an increased prevalence of cardiovascular calcifications. They are the cause of severe complications and are associated with a reduced life expectancy in these patients. Recommendations and imaging scores have been developed to detect and assess their importance, to guide and improve the management of cardiovascular risk. However, despite these recommendations, current practice teaches us that they are only partially applied. The prevention and treatment of cardiovascular calcifications go through the correction of classic risk factors associated with atherosclerosis, mineral and bone metabolism disorders and by optimizing the dose and the efficiency of dialysis. New therapeutic strategies are beginning to emerge, others are being evaluated, such as sodium thiosulfate, rheopheresis, vitamin K, magnesium supplementation, and SNF-472.

Chronic kidney disease-associated pruritus (CKD-aP) is a frequent complication, with an estimated prevalence of 24-37% in patients treated with hemodialysis. Its pathophysiology is complex and includes four interrelated axes: accumulation of uremic toxins, peripheral neuropathy, an imbalance in the opioid receptors balance, and abnormal activation of immune cells. This symptom which is associated with impaired quality of life is underestimated by caregivers and underreported by patients. Management is not uniformly codified. It includes the use of skin emollients, optimization of dialysis parameters and management of chronic kidney disease complications, and specifically the use of difelikefalin. Patients treated with hemodialysis have an increased risk of calcifications that can affect the arteries and heart valves. These calcifications are associated with decreased survival and several scores based on radiological examinations have been proposed for screening. Although recommended, this screening is rarely performed in dialysis centers. Prevention and treatment against the development of cardiovascular calcifications are the control of risk factors associated with atherosclerosis, control of phosphatemia, and new therapeutic strategies such as sodium thiosulfate, rheopheresis, vitamin K, magnesium supplementation or SNF-472, a calcium chelator currently in clinical development.