Reduction of protein-bound uraemic toxins in plasma of chronic renal failure patients: A systematic review.

BACKGROUND: Protein-bound uraemic toxins (PBUTs) accumulate in patients with chronic kidney disease and impose detrimental effects on the vascular system. However, a unanimous consensus on the most optimum approach for the reduction of plasma PBUTs is still lacking. METHODS: In this systematic review, we aimed to identify the most efficient clinically available plasma PBUT reduction method reported in the literature between 1980 and 2020. The literature was screened for clinical studies describing approaches to reduce the plasma concentration of known uraemic toxins. There were no limits on the number of patients studied or on the duration or design of the studies. RESULTS: Out of 1274 identified publications, 101 studies describing therapeutic options aiming at the reduction of PBUTs in CKD patients were included in this review. We stratified the studies by the PBUTs and the duration of the analysis into acute (data from a single procedure) and longitudinal (several treatment interventions) trials. Reduction ratio (RR) was used as the measure of plasma PBUTs lowering efficiency. For indoxyl sulphate and p-cresyl sulphate, the highest RR in the acute studies was demonstrated for fractionated plasma separation, adsorption and dialysis system. In the longitudinal trials, supplementation of haemodialysis patients with AST-120 (Kremezin®) adsorbent showed the highest RR. However, no superior method for the reduction of all types of PBUTs was identified based on the published studies. CONCLUSIONS: Our study shows that there is presently no technique universally suitable for optimum reduction of all PBUTs. There is a clear need for further research in this field.

Hypophosphatemia after high-dose iron repletion with ferric carboxymaltose and ferric derisomaltose-the randomized controlled HOMe aFers study.

BACKGROUND: In patients with iron deficiency anemia, ferric carboxymaltose (FCM) and ferric derisomaltose (FDI) allow high-dose iron repletion. While FCM is reported to induce hypophosphatemia, the frequency of hypophosphatemia after an equivalent dosage of FDI had not been assessed prospectively. METHODS: In the prospective, single-center, double-blind HOMe aFers study, 26 women with iron deficiency anemia (hemoglobin < 12 g/dL plus either plasma ferritin ≤ 100 ng/mL or a plasma ferritin ≤ 300 ng/mL and transferrin saturation (TSAT) ≤ 30%) were randomized to a single intravenous infusion of 20 mg/kg body weight (up to a maximum of 1000 mg) FCM or FDI. The primary endpoint was the incidence of hypophosphatemia (plasma phosphorus levels < 2.0 mg/dL at day 1, day 7 ± 2, and/or day 35 ± 2 after the infusion). In order to investigate potential skeletal and cardiovascular implications, we assessed changes in other components of mineral and bone metabolism, left ventricular function, and arrhythmias. RESULTS: Hypophosphatemia occurred more frequently in women treated with FCM (9 out of 12 [75%]) than in those treated with FDI (1 out of 13 [8%]; p = 0.001). Within 24 h after iron supplementation, women in the FCM group had significant higher plasma intact FGF23 (p < 0.001) and lower plasma 1.25-dihydroxyvitamin D (p < 0.001). As an indicator of urinary phosphorus losses, urinary fractional phosphorus excretion was higher in the FCM group (p = 0.021 at day 7 ± 2 after iron supplementation). We did not observe differences in skeletal and cardiovascular markers, potentially because of the limited number of participants. CONCLUSIONS: While both FCM and FDI provide efficient iron repletion in participants with iron deficiency anemia, FCM induced hypophosphatemia more often than FDI. TRIAL REGISTRATION: Clinical Trials.gov NCT02905539. Registered on 8 September 2016. 2015-004808-36 (EudraCT Number) U1111-1176-4563 (WHO Universal Trial Number) DRKS00010766 (Deutsches Register Klinischer Studien).

[Chronic kidney disease-a cardiovascular high-risk constellation]. / Chronische Nierenerkrankung ­ eine kardiovaskuläre Höchstrisikokonstellation.

Chronic kidney disease (CKD) is associated with substantial cardiovascular morbidity and mortality. This is mediated by the high prevalence of traditional cardiovascular risk factors in patients with CKD such as arterial hypertension and diabetes mellitus, but also by the presence of CKD-specific so-called nontraditional cardiovascular risk factors such as vascular calcification, uremic toxins, uremic dyslipidemia as well as inflammation and oxidative stress. Therefore, the primary and secondary prevention of cardiovascular disease represents an integral part of nephrology. This entails optimal control of blood pressure and diabetes, therapy of the uremic dyslipidemia as well as lifestyle-modifying factors such as weight reduction and smoking cessation.

[Anticoagulation in patients with chronic kidney disease : Recommendations from the working group "Heart-Kidney" of the German Cardiac Society and the German Society of Nephrology]. / Antikoagulation bei Patienten mit chronischer Niereninsuffizienz : Empfehlungen der Arbeitsgemeinschaft "Herz ­ Niere" der Deutschen Gesellschaft für Kardiologie ­ Herz- und Kreislaufforschung und der Deutschen Gesellschaft für Nephrologie.

Indications for anticoagulation are thromboembolic events, prosthetic heart valves, and atrial fibrillation with a corresponding risk score. Clinical trials have excluded patients with advanced chronic kidney disease and these data cannot be always generalized to patients with chronic kidney disease. Non-vitamin K antagonist oral anticoagulants (NOACs) are mostly not recommended or are contraindicated in advanced stages of chronic kidney disease. Observational studies have shown that dialysis patients with atrial fibrillation do not profit from coumarin anticoagulants; prospective studies are lacking.

Alloreactive T Cells to Identify Risk HLA Alleles for Retransplantation After Acute Accelerated Steroid-Resistant Rejection.

The risk of rejection by cellular alloreactivity to the transplant donor is not routinely assessed. Here we analyzed alloreactive T cells in kidney transplant recipients and report how their detection may have helped to prevent rejection of a second kidney graft in a patient with a history of acute accelerated steroid-resistant nonhumoral rejection. Alloreactive CD4 and CD8 T cells were quantified using a flow-cytometric mixed lymphocyte reaction assay based on interferon-γ induction. A group of 16 nonrejecting transplant recipients did not show any alloreactive T-cell immunity to their respective donors, whereas alloreactivity to third-party controls was detectable. In the patient with rejection, HLA-specific antibodies were not detectable before and shortly after rejection, but after transplantation the patient showed exceptionally high frequencies of alloreactive T cells against 2 of 11 HLA-typed controls (0.604% and 0.791% alloreactive CD4 T cells and 0.792% and 0.978% alloreactive CD8 T cells) who shared HLA alleles (HLA-A*24, -B*44, -C*02, -DQB1*5) with the kidney donor. These HLA alleles were subsequently excluded for allocation of a second graft. No alloreactive T cells were observed toward the second kidney donor, and this transplantation was performed successfully. Thus, shared HLA alleles between the donor and third-party controls may suggest that alloreactive T cells had contributed to rejection of the first graft. The rejecting patient highlights that determination of cellular alloreactivity before transplantation may be applied to identify unacceptable mismatches and to reduce the risk for acute cellular rejection episodes.

BK polyomavirus-specific cellular immune responses are age-dependent and strongly correlate with phases of virus replication.

BK polyomavirus (BKPyV) infection is widespread and typically asymptomatic during childhood, but may cause nephropathy in kidney transplant recipients. However, there is only limited knowledge on BKPyV-specific immunity in children and adults, and its role in BKPyV-replication and disease posttransplant. We therefore characterized BKPyV-specific immunity from 122 immunocompetent individuals (1-84 years), 38 adult kidney recipients with (n = 14) and without BKPyV-associated complications (n = 24), and 25 hemodialysis (HD) patients. Blood samples were stimulated with overlapping peptides of BKPyV large-T antigen and VP1 followed by flow-cytometric analysis of activated CD4 T cells expressing interferon-γ, IL-2 and tumor necrosis factor-α. Antibody-levels were determined using enzyme-linked immunosorbent assay. Both BKPyV-IgG levels and BKPyV-specific CD4 T cell frequencies were age-dependent (p = 0.0059) with maximum levels between 20 and 30 years (0.042%, interquartile range 0.05%). Transplant recipients showed a significantly higher BKPyV-specific T cell prevalence (57.9%) compared to age-matched controls (21.7%) or HD patients (28%, p = 0.017). Clinically relevant BKPyV-replication was associated with elevated frequencies of BKPyV-specific T cells (p = 0.0002), but decreased percentage of cells expressing multiple cytokines (p = 0.009). In conclusion, BKPyV-specific cellular immunity reflects phases of active BKPyV-replication either after primary infection in childhood or during reactivation after transplantation. Combined analysis of BKPyV-specific T cell functionality and viral loads may improve individual risk assessment.

The Primavera study protocol design: evaluating the effect of continuous erythropoiesis receptor activator (C.E.R.A.) on renal function in non-anemic patients with chronic kidney disease.

Erythropoiesis stimulating agents (ESA) are widely used for hemoglobin correction in patients suffering from renal anemia. However, their beneficial non-hematopoietic effects on renal deterioration have not been adequately assessed. The Primavera study is the first prospective, controlled trial to assess whether ESA treatment could ameliorate progression of chronic kidney disease (CKD) in non-anemic patients. Primavera is a single-blind, 24-month trial in which patients are randomized to placebo or to C.E.R.A., a continuous erythropoietin receptor activator. Patients with type 2 diabetes or who have undergone kidney transplantation are eligible to enter the study if they have CKD stage III (estimated GFR [eGFR] 30-59 mL/min/1.73 m(2)), urinary albumin to creatinine ratio (UACR) ≥ 50 g/g and ≤ 1500 g/g, or total urine protein ≥ 50mg/24h and ≤ 1500mg/24h, and hemoglobin 11-14 g/dL. The primary efficacy endpoint is the change in eGFR from baseline to month 24. Secondary efficacy endpoints are the changes in UACR, serum cystatin C and serum creatinine from baseline. Safety endpoints include adverse events and discontinuation due to pre-specified adverse events. An interim analysis will be performed after all patients have completed the first year. The planned sample size is 400 patients (200 type 2 diabetics, 200 transplant recipients) conferring 90% power to detect a prespecified significant difference of 1.5 mL/min/1.73 m(2) in the annual reduction in eGFR between treatment groups. The results of Primavera are expected in 2013.

Dosing strategies for conversion of haemodialysis patients from short-acting erythropoiesis stimulating agents to once-monthly C.E.R.A.: experience from the MIRACEL study.

AIMS: To analyse the impact of dosing decisions for continuous erythropoietin receptor activator (C.E.R.A.), a continuous erythropoietin receptor activator. METHODS: This was a prospective, multicentre, single-arm study in haemodialysis patients receiving epoetin alfa/beta or darbepoetin alfa. After a 2-month screening phase, patients were converted to monthly C.E.R.A. using pre-filled syringes during a 5-month titration phase and a 2-month evaluation phase. RESULTS: Four hundred and twenty-four eligible patients were converted to C.E.R.A. Mean Hb were 11.7 ± 0.7, 11.7 ± 0.8 and 11.5 ± 0.8 g/dl during screening, titration and evaluation, respectively. C.E.R.A. starting dose was 125 µg (n = 311) or 200 µg (n = 106), with corresponding final doses of 129 ± 61 µg and 203 ± 58 µg. The mean number of C.E.R.A. dose decreases and increases were 0.9 ± 1.0 and 1.1 ± 1.0 per patient, respectively. Hb rarely exceeded 12.5 g/dl after a C.E.R.A. dose increase (< 8%) and remained ≥ 11 g/dl after a dose reduction on approximately three-quarters of occasions. Among the 53 occasions where Hb decreased ≥ 2 g/dl between two consecutive visits, the previous dose had been withheld (n = 9), concomitant blood loss, coagulopathy or infection was present (n = 13), or iron parameters were low (n = 17). There were 104 adverse events/month during screening, and 45/month during the titration/evaluation phases. Serious adverse events occurred in 18.0 and 21.0 patients/month during the screening and titration/evaluation phases, respectively. CONCLUSION: Switching haemodialysis patients from shorter-acting ESA to once-monthly C.E.R.A. using pre-filled syringes is straightforward, and Hb levels remain stable. Starting dose recommendations and dose changes correlated well with the clinical setting. Collateral factors such as infection or aggravating concomitant medical conditions should be taken into account.

Evaluation of maintenance of stable haemoglobin levels in haemodialysis patients converting from epoetin or darbepoetin to monthly intravenous C.E.R.A.: the MIRACEL study.

BACKGROUND AND OBJECTIVES: C.E.R.A., a continuous erythropoietin receptor activator, offers once-monthly dosing without compromising haemoglobin control. This study was undertaken to examine whether monthly C.E.R.A. using pre-filled syringes maintains stable haemoglobin levels when administered according to local clinical judgement. RESEARCH, DESIGN AND METHODS: MIRACEL was a prospective, open-label, single-arm, multicentre study performed at 90 nephrology centres in Germany. After a 2-month screening phase, haemodialysis patients receiving epoetin or darbepoetin were converted to monthly intravenous C.E.R.A., with a 5-month titration phase followed by a 2-month evaluation phase. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov: NCT00413894 RESULTS: Of 661 patients screened, 424 (64.1%) started C.E.R.A. therapy (previous treatment: 72.2% epoetin, 27.8% darbepoetin); 416 were eligible for inclusion in the intent-to-treat population. A mean of two C.E.R.A. dose changes were required during the 7-month treatment period. The primary efficacy variable, haemoglobin within 11-12.5 g/dL or 10-13 g/dL during the evaluation phase, was achieved in 109 (30.8%) and 265 (74.9%) of the 354 evaluable patients, respectively, with no differences observed between patients formerly receiving epoetin or darbepoetin or different dosing frequencies. During the screening, titration and evaluation phases, mean haemoglobin was 11.7 +/- 0.7 g/dL, 11.6 +/- 0.9 g/dL and 11.4 +/- 1.0 g/dL, respectively, and 90.6% (377/416), 70.4% (293/416) and 82.9% (345/416) of patients exhibited < or = 1 g/dL change from phase-specific individual means. C.E.R.A. was well-tolerated with a safety profile similar to that reported in phase III studies. CONCLUSIONS: In this single-arm, open-label, multicentre study, conversion of a large population of haemodialysis patients from epoetin or darbepoetin to monthly C.E.R.A. administration using pre-filled syringes was shown to be practical, convenient and offer good control of haemoglobin levels, regardless of the previous type of therapy or dosing frequency.

Chronic erythropoietin treatment affects different molecular pathways of diabetic cardiomyopathy in mouse.

BACKGROUND: Recent studies in mice experimental models with acute ischaemic injury revealed that erythropoietin (EPO) has numerous tissue-protective effects in the heart, brain and kidneys. We therefore explored the tissue-protective properties of chronic EPO treatment in an experimental model of the db/db mouse with diabetic heart injury. MATERIAL AND METHODS: We randomly treated 11 db/db mice with placebo (saline), 0.4 microg of the continuous erythropoietin receptor activator (CERA) per week (n = 11) or 1.2 microg CERA per week (n = 11) for 14 weeks, and analysed cardiac tissue. The lower CERA dose was a non-haematologically effective dose, whereas the second increased the haematocrit. RESULTS: Compared with mice in the placebo group, CERA-treated mice had a reduction in TGF-beta(1) and collagen I expression in cardiac tissue (P < 0.01 vs. higher dose CERA). In addition, an increased expression of the pro-survival intracellular pathway p-AKT was observed (P < 0.05 vs. higher dose CERA). The values for the lower C.E.R.A had an intermediate nonsignificant effect. Furthermore, we were able to show that atrial natriuretic peptide (ANP) expression was increased in both CERA groups. CONCLUSIONS: Chronic treatment with CERA protects cardiac tissue in diabetic animals, i.e. it inhibits molecular pathways of cardiac fibrosis, and the effects are dose-dependent.

A hibernating kidney - ischemic preconditioning in a renal transplant recipient with a proximal stenosis of the iliac artery.

Ischemic preconditioning has been first described by Murry and coworkers as the protection conferred to ischemic myocardium by preceding brief periods of sublethal ischemia separated by periods of reperfusion. Another phenomenon closely associated to IPC is hibernation and stunning. The hibernating myocardium refers to resting left ventricular dysfunction due to reduced coronary blood flow that can be partially or completely reversed by myocardial revascularization and/or by reducing myocardial oxygen demand. Similarly as for the myocardium, these effects are reproducible for other solid organs. Here we report a case of a renal transplant recipient with decompensated proximal transplant artery stenosis due to ACE inhibition resulting in acute renal failure. The transplant perfusion was strictly dependent on systemic arterial blood pressure leading to intermittent episodes of renal ischemia and reperfusion. Renal function was severely decreased (glomerular filtration rate approximately 8 ml/min) with the need of hemodialysis treatment over a period of 4 weeks after transplantation. After dilatation of the stenosis, the patient's renal function improved rapidly and achieved values better than ever before. Referring to the definition of hibernating myocardium, here we postulate a case of a hibernating kidney in context of ischemic preconditioning.

[The kidneys and old age]. / Nieren und Alter.

With more detailed knowledge on renal function at advanced age it became clear that age-related changes of renal function are less severe than previously thought. However, these changes are significantly aggravated by classical cardiovascular risk factors such as hypertension, diabetes and smoking. As a consequence, in elderly with such co-morbidity the appearance of a primary kidney disease or acute renal failure may cause a serious deterioration of renal function. In addition, impaired homeostasis with respect to salt (and fluid) balance has important consequences for the management of the elderly who is exposed to the twin risks of dehydration and fluid overload. Finally, the kidney is the main route of excretion for many drugs and their active metabolites. Diminution of renal function with age underlies, at least in part, the known predisposition of the elderly to side effects of their medication such as non-steroidal anti-inflammatory drugs.

Erythropoietin and the endothelium - a promising link?

The major physiological function of erythropoietin (EPO) is thought to be the induction of erythropoiesis. However, a growing body of evidence indicates that EPO as well as recombinant human erythropoietin (rHuEPO) and its analogues have tissue-protective effects and prevent tissue damage during ischaemia. This mini review summarizes the present knowledge on protective vascular effects of EPO and discusses the potential underlying mechanisms.

Erythropoiesis-stimulating agents: past and future.

Renal anemia is a well-recognized complication of chronic kidney disease (CKD), and the deficiency of erythropoietin (EPO) is the primary cause. Observational population-based studies continue to demonstrate the association of low hemoglobin with adverse outcomes, and renal failure, cardiac failure, and anemia all may interact to cause or worsen each other, the so-called cardio-renal anemia syndrome. Treatment of anemia can be successfully achieved with the use of erythropoiesis-stimulating agents (ESAs). From a mechanistic point of view, however, the therapeutic benefits of ESA could be far beyond the correction of anemia. ESA modulates a broad array of cellular processes that include progenitor stem cell development, cellular integrity, and angiogenesis. A pleiotropic effect of EPO has been shown in the central nervous system, the cardiovascular system, and the kidney. While recent results of randomized controlled trials have established that there is little support for normalizing hemoglobin in CKD patients, the results of these studies do not negate renoprotective effects of EPO. A large number of patients with CKD will benefit from early recognition and appropriate correction of anemia with ESA.

Erythropoietin and progression of CKD.

In patients with primary as well as secondary chronic kidney disease (CKD), anemia has been identified as an independent risk factor for progression. In these patients anemia is thought to be a surrogate parameter for tissue hypoxia that perpetuates preexisting renal tissue injury, and treatment of anemia with recombinant human erythropoietin (rHuEPO) was therefore expected to retard progression. However, results of recently published large trials in patients with CKD did not fulfill these expectations. The reason for the discrepant findings may be distinct molecular pathways and/or EPO tissue receptor affinities that mediate the effect of EPO on erythropoiesis and tissue protection by EPO. A pivotal intracellular pathway is the activation of Akt (i.e., serine/threonine protein kinase B), but further potential pathways have been identified that may play an important role in tissue protection. In this study, we review data on the non-hematological effects of rHuEPO in different experimental settings of acute and chronic kidney injury, and discuss clinical renoprotective strategies with rHuEPO or analogue substances that are not related to anemia correction.

Vascular endothelial damage and repair in antineutrophil cytoplasmic antibody-associated vasculitis.

OBJECTIVE: Antineutrophil cytoplasmic antibody-associated vasculitis (AAV) is characterized by necrotizing vessel wall inflammation, paralleled by the detachment of endothelial cells. The repair of such endothelial defects is crucial for the maintenance of regular structure and function of the injured vessels. Bone marrow-derived endothelial progenitor cells (EPCs) are thought to play a pivotal role in the regeneration of damaged endothelium. The aim of this study was to investigate whether EPCs are involved in vascular repair in AAV. METHODS: We assessed disease activity, CD34+ hematopoietic progenitor cells (HPCs) using flow cytometry, EPCs using an in vitro assay, and circulating endothelial cells (CECs) by immunomagnetic isolation from the peripheral blood of 31 patients with active AAV at 1, 3, and 6 months after the initiation of immunosuppressive therapy. RESULTS: In patients with untreated active disease, HPC and EPC numbers were comparable with those in healthy control subjects (n = 64). With the induction of remission, the number of HPCs and EPCs increased significantly, from a median of 1.5 cells/microl (range 0.0-7.0) to a median of 3.2 cells/microl (range 0.76-9.2) (P < 0.001) and from a median of 261 cells/high-power field (range 171-643) to a median of 470 cells/high-power field (range 168-996) (P < 0.021), respectively. In contrast, the initially elevated number of CECs decreased significantly (P < 0.001). We observed no correlation between the number of HPCs or EPCs and the leukocyte count, the thrombocyte count, or kidney function. CONCLUSION: In patients with AAV, the numbers of circulating CD34+ HPCs and EPCs increased significantly after the institution of immunosuppressive therapy and disease remission. This finding points to a role of circulating CD34+ HPCs and EPCs in endothelial repair in vasculitis. Targeted stimulation of these cells might represent a new possibility of improving vascular healing in AAV.