COVID-19 and cardiovascular disease in patients with chronic kidney disease.

Millions of people worldwide have chronic kidney disease (CKD). Affected patients are at high risk for cardiovascular (CV) disease for several reasons. Among various comorbidities, CKD is associated with the more severe forms of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. This is particularly true for patients receiving dialysis or for kidney recipients. From the start of the SARS-CoV-2 pandemic, several CV complications have been observed in affected subjects, spanning acute inflammatory manifestations, CV events, thrombotic episodes and arrythmias. Several pathogenetic mechanisms have been hypothesized, including direct cytopathic viral effects on the myocardium, endothelial damage and hypercoagulability. This spectrum of disease can occur during the acute phase of the infection, but also months after recovery. This review is focussed on the CV complications of coronavirus disease 2019 (COVID-19) with particular interest in their implications for the CKD population.

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.

Iron biology.

Iron is a fundamental element for biological life, starting from bacteria till humans. Iron is essential for cell function and survival, energy production and metabolism, whereas increased levels cause oxidative stress. It is also a constituent of haemoglobin and thus it is necessary for oxygen transportation through the body. Given these multiple functions, the regulation of iron metabolism is complex and tight coupled with oxygen homeostasis at tissue and cellular levels, thanks to the interaction with the hypoxia inducible factor (HIF) system. In patients with chronic kidney disease (CKD), iron deficiency significantly contributes to anaemia development. This frequently overlaps with chronic inflammation, causing iron- restricted erythropoiesis. To add further complexity, metabolic hyperferritinemia may, on one side, increase the risk for CKD and, on the other, overlaps with functional iron deficiency. Excessive intracellular iron in certain cell types during CKD can also mediate cellular death (called ferroptosis), and contribute to the pathogenesis of kidney damage, atherosclerosis and vascular calcifications. This review is aimed at broadening the perspective of iron metabolism in the setting of CKD not just as a contributor to anaemia in CKD patients, but also as an important player with an impact on cell metabolism, renal fibrosis, and the cardiovascular system.

Quality of life: a crucial aspect for the patients, a neglected goal in the treatment of anemia in patients with CKD.

The aim of any treatment should be to add life to years and not simply years to life. Surprisingly, the label of erythropoiesis-stimulating agents for anemia treatment in chronic kidney disease does not include the indication for improving quality of life. Merit of the placebo-controlled Anemia Studies in Chronic Kidney Disease (CKD): Erythropoiesis Via a Novel Prolyl Hydroxylase Inhibitor (PHI) Daprodustat in Non-Dialysis Subjects Evaluating Hemoglobin (Hgb) and Quality of Life (ASCEND-NHQ) trial was to address this issue by analyzing the effect of anemia treatment with daprodustat aimed at the hemoglobin target range of 11-12 g/dl; the trial demonstrates that partial anemia correction improved quality of life.

Novel anemia therapies in chronic kidney disease: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference.

Anemia is common in patients with chronic kidney disease and is associated with a high burden of morbidity and adverse clinical outcomes. In 2012, Kidney Disease: Improving Global Outcomes (KDIGO) published a guideline for the diagnosis and management of anemia in chronic kidney disease. Since then, new data from studies assessing established and emerging therapies for the treatment of anemia and iron deficiency have become available. Beginning in 2019, KDIGO planned 2 Controversies Conferences to review the new evidence and its potential impact on the management of anemia in clinical practice. Here, we report on the second of these conferences held virtually in December 2021, which focused on a new class of agents-the hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHIs). This report provides a review of the consensus points and controversies from this second conference and highlights areas that warrant prioritization for future research.

SGLT2i for evidence-based cardiorenal protection in diabetic and non-diabetic chronic kidney disease: a comprehensive review by EURECA-m and ERBP working groups of ERA.

Chronic kidney disease (CKD) is a major public health issue affecting an estimated 850 million people globally. The leading causes of CKD is diabetes and hypertension, which together account for >50% of patients with end-stage kidney disease. Progressive CKD leads to the requirement for kidney replacement therapy with transplantation or dialysis. In addition, CKD, is a risk factor for premature cardiovascular disease, particularly from structural heart disease and heart failure (HF). Until 2015, the mainstay of treatment to slow progression of both diabetic and many non-diabetic kidney diseases was blood pressure control and renin-angiotensin system inhibition; however, neither angiotensin-converting enzyme inhibitors (ACEIs) nor angiotensin receptor blockers (ARBs) reduced cardiovascular events and mortality in major trials in CKD. The emergence of cardiovascular and renal benefits observed with sodium-glucose cotransporter-2 inhibitors (SGLT2i) from clinical trials of their use as anti-hyperglycaemic agents has led to a revolution in cardiorenal protection for patients with diabetes. Subsequent clinical trials, notably DAPA-HF, EMPEROR, CREDENCE, DAPA-CKD and EMPA-KIDNEY have demonstrated their benefits in reducing risk of HF and progression to kidney failure in patients with HF and/or CKD. The cardiorenal benefits-on a relative scale-appear similar in patients with or without diabetes. Specialty societies' guidelines are continually adapting as trial data emerges to support increasingly wide use of SGLT2i. This consensus paper from EURECA-m and ERBP highlights the latest evidence and summarizes the guidelines for use of SGLT2i for cardiorenal protection focusing on benefits observed relevant to people with CKD.

Mineralocorticoid receptor antagonists for nephroprotection and cardioprotection in patients with diabetes mellitus and chronic kidney disease.

Diabetic kidney disease (DKD) develops in ∼40% of patients with diabetes and is the most common cause of chronic kidney disease (CKD) worldwide. Patients with CKD, especially those with diabetes mellitus, are at high risk of both developing kidney failure and cardiovascular (CV) death. The use of renin-angiotensin system (RAS) blockers to reduce the incidence of kidney failure in patients with DKD dates back to studies that are now ≥20 years old. During the last few years, sodium-glucose co-transporter-2 inhibitors (SGLT2is) have shown beneficial renal effects in randomized trials. However, even in response to combined treatment with RAS blockers and SGLT2is, the renal residual risk remains high with kidney failure only deferred, but not avoided. The risk of CV death also remains high even with optimal current treatment. Steroidal mineralocorticoid receptor antagonists (MRAs) reduce albuminuria and surrogate markers of CV disease in patients already on optimal therapy. However, their use has been curtailed by the significant risk of hyperkalaemia. In the FInerenone in reducing kiDnEy faiLure and dIsease prOgression in DKD (FIDELIO-DKD) study comparing the actions of the non-steroidal MRA finerenone with placebo, finerenone reduced the progression of DKD and the incidence of CV events, with a relatively safe adverse event profile. This document presents in detail the available evidence on the cardioprotective and nephroprotective effects of MRAs, analyses the potential mechanisms involved and discusses their potential future place in the treatment of patients with diabetic CKD.

Hypoxia-Inducible Factor-Prolyl Hydroxyl Domain Inhibitors: From Theoretical Superiority to Clinical Noninferiority Compared with Current ESAs?

Anemia is a common complication of chronic kidney disease; it is mainly treated with erythropoiesis-stimulating agents (ESAs) and iron. Experimental studies extensively investigated the mechanisms involved in the body's response to hypoxia and led to the discovery of the hypoxia-inducible factor (HIF) pathway and the enzymes regulating its function. HIF-prolyl-hydroxyl domain (PHD) inhibitors are a new class of oral drugs developed to treat anemia in chronic kidney disease. By inhibiting the function of PHD enzymes, they mimic the exposure to moderate hypoxia and stimulate the production of endogenous erythropoietin and very likely increase iron availability. Some data also suggest that their efficacy and, consequently, dose needs are less influenced by inflammation than ESAs. Overall, data from phases 2 and 3 clinical development showed efficacy in anemia correction and maintenance for all of the class molecules compared with placebo (superiority) or erythropoiesis-stimulating agents (noninferiority). Three molecules, roxadustat, vadadustat, and daprodustat, underwent extensive clinical investigation to assess their safety on hard cardiovascular end points, mortality, and special interest events (including cancer and thrombosis). Aside from vadadustat in the nondialysis population, at the prespecified primary analyses, all three molecules met the noninferiority margin for the risk of major cardiovascular events compared with erythropoiesis-stimulating agents or placebo. The reason for this discrepancy is difficult to explain. Other safety signals came from secondary analyses of some of the other randomized clinical trials, including a higher incidence of thrombosis. A more extensive clinical experience with post-marketing data on hard safety issues is needed to define better when and how to use HIF-PHD inhibitors compared with already available ESAs.

Are all erythropoiesis-stimulating agents created equal?

Erythropoiesis-stimulating agents (ESAs) are effective drugs to correct and maintain haemoglobin (Hb) levels, however, their use at doses to reach high Hb targets has been associated with an increased risk of cardiovascular adverse events, mortality and cancer. Presently used ESAs have a common mechanism of action but different pharmacokinetic and pharmacodynamic characteristics. Accordingly, the mode of activation of the erythropoietin (EPO) receptor can exert marked differences in downstream events. It is unknown whether the various ESA molecules have different efficacy/safety profiles. The relative mortality and morbidity risks associated with the use of different types of ESAs remains poorly evaluated. Recently an observational study and a randomized clinical trial provided conflicting results regarding this matter. However, these two studies displayed several differences in patient characteristics and ESA molecules used. More importantly, by definition, randomized clinical trials avoid bias by indication and suffer less from confounding factors. Therefore they bring a higher degree of evidence. The scenario becomes even more complex when considering the new class of ESAs, called prolyl-hydroxylase domain (PHD) inhibitors. They are oral drugs that mimic exposure to hypoxia and stabilize hypoxia-inducible factor α. They profoundly differ from presently used ESAs, as they have multiple targets of action, including the stimulation of endogenous EPO synthesis, direct mobilization/absorption of iron and a higher reduction of hepcidin. Accordingly, they have the potential to be more effective in inflamed patients with functional iron deficiency, i.e. the setting of patients who are at higher risk of cardiovascular events and mortality in response to present ESA use. As for ESAs, individual PHD inhibitors differ in molecular structure and degree of selectivity for the three main PHD isoforms; their efficacy and safety profiles may therefore be different from that of presently available ESAs.

The evolution of the therapeutic approach to membranous nephropathy.

Primary membranous nephropathy (MN) is a frequent cause of nephrotic syndrome (NS) in adults. In untreated patients, the outcome is variable, with one-third of the patients entering remission while the remaining ones show persisting proteinuria or progression to end-stage renal disease. Randomized clinical trials reported the efficacy of a 6-month regimen alternating intravenous and oral glucocorticoids with an alkylating agent every other month. The potential side effects of this regimen were limited by the fact that the use of glucocorticoids and alkylating agent did not exceed 3 months each. Two randomized trials with follow-ups (FU) up to 10 years provided assurance about the long-term efficacy and safety of this cyclical therapy. Calcineurin inhibitors have also been used successfully. However, in most responders, NS relapsed after the drug was withdrawn. Conflicting results have been reported with mycophenolate salts and adrenocorticotropic hormone. Observational studies reported good results with rituximab (RTX). Two controlled trials demonstrated the superiority of RTX over antiproteinuric therapy alone and cyclosporine. However, the FUs were relatively short and no randomized trial has been published against cyclical therapy. The available results, together with the discovery that most patients with MN have circulating antibodies against the phospholipase A2 receptor 1, support the use of cytotoxic drugs or RTX in MN. It is difficult to choose between these two different treatments. RTX is easier to use, but the FUs of the available studies are short, thus doubts remain about the long-term risk of relapses and the safety of repeated administrations of RTX.

Types of erythropoiesis-stimulating agents and risk of end-stage kidney disease and death in patients with non-dialysis chronic kidney disease.

BACKGROUND: Despite the widespread use of erythropoiesis-stimulating agents (ESAs) to treat anaemia, the risk of adverse outcomes associated with the use of different types of ESAs in non-dialysis chronic kidney disease (CKD) is poorly investigated. METHODS: From a pooled cohort of four observational studies, we selected CKD patients receiving short-acting (epoetin α/ß; n = 299) or long-acting ESAs (darbepoetin and methoxy polyethylene glycol-epoetin ß; n = 403). The primary composite endpoint was end-stage kidney disease (ESKD; dialysis or transplantation) or all-cause death. Multivariable Cox models were used to estimate the relative risk of the primary endpoint between short- and long-acting ESA users. RESULTS: During follow-up [median 3.6 years (interquartile range 2.1-6.3)], the primary endpoint was registered in 401 patients [166 (72%) in the short-acting ESA group and 235 (58%) in the long-acting ESA group]. In the highest tertile of short-acting ESA dose, the adjusted risk of primary endpoint was 2-fold higher {hazard ratio [HR] 2.07 [95% confidence interval (CI) 1.37-3.12]} than in the lowest tertile, whereas it did not change across tertiles of dose for long-acting ESA patients. Furthermore, the comparison of ESA type in each tertile of ESA dose disclosed a significant difference only in the highest tertile, where the risk of the primary endpoint was significantly higher in patients receiving short-acting ESAs [HR 1.56 (95% CI 1.09-2.24); P = 0.016]. Results were confirmed when ESA dose was analysed as continuous variable with a significant difference in the primary endpoint between short- and long-acting ESAs for doses >105 IU/kg/week. CONCLUSIONS: Among non-dialysis CKD patients, the use of a short-acting ESA may be associated with an increased risk of ESKD or death versus long-acting ESAs when higher ESA doses are prescribed.

Are prolyl-hydroxylase inhibitors potential alternative treatments for anaemia in patients with chronic kidney disease?

Prolyl-hydroxylase (PHD) inhibitors (PHD-I) are the most appealing drugs undergoing clinical development for the treatment of anaemia in patients with chronic kidney disease. PHD inhibition mimics the exposure of the body to hypoxia and activates the hypoxia-inducible factor system. Among many other pathways, this activation promotes the production of endogenous erythropoietin (EPO) and the absorption and mobilization of iron. PHD-I are given orally and, differing from erythropoiesis-stimulating agents (ESAs), they correct and maintain haemoglobin levels by stimulating endogenous EPO production. Their efficacy and safety are supported by several Phases I and II studies with relatively short follow-up. This class of drugs has the potential to have a better safety profile than ESAs and there may be additional advantages for cardiovascular disease (CVD), osteoporosis and metabolism. However, possible adverse outcomes are feared. These span from the worsening or occurrence of new cancer, to eye complications or pulmonary hypertension. The data from the ongoing Phase III studies are awaited to better clarify the long-term safety and possible advantages of PHD-I.

New agents to reduce cholesterol levels: implications for nephrologists.

Statins and ezetimibe effectively reduce the burden of cardiovascular (CV) disease in patients with chronic kidney disease (CKD). Unfortunately, many subjects still die or have CV events despite cholesterol-lowering therapy. This is particularly true in patients with more advanced CKD. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease that induces the degradation of the low-density lipoprotein receptor by targeting it for lysosomal destruction. Its inhibition causes a dramatic fall in cholesterol levels on top of maximized statin therapy. This goal is obtained with different therapeutic approaches, spanning from monoclonal antibodies to non sense oligonucleotides and silencing RNA (siRNA). Two human, monoclonal antibodies are approved for clinical use; they are still very expensive. Both agents significantly lower cholesterol levels. Evolocumab and alirocumab reduce significantly the risk for CV disease without relevant safety issues. Inclisiran is an siRNA molecule that produces PCSK9-specific RNA silencing. Data from a Phase II study showed significant cholesterol-lowering efficacy. The experience accumulated so far is limited in the CKD population. PCSK9 inhibition also has the potential to reduce the burden of CV in this subset by obtaining a much greater decrease in serum cholesterol compared with statin therapy or ezetimibe. Doubts exist that this approach will improve the outcome of dialysis patients, in whom vascular calcifications predominate.

Reclassification of chronic kidney disease patients for end-stage renal disease risk by proteinuria indexed to estimated glomerular filtration rate: multicentre prospective study in nephrology clinics.

BACKGROUND: In non-dialysis chronic kidney disease (CKD), absolute proteinuria (Uprot) depends on the extent of kidney damage and residual glomerular filtration rate (GFR). We therefore evaluated, as compared with Uprot, the strength of association of proteinuria indexed to estimated GFR (eGFR) with end-stage renal disease (ESRD) risk. METHODS: In a multi-cohort prospective study in 3957 CKD patients of Stages G3-G5 referred to nephrology clinics, we tested two multivariable Cox models for ESRD risk, with either Uprot (g/24 h) or filtration-adjusted proteinuria (F-Uprot) calculated as Uprot/eGFR ×100. RESULTS: Mean ± SD age was 67 ± 14 years, males 60%, diabetics 29%, cardiovascular disease (CVD) 34%, eGFR 32 ± 13 mL/min/1.73 m2, median (interquartile range) Uprot 0.41 (0.12-1.29) g/24 h and F-Uprot 1.41 (0.36-4.93) g/24 h per 100 mL/min/1.73 m2 eGFR. Over a median follow-up of 44 months, 862 patients reached ESRD. At competing risk analysis, ESRD risk progressively increased when F-Uprot was 1.0-4.9 and ≥5.0 versus <1.0 g/24 h per 100 mL/min/1.73 m2 eGFR in Stages G3a-G4 (P < 0.001) and Stage G5 (P = 0.002). Multivariable Cox analysis showed that Uprot predicts ESRD in Stages G3a-G4 while in G5 the effect was not significant; conversely, F-Uprot significantly predicted ESRD at all stages. The F-Uprot model allowed a significantly better prediction versus the Uprot model according to Akaike information criterion. Net reclassification improvement was 12.2% (95% confidence interval 4.2-21.1), with higher reclassification in elderly, diabetes and CVD, as well as in diabetic nephropathy and glomerulonephritis, and in CKD Stages G4 and G5. CONCLUSIONS: In patients referred to nephrology clinics, F-Uprot predicts ESRD at all stages of overt CKD and improves, as compared with Uprot, reclassification of patients for renal risk, especially in more advanced and complicated disease.

Is there long-term value of pathology scoring in immunoglobulin A nephropathy? A validation study of the Oxford Classification for IgA Nephropathy (VALIGA) update.

BACKGROUND: It is unknown whether renal pathology lesions in immunoglobulin A nephropathy (IgAN) correlate with renal outcomes over decades of follow-up. METHODS: In 1130 patients of the original Validation Study of the Oxford Classification for IgA Nephropathy (VALIGA) cohort, we studied the relationship between the MEST score (mesangial hypercellularity, M; endocapillary hypercellularity, E; segmental glomerulosclerosis, S; tubular atrophy/interstitial fibrosis, T), crescents (C) and other histological lesions with both a combined renal endpoint [50% estimated glomerular filtration rate (eGFR) loss or kidney failure] and the rate of eGFR decline over a follow-up period extending to 35 years [median 7 years (interquartile range 4.1-10.8)]. RESULTS: In this extended analysis, M1, S1 and T1-T2 lesions as well as the whole MEST score were independently related with the combined endpoint (P < 0.01), and there was no effect modification by age for these associations, suggesting that they may be valid in children and in adults as well. Only T lesions were associated with the rate of eGFR loss in the whole cohort, whereas C showed this association only in patients not treated with immunosuppression. In separate prognostic analyses, the whole set of pathology lesions provided a gain in discrimination power over the clinical variables alone, which was similar at 5 years (+2.0%) and for the whole follow-up (+1.8%). A similar benefit was observed for risk reclassification analyses (+2.7% and +2.4%). CONCLUSION: Long-term follow-up analyses of the VALIGA cohort showed that the independent relationship between kidney biopsy findings and the risk of progression towards kidney failure in IgAN remains unchanged across all age groups and decades after the renal biopsy.

Performance of GFR Slope as a Surrogate End Point for Kidney Disease Progression in Clinical Trials: A Statistical Simulation.

BACKGROUND: Randomized trials of CKD treatments traditionally use clinical events late in CKD progression as end points. This requires costly studies with large sample sizes and long follow-up. Surrogate end points like GFR slope may speed up the evaluation of new therapies by enabling smaller studies with shorter follow-up. METHODS: We used statistical simulations to identify trial situations where GFR slope provides increased statistical power compared with the clinical end point of doubling of serum creatinine or kidney failure. We simulated GFR trajectories based on data from 47 randomized treatment comparisons. We evaluated the sample size required for adequate statistical power based on GFR slopes calculated from baseline and from 3 months follow-up. RESULTS: In most scenarios where the treatment has no acute effect, analyses of GFR slope provided similar or improved statistical power compared with the clinical end point, often allowing investigators to shorten follow-up by at least half while simultaneously reducing sample size. When patients' GFRs are higher, the power advantages of GFR slope increase. However, acute treatment effects within several months of randomization can increase the risk of false conclusions about therapies based on GFR slope. Care is needed in study design and analysis to avoid such false conclusions. CONCLUSIONS: Use of GFR slope can substantially increase statistical power compared with the clinical end point, particularly when baseline GFR is high and there is no acute effect. The optimum GFR-based end point depends on multiple factors including the rate of GFR decline, type of treatment effect and study design.

Targeted-release budesonide versus placebo in patients with IgA nephropathy (NEFIGAN): a double-blind, randomised, placebo-controlled phase 2b trial.

BACKGROUND: IgA nephropathy is thought to be associated with mucosal immune system dysfunction, which manifests as renal IgA deposition that leads to impairment and end-stage renal disease in 20-40% of patients within 10-20 years. In this trial (NEFIGAN) we aimed to assess safety and efficacy of a novel targeted-release formulation of budesonide (TRF-budesonide), designed to deliver the drug to the distal ileum in patients with IgA nephropathy. METHODS: We did a randomised, double-blind, placebo-controlled phase 2b trial, comprised of 6-month run-in, 9-month treatment, and 3-month follow-up phases at 62 nephrology clinics across ten European countries. We recruited patients aged at least 18 years with biopsy-confirmed primary IgA nephropathy and persistent proteinuria despite optimised renin-angiotensin system (RAS) blockade. We randomly allocated patients with a computer algorithm, with a fixed block size of three, in a 1:1:1 ratio to 16 mg/day TRF-budesonide, 8 mg/day TRF-budesonide, or placebo, stratified by baseline urine protein creatinine ratio (UPCR). Patients self-administered masked capsules, once daily, 1 h before breakfast during the treatment phase. All patients continued optimised RAS blockade treatment throughout the trial. Our primary outcome was mean change from baseline in UPCR for the 9-month treatment phase, which was assessed in the full analysis set, defined as all randomised patients who took at least one dose of trial medication and had at least one post-dose efficacy measurement. Safety was assessed in all patients who received the intervention. This trial is registered with ClinicalTrials.gov, number NCT01738035. FINDINGS: Between Dec 11, 2012, and June 25, 2015, 150 randomised patients were treated (safety set) and 149 patients were eligible for the full analysis set. Overall, at 9 months TRF-budesonide (16 mg/day plus 8 mg/day) was associated with a 24·4% (SEM 7·7%) decrease from baseline in mean UPCR (change in UPCR vs placebo 0·74; 95% CI 0·59-0·94; p=0·0066). At 9 months, mean UPCR had decreased by 27·3% in 48 patients who received 16 mg/day (0·71; 0·53-0·94; p=0·0092) and 21·5% in the 51 patients who received 8 mg/day (0·76; 0·58-1·01; p=0·0290); 50 patients who received placebo had an increase in mean UPCR of 2·7%. The effect was sustained throughout followup. Incidence of adverse events was similar in all groups (43 [88%] of 49 in the TRF-budesonide 16 mg/day group, 48 [94%] of 51 in the TRF-budesonide 8 mg/day, and 42 [84%] of 50 controls). Two of 13 serious adverse events were possibly associated with TRF-budesonide-deep vein thrombosis (16 mg/day) and unexplained deterioration in renal function in follow-up (patients were tapered from 16 mg/day to 8 mg/day over 2 weeks and follow-up was assessed 4 weeks later). INTERPRETATION: TRF-budesonide 16 mg/day, added to optimised RAS blockade, reduced proteinuria in patients with IgA nephropathy. This effect is indicative of a reduced risk of future progression to end-stage renal disease. TRF-budesonide could become the first specific treatment for IgA nephropathy targeting intestinal mucosal immunity upstream of disease manifestation. FUNDING: Pharmalink AB.

Will there still be a role for the originator erythropoiesis-simulating agents after the biosimilars and the hypoxia-inducible factor stabilizers approval?

PURPOSE OF REVIEW: To discuss if there will still be a role for the originator ESAs after the already available biosimilars and the approval of HIF stabilizers in the near future. RECENT FINDINGS: Current treatment with erythropoiesis-simulating agents (ESAs) is effective and generally well tolerated, but requires parenteral injections. It is also surrounded by safety concerns and is still expensive. Functional iron deficiency is the major obstacle for efficient ESA therapy. ESA resistance may develop, calling for high ESA doses, further increasing the side effects associated with ESA use. Biosimilars were introduced for reducing costs. In searching for an ideal antianemic drug, new investigational strategies have been proposed including the attractive alternative hypoxia-inducible factor (HIF) stabilizers, which stimulate endogenous EPO production. However, we should caution in translating the historical results referring to the side effects of ESAs to current clinical practice, considering that hemoglobin targets and ESAs doses are now much lower. We could anticipate that side effects will be much less. SUMMARY: According to preliminary data, orally administered HIF stabilizers could provide pharmacological advantages over the existing ESAs. These will need confirmation by the findings of large, phase-3, clinical trials. Finally, cost will be an important issue determining their future use.

Haemodialysis or haemodiafiltration: that is the question.

Despite the technological and pharmacological advancements in the last 30 years, morbidity and mortality of dialysis patients are still astonishingly high. Today, convective treatments, such as high-flux haemodialysis (hf-HD) and haemodiafiltration (HDF), are established techniques; the online production of fresh pure dialysate has provided clinical and economic advantages. Nevertheless, the actual benefits of HDF, even with high-convective-volume treatments, are still debatable. Three recent, randomized controlled trials compared survival outcomes in prevalent patients receiving conventional HD or post-dilution HDF and reported conflicting results. The meta-analyses of the published trials were ultimately incapable of providing a clear and definitive answer on the possible beneficial effects of choosing one treatment over the other. All-cause mortality, anaemia, phosphate control and clearance of small molecules seemed to be unaffected by the treatment modality. On the other hand, cardiovascular mortality, intradialytic vascular stability and the clearance of protein-bound molecules fared better in patients treated with HDF. These results were not consistent between the studies. Thus, there is still no conclusive answer to the question that nephrologists would like to have answered: 'Which is the best treatment for my patient?' In the age of evidence-based medicine, we need strong data to support the superiority of a treatment in comparison with another, although theoretically plausible. There is the need for a well-designed clinical trial comparing outcomes for patients randomly assigned to high- or moderate-convection-volume HDF versus hf-HD to clearly prove the clinical superiority of HDF, including the effect of different infusion volumes.