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.

Chronic kidney disease and the global public health agenda: an international consensus.

Early detection is a key strategy to prevent kidney disease, its progression and related complications, but numerous studies show that awareness of kidney disease at the population level is low. Therefore, increasing knowledge and implementing sustainable solutions for early detection of kidney disease are public health priorities. Economic and epidemiological data underscore why kidney disease should be placed on the global public health agenda - kidney disease prevalence is increasing globally and it is now the seventh leading risk factor for mortality worldwide. Moreover, demographic trends, the obesity epidemic and the sequelae of climate change are all likely to increase kidney disease prevalence further, with serious implications for survival, quality of life and health care spending worldwide. Importantly, the burden of kidney disease is highest among historically disadvantaged populations that often have limited access to optimal kidney disease therapies, which greatly contributes to current socioeconomic disparities in health outcomes. This joint statement from the International Society of Nephrology, European Renal Association and American Society of Nephrology, supported by three other regional nephrology societies, advocates for the inclusion of kidney disease in the current WHO statement on major non-communicable disease drivers of premature mortality.

Butyrate promotes kidney resilience through a coordinated kidney protective response in tubular cells.

Acute kidney injury (AKI) is common in hospitalized patients and increases short-term and long-term mortality. Treatment options for AKI are limited. Gut microbiota products such as the short-chain fatty acid butyrate have anti-inflammatory actions that may protect tissues, including the kidney, from injury. However, the molecular mechanisms of tissue protection by butyrate are poorly understood. Treatment with oral butyrate for two weeks prior to folic acid-induced AKI and during AKI improved kidney function and decreased tubular injury and kidney inflammation while stopping butyrate before AKI was not protective. Continuous butyrate preserved the expression of kidney protective factors such as Klotho, PGC-1α and Nlrp6 which were otherwise downregulated. In cultured tubular cells, butyrate blunted the maladaptive tubular cell response to a proinflammatory milieu, preserving the expression of kidney protective factors. Kidney protection afforded by this continuous butyrate schedule was confirmed in a second model of nephrotoxic AKI, cisplatin nephrotoxicity, where the expression of kidney protective factors was also preserved. To assess the contribution of preservation of kidney protective factors to kidney resilience, recombinant Klotho was administered to mice with cisplatin-AKI and shown to preserve the expression of PGC-1α and Nlrp6, decrease kidney inflammation and protect from AKI. In conclusion, butyrate promotes kidney resilience to AKI and decreases inflammation by preventing the downregulation of kidney protective genes such as Klotho. This information may be relevant to optimize antibiotic management during hospitalization.

The ERA Registry Annual Report 2021: a summary.

Background: The European Renal Association (ERA) Registry collects data on kidney replacement therapy (KRT) in patients with end-stage kidney disease (ESKD). This paper is a summary of the ERA Registry Annual Report 2021, including a comparison across treatment modalities. Methods: Data was collected from 54 national and regional registries from 36 countries, of which 35 registries from 18 countries contributed individual patient data and 19 registries from 19 countries contributed aggregated data. Using this data, incidence and prevalence of KRT, kidney transplantation rates, survival probabilities and expected remaining lifetimes were calculated. Result: In 2021, 533.2 million people in the general population were covered by the ERA Registry. The incidence of KRT was 145 per million population (pmp). In incident patients, 55% were 65 years or older, 64% were male, and the most common primary renal disease (PRD) was diabetes (22%). The prevalence of KRT was 1040 pmp. In prevalent patients, 47% were 65 years or older, 62% were male, and the most common PRDs were diabetes and glomerulonephritis/sclerosis (both 16%). On 31 December 2021, 56% of patients received haemodialysis, 5% received peritoneal dialysis, and 39% were living with a functioning graft. The kidney transplantation rate in 2021 was 37 pmp, a majority coming from deceased donors (66%). For patients initiating KRT between 2012-2016, 5-year survival probability was 52%. Compared to the general population, life expectancy was 65% and 68% shorter for males and females receiving dialysis, and 40% and 43% shorter for males and females living with a functioning graft.

Sex disparities in mortality and cardiovascular outcomes in chronic kidney disease.

Sex (biologically determined) and gender (socially constructed) modulate manifestations and prognosis of a vast number of diseases, including cardiovascular disease (CVD) and chronic kidney disease (CKD). CVD remains the leading cause of death in CKD patients. Population-based studies indicate that women present a higher prevalence of CKD and experience less CVD than men in all CKD stages, although this is not as clear in patients on dialysis or transplantation. When compared to the general population of the same sex, CKD has a more negative impact on women on kidney replacement therapy. European women on dialysis or recipients of kidney transplants have life expectancy up to 44.8 and 19.8 years lower, respectively, than their counterparts of similar age in the general population. For men, these figures stand at 37.1 and 16.5 years, representing a 21% to 20% difference, respectively. Hormonal, genetic, societal, and cultural influences may contribute to these sex-based disparities. To gain a more comprehensive understanding of these differences and their implications for patient care, well-designed clinical trials that involve a larger representation of women and focus on sex-related variables are urgently needed. This narrative review emphasizes the importance of acknowledging the epidemiology and prognosis of sex disparities in CVD among CKD patients. Such insights can guide research into the underlying pathophysiological mechanisms, leading to optimized treatment strategies and ultimately, improved clinical outcomes.

The role of anticomplement therapy in the management of the kidney allograft.

As the number of patients living with kidney failure grows, the need also grows for kidney transplantation, the gold standard kidney replacement therapy that provides a survival advantage. This may result in an increased rate of transplantation from HLA-mismatched donors that increases the rate of antibody-mediated rejection (AMR), which already is the leading cause of allograft failure. Plasmapheresis, intravenous immunoglobulin therapy, anti-CD20 therapies (i.e., rituximab), bortezomib and splenectomy have been used over the years to treat AMR as well as to prevent AMR in high-risk sensitized kidney transplant recipients. Eculizumab and ravulizumab are monoclonal antibodies targeting the C5 protein of the complement pathway and part of the expanding field of anticomplement therapies, which is not limited to kidney transplant recipients, and also includes complement-mediated microangiopathic hemolytic anemia, paroxysmal nocturnal hemoglobinuria, and ANCA-vasculitis. In this narrative review, we summarize the current knowledge concerning the pathophysiological background and use of anti-C5 strategies (eculizumab and ravulizumab) and C1-esterase inhibitor in AMR, either to prevent AMR in high-risk desensitized patients or to treat AMR as first-line or rescue therapy and also to treat de novo thrombotic microangiopathy in kidney transplant recipients.

Treatment of Chronic Heart Failure in Advanced Chronic Kidney Disease: The HAKA Multicenter Retrospective Real-World Study.

INTRODUCTION: Chronic heart failure (HF) has high rates of mortality and hospitalization in patients with advanced chronic kidney disease (aCKD). However, randomized clinical trials have systematically excluded aCKD population. We have investigated current HF therapy in patients receiving clinical care in specialized aCKD units. METHODS: The Heart And Kidney Audit (HAKA) was a cross-sectional and retrospective real-world study including outpatients with aCKD and HF from 29 Spanish centers. The objective was to evaluate how the treatment of HF in patients with aCKD complied with the recommendations of the European Society of Cardiology Guidelines for the diagnosis and treatment of HF, especially regarding the foundational drugs: renin-angiotensin system inhibitors (RASi), angiotensin receptor blocker/neprilysin inhibitors (ARNI), beta-blockers (BBs), mineralocorticoid receptor antagonists (MRAs), and sodium-glucose cotransporter-2 inhibitors (SGLT2i). RESULTS: Among 5,012 aCKD patients, 532 (13%) had a diagnosis of HF. Of them, 20% had reduced ejection fraction (HFrEF), 13% mildly reduced EF (HFmrEF), and 67% preserved EF (HFpEF). Only 9.3% of patients with HFrEF were receiving quadruple therapy with RASi/ARNI, BB, MRA, and SGLT2i, but the majority were not on the maximum recommended doses. None of the patients with HFrEF and CKD G5 received quadruple therapy. Among HFmrEF patients, approximately half and two-thirds were receiving RASi and/or BB, respectively, while less than 15% received ARNI, MRA, or SGLT2i. Less than 10% of patients with HFpEF were receiving SGLT2i. CONCLUSIONS: Under real-world conditions, HF in aCKD patients is sub-optimally treated. Increased awareness of current guidelines and pragmatic trials specifically enrolling these patients represent unmet medical needs.

A comparison of the epidemiology of kidney replacement therapy between Europe and the United States: 2021 data of the ERA Registry and the USRDS.

BACKGROUND AND HYPOTHESIS: This paper compares the most recent data on the incidence and prevalence of kidney replacement therapy (KRT), kidney transplantation rates, and mortality on KRT from Europe to those from the United States (US), including comparisons of treatment modalities (haemodialysis (HD), peritoneal dialysis (PD), and kidney transplantation (KTx)). METHODS: Data were derived from the annual reports of the European Renal Association (ERA) Registry and the United States Renal Data System (USRDS). The European data include information from national and regional renal registries providing the ERA Registry with individual patient data. Additional analyses were performed to present results for all participating European countries together. RESULTS: In 2021, the KRT incidence in the US (409.7 per million population (pmp)) was almost 3-fold higher than in Europe (144.4 pmp). Despite the substantial difference in KRT incidence, approximately the same proportion of patients initiated HD (Europe: 82%, US: 84%), PD (14%; 13% respectively), or underwent pre-emptive KTx (4%; 3% respectively). The KRT prevalence in the US (2436.1 pmp) was 2-fold higher than in Europe (1187.8 pmp). Within Europe, approximately half of all prevalent patients were living with a functioning graft (47%), while in the US, this was one third (32%). The number of kidney transplantations performed was almost twice as high in the US (77.0 pmp) compared to Europe (41.6 pmp). The mortality of patients receiving KRT was 1.6-fold higher in the US (157.3 per 1000 patient years) compared to Europe (98.7 per 1000 patient years). CONCLUSIONS: The US had a much higher KRT incidence, prevalence, and mortality compared to Europe, and despite a higher kidney transplantation rate, a lower proportion of prevalent patients with a functioning graft.

The error of estimated GFR in predialysis care.

The error of estimated glomerular filtration rate (eGFR) and its consequences in predialysis are unknown. In this prospective multicentre study, 315 predialysis patients underwent measured GFR (mGFR) by the clearance of iohexol and eGFR by 52 formulas. Agreement between eGFR and mGFR was evaluated by concordance correlation coefficient (CCC), total deviation index (TDI) and coverage probability (CP). In a sub-analysis we assessed the impact of eGFR error on decision-making as (i) initiating dialysis, (ii) preparation for renal replacement therapy (RRT) and (iii) continuing clinical follow-up. For this sub-analysis, patients who started RRT due to clinical indications (uremia, fluid overload, etc.) were excluded. eGFR had scarce precision and accuracy in reflecting mGFR (average CCC 0.6, TDI 70% and cp 22%) both in creatinine- and cystatin-based formulas. Variations -larger than 10 ml/min- between mGFR and eGFR were frequent. The error of formulas would have suggested (a) premature preparation for RTT in 14% of stable patients evaluated by mGFR; (b) to continue clinical follow-up in 59% of subjects with indication for RTT preparation due to low GFRm and (c) to delay dialysis in all asymptomatic patients (n = 6) in whom RRT was indicated based on very low mGFR. The error of formulas in predialysis was frequent and large and may have consequences in clinical care.

Consensus on the approach to hydrosaline overload in acute heart failure. SEMI/SEC/S.E.N. recommendations.

Most of the signs and symptoms of heart failure can be explained by fluid overload, which is also related to disease progression. Fluid overload is a complex phenomenon that extends beyond increased intravascular pressures and poses challenges for accurate diagnosis and effective treatment. Current recommendations advise a multiparametric approach, including clinical data (symptoms/signs), imaging tests, and biomarkers. This article proposes a practical therapeutic approach to managing hydrosaline overload in heart failure in both inpatient and outpatient settings. This document is an initiative of the Spanish Society of Internal Medicine (SEMI) in collaboration with the Spanish Society of Cardiology (SEC) and the Spanish Society of Nephrology (S.E.N.).

Effects of Aerobic Exercise Therapy through Nordic Walking Program in Lactate Concentrations, Fatigue and Quality-of-Life in Patients with Long-COVID Syndrome: A Non-Randomized Parallel Controlled Trial.

BACKGROUND: Long-COVID syndrome comprises a variety of signs and symptoms that develop during or after infection with COVID-19 which may affect the physical capabilities. However, there is a lack of studies investigating the effects of Long-COVID syndrome in sport capabilities after suffering from COVID-19 infection. The purpose of the study was to evaluate and compare lactate concentration and quality of life (QoL) in patients with Long-COVID with those who have not developed non-Long-COVID during Nordic walking exercise therapy. METHODS: Twenty-nine patients (25.5 ± 7.1 years) took part in a non-randomized controlled trial, divided into two groups: a Long-COVID group (n = 16) and a non-Long-COVID control (n = 13). Patients were confirmed as having Long-COVID syndrome if they experienced fatigue or tiredness when performing daily activities and worsening of symptoms after vigorous physical or mental activity. All participants underwent a 12-week Nordic Walking program. Lactate concentration after exercise and distance covered during all sessions were measured. Pre- and Long-Nordic Walking program, the Modified Fatigue Impact Scale (MFIS), the Short Form 36 Health Survey (SF-36), and EURO QoL-5D (EQ-ED) were administered to assess fatigue and quality of life, respectively. RESULTS: There was a lactate concentration effect between groups (F = 5.604; p = 0.024). However, there was no significant effect as a result of the session (F = 3.521; p = 0.121) with no interaction of group × session (F = 1.345; p = 0.414). The group main effect (F = 23.088; p < 0.001), time effect (F = 6.625; p = 0.026), and group × time (F = 4.632; p = 0.002) interaction on the SF-36 scale were noted. Also, there were a significant group main effect (F = 38.372; p < 0.001), time effect (F = 12.424; p = 0.005), and group × time interaction (F = 4.340; p = 0.014) on EQ-5D. However, there was only a significant group main effect (F = 26.235; p < 0.001) with no effect on time (F = 2.265; p = 0.160) and group × time (F = 1.584; p = 0.234) interaction on the MFIS scale. CONCLUSIONS: The Long-COVID group showed higher lactate concentration compared with the control group during the 12 weeks of the Nordic Walking program. The Long-COVID group presented a decrease in fatigue with respect to the control group according to the MFIS scale, as well as improvement in quality of life after aerobic exercise therapy.

RIPK3 and kidney disease / RIPK3 y nefropatía

Receptor interacting protein kinase 3 (RIPK3) is an intracellular kinase at the crossroads of cell death and inflammation. RIPK3 contains a RIP homotypic interaction motif (RHIM) domain which allows interactions with other RHIM-containing proteins and a kinase domain that allows phosphorylation of target proteins. RIPK3 may be activated through interaction with RHIM-containing proteins such as RIPK1, TRIF and DAI (ZBP1, DLM-1) or through RHIM-independent mechanisms in an alkaline intracellular pH. RIPK3 mediates necroptosis and promotes inflammation, independently of necroptosis, through either activation of NFκB or the inflammasome. There is in vivo preclinical evidence of the contribution of RIPK3 to both acute kidney injury (AKI) and chronic kidney disease (CKD) and to the AKI-to-CKD transition derived from RIPK3 deficient mice or the use of small molecule RIPK3 inhibitors. In these studies, RIPK3 targeting decreased inflammation but kidney injury improved only in some contexts. Clinical translation of these findings has been delayed by the potential of some small molecule inhibitors of RIPK3 kinase activity to trigger apoptotic cell death by inducing conformational changes of the protein. A better understanding of the conformational changes in RIPK3 that trigger apoptosis, dual RIPK3/RIPK1 inhibitors or repurposing of multiple kinase inhibitors such as dabrafenib may facilitate clinical development of the RIPK3 inhibition concept for diverse inflammatory diseases, including kidney diseases (AU)

La proteína quinasa 3 que interactúa con el receptor (RIPK3) es una quinasa intracelular que se encuentra a medio camino entre la muerte celular y la inflamación. La RIPK3 contiene un dominio motivo de interacción homotípica de RIP (RHIM), que permite las interacciones con otras proteínas que contienen RHIM, y un dominio de quinasa que permite la fosforilación de las proteínas diana. La RIPK3 puede ser activada a través de la interacción con las proteínas que contienen RHIM tales como RIPK1, TRIF y DAI (ZBP1, DLM-1), o a través de mecanismos independientes de RHIM en un pH intracelular alcalino. La RIPK3 media en la necroptosis y promueve la inflamación, independientemente de la necroptosis, bien a través de la activación de NFκB, o del inflamasoma. Existe evidencia preclínica in vivo de la contribución de RIPK3 a la insuficiencia renal aguda (IRA) y la enfermedad renal crónica (ERC), así como a la transición IRA-ERC derivada de ratones con deficiencia de RIPK3 o del uso de pequeñas moléculas inhibidoras de RIPK3. En dichos estudios, el tener a RIPK3 como objetivo redujo la inflamación, pero la nefropatía mejoró solo en algunos contextos. La traducción clínica de estos hallazgos se ha demorado debido al potencial de ciertas pequeñas moléculas inhibidoras de la actividad de la quinasa RIPK3 para activar la muerte celular induciendo cambios conformacionales de la proteína. Comprender mejor los cambios conformacionales de RIPK3 activadores de la apoptosis, los inhibidores duales RIPK3/RIPK1 o la reconversión de múltiples inhibidores de la quinasa tales como dabrafenib podría facilitar el desarrollo clínico del concepto de la inhibición de RIPK3 para diversas enfermedades inflamatorias, incluyendo las enfermedades renales (AU)

A European Renal Association (ERA) synopsis for nephrology practice of the 2023 European Society of Hypertension (ESH) Guidelines for the Management of Arterial Hypertension.

In June 2023, the European Society of Hypertension (ESH) presented and published the new 2023 ESH Guidelines for the Management of Arterial Hypertension, a document that was endorsed by the European Renal Association (ERA). Following the evolution of evidence in recent years, several novel recommendations relevant to the management of hypertension in patients with chronic kidney disease (CKD) appeared in these Guidelines. These include recommendations for target office BP < 130/80 mmHg in most and against target office BP < 120/70 mmHg in all patients with CKD; recommendations for use of spironolactone or chlortalidone for patients with resistant hypertension with eGFR higher or lower than 30 ml/min/1.73 m2, respectively; use of an SGLT2-inhibitor for patients with CKD and eGFR ≥20 ml/min/1.73 m2; use of finerenone for patients with CKD, type 2 DM, albuminuria, eGFR ≥25 ml/min/1.73 m2 and serum potassium < 5.0 mmol/L; and revascularization in patients with atherosclerotic renovascular disease and secondary hypertension or high-risk phenotypes if stenosis ≥ 70% is present. The present report is a synopsis of sections of the ESH Guidelines that are relevant to the daily clinical practice of nephrologists, prepared by experts of ESH and ERA. The sections summarized are those referring to the role of CKD in hypertension staging and cardiovascular risk stratification, the evaluation of hypertension-mediated kidney damage and the overall management of hypertension in patients with CKD.

Incidence and outcomes of kidney replacement therapy for end-stage kidney disease due to primary glomerular disease in Europe: findings from the ERA Registry.

BACKGROUND AND HYPOTHESIS: Primary glomerular disease (PGD) is a major cause of end-stage kidney disease (ESKD) leading to kidney replacement therapy (KRT). We aimed to describe incidence (trends) in individuals starting KRT for ESKD due to PGD and to examine their survival and causes of death. METHODS: We used data from the European Renal Association (ERA) Registry on 69 854 patients who started KRT for ESKD due to PGD between 2000 and 2019. ERA primary renal disease codes were used to define six PGD subgroups. We examined age and sex standardized incidence, trend of the incidence, and survival. RESULTS: The standardized incidence of KRT for ESKD due to PGD was 16.6 per million population (pmp), ranging from 8.6 pmp in Serbia to 20.0 pmp in France. IgA nephropathy (IgAN) and focal segmental glomerulosclerosis (FSGS) had the highest incidence of 4.6 pmp and 2.6 pmp, respectively. Histologically non-examined PGDs represented over 50% of cases in Serbia, Bosnia and Herzegovina, and Romania and were also common in Greece, Estonia, Belgium, and Sweden. The incidence declined from 18.6 pmp in 2000 to 14.5 pmp in 2013, after which it stabilized. All PGD subgroups had five-year survival probabilities above 50%, with crescentic glomerulonephritis having the highest risk of death (adjusted hazard ratio: 1.8 [95% confidence interval: 1.6-1.9]) compared with IgAN. Cardiovascular disease was the most common cause of death (33.9%). CONCLUSION: The incidence of KRT for ESKD due to PGD showed large differences between countries and was highest and increasing for IgAN and FSGS. Lack of kidney biopsy facilities in some countries may have affected accurate assignment of the cause of ESKD. The recognition of the incidence and outcomes of KRT among different PGD subgroups may contribute to a more individualized patient care approach.

Glomerular hyperfiltration as a therapeutic target for CKD.

The global burden of chronic kidney disease (CKD) is high and increasing. Early diagnosis and intervention are key to improve outcomes. Single nephron glomerular hyperfiltration is an early pathophysiologic manifestation of CKD that may result in absolute glomerular hyperfiltration, i.e. a high glomerular filtration rate (GFR) or be associated with normal or low GFR because of nephron loss (relative glomerular hyperfiltration). Even though compensatory glomerular hyperfiltration may contribute to maintain kidney function after loss of kidney mass, the associated increased glomerular capillary pressure and glomerular and podocyte size drive podocyte loss, albuminuria and proximal tubular overload, contributing to CKD progression. In this regard, all kidney protective drugs in clinical use so far, from renin-angiotensin system blockers to mineralocorticoid receptor blockers to sodium-glucose cotransporter-2 inhibitors to tolvaptan, induced an early dip in glomerular filtration that is thought to represent reversal of hyperfiltration. As glomerular hyperfiltration may be present early in the course of kidney disease, its recognition may provide an effective intervention window that may predates current criteria based on high albuminuria or loss of GFR. Nevertheless, there is no diagnostic method with high sensitivity and specificity to identify single nephron glomerular hyperfiltration, except when it leads to obvious absolute glomerular hyperfiltration, as observed in the early stages of diabetic kidney disease when nephron mass is still preserved. We now review the concept of glomerular hyperfiltration as an indicator of CKD risk, including definitions, challenges in diagnosis and evaluation, underlying pathophysiological mechanisms, potential therapeutic approaches and unanswered questions.