Since more than two decades erythropoiesis-stimulating agents are the main pillar for treatment of anemia associated with chronic kidney disease. Methoxy polyethylene glycol-epoetin beta (MPG-EPO), also called continuous erythropoietin receptor activator, is the longest acting erythropoiesis-stimulating agent currently available. MPG-EPO is characterized by an elimination half-life of approximately 137 h and offers extended dosing intervals up to 4 weeks. Numerous phase I/II studies and a comprehensive clinical phase III program demonstrated the feasibility of MPG-EPO therapy for anemia correction and maintenance of stable hemoglobin levels in adult chronic kidney disease patients. Due to patent disputes MPG-EPO was only available outside the US market so far. In view of a prevailing US market introduction, this review focuses on efficacy and safety data from pivotal trials, summarizes recent clinical research and finally tries to substantiate potential benefits associated with the use of this anti-anemic drug.

Introduction: The main pillars for the treatment of chronic kidney disease (CKD) associated anemia are peptidic erythropoiesis stimulating agents (ESAs) and iron preparations. Both approaches benefit from long-term efficacy and safety data but are surrounded by clinical and economic concerns, driving the search for novel anti-anemic drugs.Areas covered: By answering pivotal questions, the authors describe the recent developments of next generation ESAs, introduce cutting-edge iron formulations and focus on investigational approaches that interact with pathways involved in erythropoietin (Epo) synthesis and myeloid hematopoiesis. Finally, the challenges encountered with these drug candidates are discussed.Expert opinion: Current peptidic ESAs are effective and well-tolerated, but are costly, require parenteral application and iron supplementation. ESA resistance may develop calling for increased doses. Therefore, orally available hypoxia-inducible factor (HIF) stabilizing compounds are attractive alternatives, which may be approved in the near future. Prominent compounds are molidustat, daprodustat and roxadustat. HIF stabilizers suppress hepcidin production and improve iron balance as the present ESAs, but also raise safety concerns in association with their pleiotropic actions. Other investigational erythropoietic biologics are growth-differentiation factor-11 (GDF11) ligand traps (sotatercept, luspatercept), which are also well advanced in development. Possibly, they will provide an add-on for established therapies. However, immunogenicity of these compounds still needs to be carefully investigated.

A biosimilar is an officially regulated and approved copy of an originator biologic therapy. Improved affordability and consequent wider patient access compared with biologics are a significant appeal of biosimilars. Regulatory guidelines for biosimilar development and approval are rigorous and undergoing constant refinement. The process of licensing approval for all biosimilars requires demonstration of comparability in quality, efficacy, and safety between the biosimilar and reference (originator) product, which is undertaken in a stepwise procedure of nonclinical and clinical evaluation. The approval of >20 biosimilars in Europe in several drug classes, including the first monoclonal antibody biosimilar, bears testimony to the increasing regulatory acceptance of these agents. In contrast, the clinical application of biosimilars remains underrecognized by physicians across therapy areas. Therefore, this article aims to provide a comprehensive review of the biosimilar development process and to provide multidisciplinary guidance on the potential therapeutic utility of biosimilars in clinical practice. Specifically, experts discuss clinical developments in the introduction of biosimilars across the disciplines of gastroenterology, nephrology, oncology, and rheumatology, and from a payer perspective, and also highlight a common need for ongoing pharmacovigilance, robust head-to-head clinical studies, and real-world data to establish the long-term risk-benefit profile of biosimilars. In conclusion, significant potential exists for biosimilars to revolutionize biologic therapy by widening patient access across therapy areas.

Introduction: Hyperphosphatemia is a frequent complication of chronic kidney disease and is associated with increased mortality. Despite side effects, risk of accumulation and high costs, phosphate binders (PBs) have become the crucial cornerstone of therapy. The iron-containing PB sucroferric oxyhydroxide (SO) and ferric citrate hydrate (FCH) have entered the market and other candidates are prior market entry.Areas covered: A literature search was performed using MEDLINE and EMBASE databases to identify references on iron-containing PB with particular regard to efficacy, safety and potential benefits. Additional hand searches were conducted along with a full-text review of any citation that appeared relevant.Expert opinion: On the highly competitive market, where the 'ideal' PB is still unknown, novel substances that offer clear benefits over available drugs are desired. Although SO and FCH showed similar efficacy and safety compared to sevelamer, head-to-head studies with lanthanum carbonate are absent. Clinical 1-year data in a limited patient cohort suggested improved adherence for SO and a large randomized controlled trial showed significant reduction in hospitalizations and costs for FCH. Additional large randomized controlled trials have now to prove these possible advantages. Cost-effectiveness in comparison to other PB and the exclusion of significant harms under long-term treatment will determine the future use of both drugs.

BACKGROUND:Erythropoiesis-stimulating agents (ESAs) are the mainstay of anemia therapy. Continuous erythropoietin receptor activator (CERA) is a highly effective, long-acting ESA developed for once-monthly dosing. A multitude of clinical studies has evaluated the safety and efficiency of this treatment option for patients with renal anemia. In times of permanent financial pressure on health care systems, the cost-effectiveness of CERA should be of particular importance for payers and clinicians.OBJECTIVE:To critically analyze, from the nephrologists' point of view, the published literature focusing on the cost-effectiveness of CERA for anemia treatment.METHODS:The detailed literature search covered electronic databases including MEDLINE, PubMed, and Embase, as well as international conference abstract databases.RESULTS:Peer-reviewed literature analyzing the definite cost-effectiveness of CERA is scarce, and most of the available data originate from conference abstracts. Identified data are restricted to the treatment of anemia due to chronic kidney disease. Although the majority of studies suggest a considerable cost advantage for CERA, the published literature cannot easily be compared. While time and motion studies clearly indicate that a switch to CERA could minimize health care staff time in dialysis units, the results of studies comparing direct costs are more ambivalent, potentially reflecting the differences between health care systems and variability between centers.CONCLUSION:Analyzed data are predominantly insufficient; they miss clear evidence and have to thus be interpreted with great caution. In this day and age of financial restraints, results from well-designed, head-to-head studies with clearly defined endpoints have to prove whether CERA therapy can achieve cost savings without compromising anemia management.

INTRODUCTION:Erythropoiesis-stimulating agents (ESAs) are the mainstay of treatment in anemic chronic kidney disease (CKD) patients. A tailored ESA therapy should combine maximal efficacy and safety with greatest convenience in dosing. Peginesatide, recently approved in the US for once-monthly dosing in adult patients on dialysis, is a promising novel PEGylated erythropoietin-mimetic peptide for the treatment of renal disease-induced anemia.AREAS COVERED:Published animal and human studies that evaluated the pharmacodynamics, pharmacokinetics, clinical efficacy and safety of peginesatide were critically analyzed.EXPERT OPINION:Peginesatide has a well-studied pharmacological and immunological profile, and latest published data favor the use of peginesatide in place of epoetin in dialysis patients. A more detailed evaluation of its safety profile particularly in trials with CKD patients not requiring dialysis is urgently needed, as peginesatide could be a perfect treatment solution for these patients. In addition, clinical long-term data and results from supplemental studies, e.g., with the PEGylated continuous erythropoietin receptor activator as comparator, should briefly follow. The fate of peginesatide on the highly competitive ESA market is currently not predictable and depends on safety and efficacy results of upcoming trials as well as finally on market and price policy.

BACKGROUND:Nasal colonization with methicillin-resistant Staphylococcus aureus (MRSA) is a well defined risk factor for subsequent bacteremia and death in various groups of patients, but its impact on outcome in patients receiving long-term hemodialysis (HD) is under debate.METHODS:This prospective interventional cohort study (performed 2004 to 2010) enrolled 289 HD outpatients of an urban dialysis-unit. Nasal swab cultures for MRSA were performed in all patients upon first admission, at transfer from another dialysis facility or readmission after hospitalisation. Nasal MRSA carriers were treated in a separate ward and received mupirocin nasal ointment. Concomitant extra-nasal MRSA colonization was treated with 0.2% chlorhexidine mouth rinse (throat) or octenidine dihydrochloride containing antiseptic soaps and 2% chlorhexidine body washes (skin). Clinical data and outcome of carriers and noncarriers were systematically analyzed.RESULTS:The screening approach identified 34 nasal MRSA carriers (11.7%). Extra-nasal MRSA colonization was observed in 11/34 (32%) nasal MRSA carriers. History of malignancy and an increased Charlson Comorbidity Index were significant predictors for nasal MRSA carriers, whereas traditional risk factors for MRSA colonization or markers of inflammation or malnutrition were not able to discriminate. Kaplan-Meier analysis demonstrated significant survival differences between MRSA carriers and noncarriers. Mupirocin ointment persistently eliminated nasal MRSA colonization in 26/34 (73.5%) patients. Persistent nasal MRSA carriers with failure of this eradication approach had an extremely poor prognosis with an all-cause mortality rate >85%.CONCLUSIONS:Nasal MRSA carriage with failure of mupirocin decolonization was associated with increased mortality despite a lack of overt clinical signs of infection. Further studies are needed to demonstrate whether nasal MRSA colonization represents a novel predictor of worse outcome or just another surrogate marker of the burden of comorbid diseases leading to fatal outcome in HD patients.

Survival of end-stage renal disease (ESRD) patients remains unacceptably poor. The excessive mortality of hemodialysis (HD) patients may result, at least in part, from the insufficient removal of medium or high molecular weight uremic toxins and from the systemic inflammatory response induced by the bioincompatibility of HD systems. Hemodiafiltration (HDF) combines diffusion and convection in a single modality, and it appears to be a promising method to improve ESRD patient outcomes. Emerging evidence suggests that this technique may be superior to classic diffusive HD in terms of patient morbidity. Despite the more widespread use of online HDF, evidence for survival benefits of HDF over other treatment modalities is scarce. Results of observational studies suggest lower mortality of HDF patients as compared to HD patients. Recent prospective randomized trials, however, failed to demonstrate any improvement in survival. Subanalyses of these trials, however, showed a significant survival benefit of HDF patients receiving high substitution volumes (17 L per session and more) compared to HD patients and to HDF patients receiving lower volumes. The explanation for this volume-dependent effect remains elusive. There is an urgent need for further randomized controlled trials to confirm previous findings and to identify those ESRD patients that are likely to benefit mostly from HDF.

Anemia is a prevalent and premature comorbidity in chronic kidney disease (CKD) and associated with multiple adverse clinical consequences including increased mortality. Today Erythropoiesis-stimulating agents (ESAs), together with iron supplementation, are the cornerstones of therapy for correcting anemia in CKD patients. As no generally accepted dosing algorithms for these agents exist, current recommendations prefer a partial but not complete anemia correction thereby favoring a more conservative and individualized ESA and iron dosing. Here we discuss in detail current evidence derived from large randomized trials about the proposed hemoglobin targets to aim at in CKD and End-Stage renal disease patients and report recent data from the thriving European market of biosimilar erythropoietins. We summarize promising investigational strategies including peginesatide and prolyl hydroxylase inhibitors for stabilization of the hypoxia inducible factor and provide a clinical review of novel high dose iron formulations like ferumoxytol or iron (III)-carboxymaltose. Taking these findings together, treatment strategies for anemia of CKD have got considerably more complicated so that a careful balance between maximization of patient`s quality of life while minimizing all risks associated with anemia treatment has become a major task of current nephrology.

Background: Ubiquitous mitochondrial creatine kinase (uMtCK) accumulates as macroenzyme creatine kinase type 2 (macro CK2) in the serum of HIV-infected patients under a tenofovir disoproxil fumarate (TDF)-containing antiretroviral regimen. The genesis and clinical significance of this finding is unclear.Methods: A prospective observational 5-year follow-up study was performed on those patients in which macro CK2 appearance was initially described ('TDF switchstudy' cohort). In addition, tenofovir (TFV), its prodrug TDF and its active, intracellular derivative TFV diphosphate (TDP) were tested in vitro for their effects on different key properties of uMtCK to clarify possible interactions of uMtCK with TFV compounds.Results: In just under 5 years of continuous TDF treatment, only 4/12 (33%) patients remained macro CK2-positive, whereas 8/12 (66%) originally positive patients were macro CK2-negative at the end of follow-up. Prospective clinical follow-up data indicate that macro CK2 appearance under TDF is not associated with significant cell damage or occurrence of malignancies. A trend towards grade 1 hypophosphataemia suggests subclinical proximal tubular dysfunction in macro-CK2-positive patients, although it was not associated with a significant decrease in estimated glomerular filtration rate. In vitro, TFV, TDF and TDP did not interfere with uMtCK enzyme activity as competitive inhibitors or pseudo-substrates, but TFV and TDF stabilized the native uMtCK octameric structure in dilute solutions.Conclusions: Appearance of octameric uMtCK as macro CK2 in the serum of TDF-treated patients is suggested to result from a combination of low-level mitochondrial damage caused by subclinical renal tubular dysfunction together with possible compensatory uMtCK overexpression and a putative concomitant stabilization of uMtCK octamers by higher levels of TFV in proximal tubules.

Polyomavirus-associated nephropathy (PVAN) is a significant complication after kidney transplantation, often leading to premature graft loss. In order to identify antiviral responses of the renal tubular epithelium, we studied activation of the viral DNA and the double-stranded RNA (dsRNA) sensors Toll-like receptor 3 (TLR3) and retinoic acid inducible gene-I (RIG-I) in allograft biopsy samples of patients with PVAN, and in human collecting duct cells in culture after stimulation by the dsRNA mimic polyriboinosinic: polyribocytidylic acid (poly(I: C)), cytokines, or infection with BK virus. Double staining using immunofluorescence for BK virus and TLR3 showed strong signals in epithelial cells of distal cortical tubules and the collecting duct. In biopsies microdissected to isolate tubulointerstitial lesions, TLR3 but not RIG-I mRNA expression was found to be increased in PVAN. Collecting duct cells in culture expressed TLR3 intracellularly, and activation of TLR3 and RIG-I by poly(I:C) enhanced expression of cytokine, chemokine, and IFN-beta mRNA. This inflammatory response could be specifically blocked by siRNA to TLR3. Finally, infection of the collecting duct cells with BK virus enhanced the expression of cytokines and chemokines. This led to an efficient antiviral immune response with TLR3 and RIG-I upregulation without activation of IL-1 beta or components of the inflammasome pathway. Thus, PVAN activation of innate immune defense mechanisms through TLR3 is involved in the antiviral and anti-inflammatory response leading to the expression of proinflammatory cytokines and chemokines. Kidney International (2012) 81, 100-111; doi:10.1038/ki.2011.311; published online 14 September 2011

BACKGROUNDBone morphogenetic protein-5 (BMP-5) has been shown to be essential for nephrogenesis. Its role in adult kidney and in patients with hypertensive nephrosclerosis is still unknown.METHODSBMP-5 expression was evaluated by immunostaining and real-time PCR in tissue samples from normal and nephrosclerotic human kidneys. The impact of transforming growth factor-ß (TGF-ß), tumor necrosis factor-α (TNF-α) and angiotensin-II (AT-II) on expression of BMP-5 and its receptors was quantified in proximal tubular cells (HK-2). Functional characteristics of BMP-5 were evaluated by testing its influence on TGF-ß-induced epithelial-to-mesenchymal transition (EMT), TNF-α-induced apoptosis of HK-2 cells and inflammatory cell infiltration.RESULTSBMP-5 expression was localized in tubular epithelial cells and significantly decreased in nephrosclerotic kidneys. Stimulation of HK-2 cells with TGF-ß, TNF-α and AT-II resulted in a significant decreased expression of BMP-5 and its receptors. BMP-5 attenuated TGF-ß-induced EMT, TNF-α-induced apoptosis and migration of mononuclear cells.CONCLUSIONSBMP-5 is expressed in the tubuli of adult kidneys. Its decreased expression in nephrosclerosis along with its regenerative capabilities in HK-2 cells may point to a protective role in hypertensive nephrosclerosis.

The progression of diabetic nephropathy is associated with an infiltration of macrophages expressing different phenotypes. As classically activated chemokine receptor CCR2+ macrophages are thought to drive tissue inflammation and remodeling, we tested whether blocking CCR2 could reduce intrarenal inflammation and prevent glomerulosclerosis in type 2 diabetes. This was achieved with RO5234444, an orally active small-molecule CCR2 antagonist that blocks ligand binding, its internalization, and monocyte chemotaxis. Male type 2 diabetic db/db mice were uninephrectomized to increase glomerular hyperfiltration to accelerate the development of glomerulosclerosis. From 16 weeks until killing at 24 weeks of age, mice were chow fed with or without admixed antagonist to achieve a trough plasma concentration above IC50 for binding in the mouse. CCR2 blockade reduced circulating monocyte levels, but did not affect total leukocyte or neutrophil numbers, and was associated with a reduction in the number of macrophages and apoptotic podocytes in the glomerulus. This treatment resulted in a higher total number of podocytes, less glomerulosclerosis, reduced albuminuria, and a significantly improved glomerular filtration rate. This successful preclinical trial suggests that this antagonist may now be ready for testing in humans with the nephropathy of diabetes mellitus.

PURPOSE OF REVIEW:Left-ventricular hypertrophy (LVH) represents an important marker of cardiovascular morbidity and mortality. Numerous noninterventional studies in patients with chronic kidney disease (CKD) revealed a consistent relationship of LVH with modifiable risk factors attributable to failing renal function, particularly anemia and hypertension.RECENT FINDINGS:Given the clear role for anemia in initiating or accelerating LVH, it seems imperative to correct renal anemia with erythropoiesis-stimulating agents (ESAs). A few nonrandomized studies have described a regression of LVH with correction of anemia, but prospective randomized trials showed no evidence that ESA treatment is able to improve cardiac prognosis in the CKD patient. Current data alert physicians that normalization of hemoglobin in patients with advanced CKD is harmful. Recent studies are now trying to clarify the mechanisms for harm focussing on the influence of comorbidities, ESA doses, and hemoglobin variability. The pathogenesis of hypertension in CKD is multifactorial and only a small percentage of CKD patients have controlled their blood pressure, indicating poor medication adherence, insufficient control of volume overload and undertreatment.SUMMARY:This review provides an update of ESA treatment, hypertension and LVH in the CKD patient, indicating that pathogenesis of LVH in this population is currently not completely understood. In addition, the impact of pharmacological interventions targeted to prevent or reduce LVH in anemic or hypertensive CKD patients is not well defined. As adoption of the Framingham approach seems not feasible in the CKD patient, evidence from large-scale randomized clinical trials is mandatory to resolve this dilemma.