Hypoxia-inducible factor prolyl hydroxylase inhibitors for anaemia in chronic kidney disease: a document by the European Renal Best Practice board of the European Renal Association.

Anaemia is a common complication of chronic kidney disease (CKD) and is associated with poor long-term outcomes and quality of life. The use of supplemental iron, erythropoiesis stimulating agents (ESAs) and blood transfusions has been the mainstay of treatment of anaemia in CKD for more than three decades. Despite available treatments, CKD patients with anaemia are undertreated and moderate-to-severe anaemia remains prevalent in the CKD population. Anaemia has consistently been associated with greater mortality, hospitalisation, cardiovascular events, and CKD progression in patients with CKD, and the risk increases with anaemia severity. Hypoxia-inducible factor (HIF) prolyl hydroxylase (PH) inhibitors have a novel mechanism of action by mimicking the body's response to hypoxia and have emerged as an alternative to ESAs for the treatment of anaemia in CKD. Their efficacy in correcting and maintaining haemoglobin has been demonstrated in over 30 phase 3 clinical trials. Additionally, HIF activation results in various pleiotropic effects beyond erythropoiesis with cholesterol reduction and improved iron homeostasis and potential anti-inflammatory effects. The long-term safety of these agents, particularly with respect to cardiovascular and thromboembolic events, and their possible effect on tumor growth requires to be fully elucidated. This document presents in detail the effects of HIF-PH inhibitors, describes their mechanisms of action and pharmacologic properties, and discusses their place in the treatment of anaemia in CKD according to the available evidence.

Capacity for the management of kidney failure in the International Society of Nephrology Eastern and Central Europe region: report from the 2023 ISN Global Kidney Health Atlas (ISN-GKHA).

Delivery of care for kidney failure (KF) globally has a significant disparity; even in some countries, it means end of life for the person. The International Society of Nephrology Global Kidney Health Atlas (ISN-GKHA) tries to address gaps in KF care and standardize global nephrology care. From the third iteration of the ISN-GKHA, we present data for countries in the ISN Eastern and Central Europe region. The median prevalences of chronic kidney disease (12.8%) and treated KF (873.5 pmp) were higher than the global rates, respectively. Hemodialysis was the most preferred modality for KF in adults, whereas kidney replacement therapy was more balanced in children. Although most of the countries in the region had lower-middle-income and upper-middle-income levels, health expenditures for kidney health care were almost generally covered publicly. Nephrologists were responsible for the medical kidney care of people with KF in all countries. There was adequate infrastructure to provide all kinds of treatment for kidney care in the region. Regional characteristics such as high levels of obesity, smoking, and Balkan nephropathy as an endemic disease coupled with a shortage of workforce and finance continued to affect kidney care in the region negatively. By making organizational and legislative arrangements, partnerships with national authorities and societies may accelerate the improvement of kidney health care in the region.

Kidney Transplantation During COVID-19 Outbreak: Data From Public and Non-Public Dialysis Network.

BACKGROUND: The COVID-19 pandemic significantly affected medical services in Poland. All restrictions, additional procedures, and numerous infections among medical staff affected transplantation in the country. This study aimed to analyze reports prepared by the Polish Transplant Coordination Center Poltransplant and internal Fresenius Nephrocare Poland to assess differences in the number of patients who qualified for kidney transplantation and transplanted during the pandemic compared with a pre-pandemic year. METHODS: Official data from the Polish Transplant Coordinating Centre Poltransplant bulletin from 2019, 2020, and 2021 was analyzed to determine the number of patients on the waiting list for solid organ transplantation. The number of transplantations reported by Polish transplant centers was also considered. RESULTS: During the SARS-CoV-2 outbreak, the number of qualified and transplanted patients was significantly lower than in the pre-pandemic period. The worst data concerns the new qualifications, which were significantly lower in the first year of the pandemic due to all the restrictions implemented. The number of kidney transplant procedures provided during the 2-year pandemic period decreased significantly (-20.8%) in 2020, and in the second year, the negative trend continued (-0.8%). For private dialysis providers, the number of active patients on the waiting list for kidney transplantation was a bit better-it decreased from 265 to 239 in 2020 (-9.8%) and increased to 259 in 2021 (+8.4%). The decline in the number of patients treated in Fresenius Nephrocare dialysis centers was more significant, decreasing by 27.8% in 2020 compared with 2019. In 2021, the number of transplanted patients slightly increased by about 2.5%. CONCLUSIONS: The decrease in qualified and transplanted patients during the SARS-CoV-2 outbreak clearly shows the need to undertake multidisciplinary discussions among all stakeholders to create new procedures and processes that will help protect the health care system and patients in future crisis situations.

Efficacy of erythropoietin as a neuroprotective agent in CKD-associated cognitive dysfunction: A literature systematic review.

Patients with chronic kidney disease (CKD) often experience mild cognitive impairment and other neurocognitive disorders. Studies have shown that erythropoietin (EPO) and its receptor have neuroprotective effects in cell and animal models of nervous system disorders. Recombinant human EPO (rHuEPO), commonly used to treat anemia in CKD patients, could be a neuroprotective agent. In this systematic review, we aimed to assess the published studies investigating the cognitive benefits of rHuEPO treatment in individuals with reduced kidney function. We comprehensively searched Pubmed, Cochrane Library, Scopus, and Web of Science databases from 1990 to 2023. After selection, 24 studies were analyzed, considering study design, sample size, participant characteristics, intervention, and main findings. The collective results of these studies in CKD patients indicated that rHuEPO enhances brain function, improves performance on neuropsychological tests, and positively affects electroencephalography measurements. These findings suggest that rHuEPO could be a promising neuroprotective agent for managing CKD-related cognitive impairment.

Transplantation in the Context of Migration and Refugees: A Summary of the DICG and TTS Ethics Committee Workshop, Buenos Aires, Argentina, September 2022.

Global conflicts and humanitarian crises have resulted in an unprecedented number of refugees and migrants. This challenges the limited resources of health care systems and jeopardizes the availability of transplant care for these deserving migrants and refugees. This was the basis for a workshop held during the Congress of the Transplantation Society (Buenos Aires, 2022). We elaborate on the proceedings of the workshop entitled "Transplantation in the Context of Migration and Refugees," organized by the Ethics Committee of The Transplantation Society and Declaration of Istanbul Custodian Group. Transplant providers from around the world shared strategies of how each region has responded to providing access to care for refugees and migrants in need of transplant services. The potential exploitation of this vulnerable group leading to illicit organ removal was addressed for each region. The Transplantation Society, Declaration of Istanbul Custodian Group, and global transplant community should continue to focus on the status of refugees and migrants and collaborate on strategies to provide access to transplant care for this deserving population. Global cooperation will be essential to provide vigilant oversight to prevent exploitation of this vulnerable population.

A review and recommendations for oral chaperone therapy in adult patients with Fabry disease.

Fabry disease (FD) is a rare, X-linked lysosomal storage disorder affecting both males and females caused by genetic abnormalities in the gene encoding the enzyme α-galactosidase A. FD-affected patients represent a highly variable clinical course with first symptoms already appearing in young age. The disease causes a progressive multiple organ dysfunction affecting mostly the heart, kidneys and nervous system, eventually leading to premature death. Disease-specific management of FD includes enzyme replacement therapy with agalsidase α and ß or pharmacological oral chaperone migalastat. Migalastat is a low-molecular-mass iminosugar, that reversibly binds to active site of amenable enzyme variants, stabilizing their molecular structure and improving trafficking to the lysosome. Migalastat was approved in the EU in 2016 and is an effective therapy in the estimated 35-50% of all patients with FD with amenable GLA gene variants. This position statement is the first comprehensive review in Central and Eastern Europe of the current role of migalastat in the treatment of FD. The statement provides an overview of the pharmacology of migalastat and summarizes the current evidence from the clinical trial program regarding the safety and efficacy of the drug and its effects on organs typically involved in FD. The position paper also includes a practical guide for clinicians on the optimal selection of patients with FD who will benefit from migalastat treatment, recommendations on the optimal selection of diagnostic tests and the use of tools to identify patients with amenable GLA mutations. Areas for future migalastat clinical research have also been identified.

The Clock Drawing Task reveals executive dysfunction in the dialysis population - an underrecognized and underestimated problem.

AIM OF THE STUDY: The study aimed to assess the prevalence of executive function impairment among patients with chronic kidney disease (CKD) undergoing dialysis, with no subjective cognitive problems and with normal global cognition on the Mini-Mental State Examination (MMSE). We also investigated the relationship between cardiovascular risk factors and cognitive test results. RATIONALE FOR THE STUDY: Patients with CKD, including those undergoing renal replacement therapy, are at a higher risk of developing cognitive impairment (CI) than the general population. Recent research has shown CI to be a growing problem among CKD patients worldwide. Yet, it remains underdiagnosed, even though it may significantly influence the lives of patients. MATERIALS AND METHODS: In this cross-sectional, prospective study, 58 dialysis patients with no cognitive decline on the MMSE screening were assessed for executive function impairment using the Executive Clock-Drawing Task (CLOX). Moreover, past medical history, demographic data, and laboratory test results were collected. RESULTS: The mean patient age was 59.47 ± 14.98 years, and the mean duration of dialysis was 45.93 ± 48.49 months. The prevalence of executive function impairment amounted to 8.6%. Moreover, remarkably similar pattern of clock drawing was observed, with numbers written outside the clock face in the CLOX1 test. CONCLUSIONS: Executive dysfunctions in dialysis patients may manifest itself before the onset of global cognitive impairment. There appear to be a deficit in the spatial domain as well. Better education may play a protective role.

Effect of time-dependent dialysate bicarbonate concentrations on acid-base and uremic solute kinetics during hemodialysis treatments.

Recent studies have suggested benefits for time-dependent dialysate bicarbonate concentrations (Dbic) during hemodialysis (HD). In this clinical trial, we compared for the first time in the same HD patients the effects of time-dependent changes with constant Dbic on acid-base and uremic solute kinetics. Blood acid-base and uremic solute concentration were measured in twenty chronic HD patients during 4-h treatments with A) constant Dbic of 35 mmol/L; B) Dbic of 35 mmol/L then 30 mmol/L; and C) Dbic of 30 mmol/L then 35 mmol/L (change of Dbic after two hours during Treatments B and C). Arterial blood samples were obtained predialysis, every hour during HD and one hour after HD, during second and third treatments of the week with each Dbic concentration profile. Blood bicarbonate concentration (blood [HCO3]) during Treatment C was lower only during the first three HD hours than in Treatment A. Overall blood [HCO3] was reduced during Treatment B in comparison to Treatment A at each time points. We conclude that a single change Dbic in the middle of HD can alter the rate of change in blood [HCO3] and pH during HD; time-dependent Dbic had no influence on uremic solute kinetics.

Drugs with a negative impact on cognitive functions (Part 2): drug classes to consider while prescribing in CKD patients.

There is growing evidence that chronic kidney disease (CKD) is an independent risk factor for cognitive impairment, especially due to vascular damage, blood-brain barrier disruption and uremic toxins. Given the presence of multiple comorbidities, the medication regimen of CKD patients often becomes very complex. Several medications such as psychotropic agents, drugs with anticholinergic properties, GABAergic drugs, opioids, corticosteroids, antibiotics and others have been linked to negative effects on cognition. These drugs are frequently included in the treatment regimen of CKD patients. The first review of this series described how CKD could represent a risk factor for adverse drug reactions affecting the central nervous system. This second review will describe some of the most common medications associated with cognitive impairment (in the general population and in CKD) and describe their effects.

Continuous glucose monitoring in people with diabetes and end-stage kidney disease-review of association studies and Evidence-Based discussion.

Diabetic nephropathy is currently the leading cause of end-stage kidney disease. The present methods of assessing diabetes control, such as glycated hemoglobin or self-monitoring of blood glucose, have limitations. Over the past decade, the field of continuous glucose monitoring has been greatly improved and expanded. This review examines the use of continuous glucose monitoring in people with end-stage kidney disease treated with hemodialysis (HD), peritoneal dialysis (PD), or kidney transplantation. We assessed the use of both real-time continuous glucose monitoring and flash glucose monitoring technology in terms of hypoglycemia detection, glycemic variability, and efficacy, defined as an improvement in clinical outcomes and diabetes control. Overall, the use of continuous glucose monitoring in individuals with end-stage kidney disease may improve glycemic control and detection of hypoglycemia. However, most of the published studies were observational with no control group. Moreover, not all studies used the same assessment parameters. There are very few studies involving subjects on peritoneal dialysis. The small number of studies with limited numbers of participants, short follow-up period, and small number of manufacturers of continuous glucose monitoring systems are limitations of the review. More studies need to be performed to obtain more reliable results.

The prevalence of anemia in people with chronic kidney disease after hematopoietic stem cell transplantation.

The hematopoietic stem cell transplantation (HSCT) is performed for various hematological diseases. Chronic kidney disease (CKD) occurs relatively often after HSCT. Anemia after HSCT may be due to CKD and/or other reasons. The aim of this study is to assess the prevalence of anemia and its possible relationship to the presence of CKD in patients at least 3 months after HSCT. The study included 156 patients who underwent allogeneic HSCT treatment in our center in the years 1998 to 2021 due to different hematologic pathologies (acute myeloid leukemia, acute lymphoblastic leukemia, lymphoma, and others). Anemia was diagnosed in 13% of women and 35% of men. Anemia was most common in people after HSCT due to a history of acute myeloid leukemia (55% women, 30% men). In 56% of women and 17% of men, anemia was associated with chronic kidney disease. In patients with anemia, age was related to the eGFR (r = -0.39, p < 0.001), in patients without anemia age was negatively related to eGFR (r = -0.56, p < 0.001), and hemoglobin was positively related to platelet count (r = 0.62, p < 0.001). Concluding, anemia, was relatively common in CKD after HSCT. In CKD, in particular with coexistent anemia, nephrology referral is to be taken into account to optimize therapy, including nephroprotection.

Proenkephalin Levels and Its Determinants in Patients with End-Stage Kidney Disease Treated with Hemodialysis and Peritoneal Dialysis.

Recently, proenkephalin A (PENK A) has been shown to reflect glomerular dysfunction and to predict new-onset acute kidney injury and heart failure. While previous studies have investigated PENK A as a biomarker in individuals with preserved renal function, PENK A concentration in patients with end-stage kidney disease (ESKD) was not investigated. Plasma PENK A concentration was assessed in 88 patients with ESKD treated with hemodialysis (HD) or peritoneal dialysis (PD), and its associations with kidney function and heart failure indicators were investigated. In HD patients, the difference in PENK A levels before and after hemodialysis, was measured and further assessed for an association with the type of HD membrane used. PENK A levels did not differ significantly between HD and PD patients. In HD patients, the median PENK A concentration was significantly higher before than after hemodialysis (1.368 vs. 2.061, p = 0.003). No correlation was found between PENK A level and urea (p = 0.192), eGFR (p = 0.922), dialysis vintage (p = 0.637), and residual urine output (p = 0.784). Heart failure (p = 0.961), EF (p = 0.361), and NT-proBNP (p = 0.949) were not associated with increased PENK A concentration. PENK A does not reflect renal function and cardiac status in patients with ESKD. Further research is required to establish the clinical utility of the new biomarker in patients with impaired kidney function.

Apparently Resistant Hypertension in Polish Hemodialyzed Population: Prevalence and Risk Factors.

BACKGROUND: The aim of this study was to assess the prevalence, characteristics, and determinants of apparent treatment-resistant hypertension (aTRH) in an unselected large population of patients with end-stage kidney disease (ESKD) treated with hemodialysis (HD) throughout the country. METHODS: A database of 5879 patients (mean age 65.2 ± 14.2 years, 60% of males receiving hemodialysis) was obtained from the biggest provider of hemodialysis in the country. Hypertension and aTRH were defined using pre- or/and post-dialysis BP values. Patients with and without aTRH (non-aTRH) were compared. RESULTS: Using pre- and post-dialysis criteria, hypertension was diagnosed in 90.7% and 89.1% of subjects, respectively. According to pre- and post-dialysis blood pressure criteria, aTRH incidences were 40.9% and 38.4%, respectively. The hypertensive patients with aTRH versus non-aTRH were younger, had a higher rate of cardiovascular disease, lower dialysis vintage, shorter time on dialysis, higher eKt/V, higher ultrafiltration, higher pre- and post-dialysis BP and HR, and higher use of antihypertensive drugs. Factors that increase the risk of aTRH according to both pre- and post-dialysis BP criteria were age-OR 0.99 [0.98-0.99] and 0.99 [0.98-0.99], the history of CVD 1.26 [1.08-1.46] and 1.30 [1.12-1.51], and diabetes 1.26 [1.08-1.47] and 1.28 [1.09-1.49], adjusted OR with 95% CI. CONCLUSIONS: In the real-life world, as much as 40% of HD patients may have aTRH. In ESKD HD patients, aTRH seems to be multifactorial, influenced by patient-related rather than dialysis-related factors. Various definitions of aTRH preclude easy comparisons between studies.

Cognitive Impairment and Anxiety Are Prevalent in Kidney Transplant Recipients.

INTRODUCTION: Cognitive impairment (CI) is common in end-stage kidney disease (ESKD), including kidney transplant recipients. Patients with cognitive problems may find it difficult to comply with medical recommendations after kidney transplantation (KT), which can be the cause of many complications, poorer prognosis, and increased hospitalization rates after transplantation. Additionally, some patients after KT may experience depression and anxiety, which are prevalent comorbidities in patients with ESKD. METHODS: In this single-center, cross-sectional study, we included 56 consecutive adult patients after KT. Cognitive function was assessed using the Addenbrooke Cognitive Test III (ACE III). In addition, all patients were screened for depression and anxiety using the Hospital Anxiety and Depression Scale (HADS). The impact of immunosuppressive therapy and other disease-related variables on cognitive function was also assessed. RESULTS: A total of 56 KT patients, with a mean age of 50.3 ± 11.7 years, transplanted ≤35 months ago were included in the study. The prevalence of CI was 30%. Compared with cognitively unimpaired patients, patients with CI scored significantly lower in all cognitive domains. Furthermore, better cognitive functioning after KT was significantly associated with more years of schooling. We found no significant correlation between CI and age at assessment, duration of dialysis before KT, creatinine levels, creatinine clearance, uric acid levels, hemoglobin levels, comorbid cardiovascular diseases, and immunosuppressive therapy. In addition, the prevalence of depression and anxiety in screening tests was 12.5% and 27%, respectively, and patients receiving higher daily dose of prednisone had higher HADS scores on both the depression and anxiety subscales (not statistically significant). DISCUSSION: Cognitive disorders are a relevant issue in kidney transplant recipients. There might be many factors, both before and after KT, that have a negative impact on cognition. Therefore, further research is needed to increase knowledge about the course and profile of cognitive function after KT.

Methodological challenges and biases in the field of cognitive function among patients with chronic kidney disease.

Chronic kidney disease (CKD) affects approximately 850 million people globally and is associated with an increased risk of cognitive impairment. The prevalence of cognitive impairment among CKD patients ranges from 30 to 60%, and the link between CKD and cognitive impairment is partially understood. Methodological challenges and biases in studying cognitive function in CKD patients need to be addressed to improve diagnosis, treatment, and management of cognitive impairment in this population. Here, we review the methodological challenges and study design issues, including observational studies' limitations, internal validity, and different types of bias that can impact the validity of research findings. Understanding the unique challenges and biases associated with studying cognitive function in CKD patients can help to identify potential sources of error and improve the quality of future research, leading to more accurate diagnoses and better treatment plans for CKD patients.

Free-Circulating Nucleic Acids as Biomarkers in Patients After Solid Organ Transplantation.

A number types of extracellular DNA (eg, cell-free, cfDNA) circulate in human blood, including mitochondrial, transcriptome, and regulatory DNA, usually at low concentrations. Larger amounts of cfDNA appear in any inflammatory condition, including organ damage due to a variety of reasons. The role of cfDNA in solid organ transplantation is discussed in this review as a valuable additional tool in the standard of care of transplant patients. Post-transplant monitoring requires the use of high-quality biomarkers for early detection of graft damage or rejection to be able to apply early therapeutic intervention. CfDNA complements the traditional monitoring strategies, being a risk stratification tool and an important prognostic marker. However, improving the sensitivity and specificity of cfDNA detection is necessary to facilitate personalized patient management, warranting further research in terms of measurement, test standardization, and storage, processing, and shipping. A diagnostic test (Allosure, CareDx, Inc., Brisbane, CA) for kidney, heart and lung transplant patients is now commercially available, and validation for other organs (eg, liver) is pending. To date, donor-derived cfDNA in combination with other biomarkers appears to be a promising tool in graft rejection as it is minimally invasive, time-sensitive, and cost-effective. However, improvement of sensitivity and specificity is required to facilitate personalized patient management. Whether it could be an alternate to graft biopsy remains unclear.

Iron status and anemia control are related to peritoneal membrane properties in peritoneally dialyzed patients.

Background: Characteristics of peritoneal membrane is unique and individually different in peritoneal dialysis patients. Relationship between specific nature of peritoneal transport, anemia and inflammation has not yet been extensively studied. We attempted to outline the complex interplay of several biomarkers of iron status and their association with peritoneal transport, degree of inflammation and residual renal function. Methods: A total of 58 patients treated with peritoneal dialysis either CAPD or APD for at least 3 months were enrolled in this study. Full blood count, traditional markers of iron status (transferrin saturation-TSAT and ferritin), serum erythroferrone-ERFE, soluble transferrin receptor (sTfR), hepcidin, zonulin, growth differentiation factor -15 (GDF15), IL-16, hsCRP and hypoxia-inducible factor-α (HIF-1-α; in serum and dialysate) were measured using commercially available tests. We also performed Peritoneal Equilibrium Test and assessed GFR level. Results: Hb levels above 10 g/dL was found in 74% of patients. Hb levels positively correlated with residual renal function and nutritional status. Adequate iron status was diagnosed in 69% of subjects, only in 9% of patients, criteria for absolute iron deficiency were met. Serum ERFE correlated inversely with hepcidin levels but was not associated with erythropoietin stimulating agent dose. Peritoneal transport had strong correlation with dialysate sTfR (p < 0.05), dialysate hepcidin (p < 0.05), dialysate GDF15 (p < 0.01) and dialysate zonulin (p < 0.001) levels, as well as serum IL6 (p = 0.03), serum hs-CRP (p = 0.04) and dialysate hs-CRP (p = 0.04). Conclusion: Residual kidney function contributes considerably to better control of anemia. Various degree of inflammation is inherent to PD patients. Additionally, fast-average peritoneal transport is associated with greater degree of inflammation and higher concentration of markers of iron status, GDF15 and zonulin in dialysate. This finding may indicate more effective clearance of higher-range middle molecules in fast-average transporters. The role of ERFE as a marker of erythropoiesis in PD patients requires further investigation.