A systematic literature review and meta-analysis of the incidence of serious or severe hypersensitivity reactions after administration of ferric derisomaltose or ferric carboxymaltose.

BACKGROUND: Intravenous iron is the preferred treatment for patients with iron deficiency anemia in a variety of clinical situations. Although uncommon, administration of modern IV iron formulations can result in hypersensitivity reactions (HSRs) and, rarely, anaphylactic or anaphylactoid reactions. AIM: The objective of the present study was to systematically review the literature to identify and analyze data on the incidence of HSRs after administration of ferric derisomaltose (FDI) or ferric carboxymaltose (FCM). METHOD: A prospectively-registered systematic literature review was conducted to identify prospective randomized controlled trials comparing FDI and FCM with other intravenous iron formulations or oral iron. Searches were conducted in PubMed (including MEDLINE), EMBASE, and the Cochrane Library in November 2020. The relative incidence of serious or severe HSRs occurring on the day or day after dosing of intravenous iron, recorded under the standardized Medical Dictionary for Regulatory Activities query for anaphylactic reaction. RESULTS: Data were obtained from seven randomized controlled trials of FCM (N = 2683) and ten of FDI (N = 3474) enrolling 10,467 patients in total. The number of patients experiencing any serious or severe HSR event was 29/2683 (1.08%) with FCM versus 5/3474 with FDI (0.14%). Bayesian inference of proportions showed the event rates to be significantly lower with FDI relative to FCM. CONCLUSION: HSR events were uncommon with both intravenous iron formulations; however, the present study showed a significantly lower incidence of HSRs with FDI relative to FCM. Further large-scale, head-to-head trials of the iron formulations would be required to confirm this finding.

Indirect methods of comparison of the safety of ferric derisomaltose, iron sucrose and ferric carboxymaltose in the treatment of iron deficiency anemia.

Objectives: The benefits of intravenous (IV) iron greatly outweigh the risks, but IV iron formulations carry a small risk of hypersensitivity reactions (HSRs). The objective was to use standardized Medical Dictionary for Regulatory Activities queries (SMQs) to compare the safety of ferric derisomaltose/iron isomaltoside 1000 (FDI), iron sucrose (IS), and ferric carboxymaltose (FCM) using prospective trial data.Methods: Prospective trials reporting the incidence of SMQ-coded serious or severe HSRs were identified in the literature. Four SMQs were used: narrow hypersensitivity terms (A), and broad terms pertaining to potential respiratory HSRs (B), skin HSRs (C), and cardiovascular HSRs (D). Bayesian inference, naïve pooling, and adjusted indirect approaches were employed to compare HSR incidence.Results: Twenty one prospective trials including over 8,000 patients receiving FDI, FCM or IS were retrieved. Odds ratios of any serious or severe HSR (all groups) with FDI relative to FCM were 0.41, 0.39, and 0.45 according to the Bayesian, naïve and adjusted approaches, respectively.Conclusions: The risk of serious or severe HSRs was lower with FDI relative to FCM and IS. Using data from prospective trials including over 8,000 patients coded using a well-defined standard (SMQs) enabled a robust comparison of HSR incidence between the iron formulations.

Needs Around Dialysis Treatment from Different Perspectives (NADIP): Results of the Exploratory German Multicenter Survey.

BACKGROUND/AIMS: In 2015, approximately 70,000 patients with end-stage renal disease were treated chronically with dialysis in Germany. However, there is only sparse information regarding subjective appreciation of the different aspects of extracorporeal renal replacement therapies. This study was performed to gain insight into the needs and appreciation of services in dialysis centers in Germany including the views not only of the patients but also of the caregivers, physicians, and nurses. METHODS: A cross-sectional written voluntary questionnaire survey based on the international RAND Kidney Disease Quality of Life Short Form (version 1.3) comprising 510 adult dialysis patients, 274 caregivers, 29 physicians, and 60 nurses in 30 dialysis centers across Germany. RESULTS: Although patients were mostly satisfied with present treatment options, room for improvement exists. Patients were less critical of services than doctors and nurses. Factors such as trustworthy contact with staff at the centers as well as information exchange with other patients and among caregivers play a significant role in the patients' perception of a high-quality dialysis treatment facility. Therefore, continued cost saving, in particular regarding personnel, may subjectively counteract the objective technical improvements of dialysis. CONCLUSIONS: High-quality technical standards are essential for successful dialysis therapy; however, additionally, we recommend an array of communicative and social tools employed by all stakeholders to convey and exchange information and also support subjective well-being. This survey represents one of the largest evaluations to date. The data are also of potential international relevance for non-German health management systems.

[Intravenous Iron Substitution in Chronic Disease - in Whom, When and How?] / Intravenöse Eisensubstitution bei chronischer Erkrankung ­ bei wem, wann und wie?

In recent years, considerable progress has been made in the detection and treatment of iron deficiency. The results are also relevant for many specialist areas and, in particular, for patients with chronic inflammatory diseases. In daily practice, iron deficiency is often neither identified nor consistently treated.An iron deficiency can - even before anaemia occurs - reduce the quality of life and influence the course of the underlying disease. In patients with chronic diseases , the iron status should be monitored regularly. Especially, the currently available oral iron preparations for these patients are inefficient, because of the limitated tolerability and, furthermore, because of restricted enteral iron uptake due to inflammation. For this reason, various guidelines recommend intravenous iron substitution.

Treatment of renal anemia: Erythropoiesis stimulating agents and beyond.

Anemia, complicating the course of chronic kidney disease, is a significant parameter, whether interpreted as subjective impairment or an objective prognostic marker. Renal anemia is predominantly due to relative erythropoietin (EPO) deficiency. EPO inhibits apoptosis of erythrocyte precursors. Studies using EPO substitution have shown that increasing hemoglobin (Hb) levels up to 10-11 g/dL is associated with clinical improvement. However, it has not been unequivocally proven that further intensification of erythropoiesis stimulating agent (ESA) therapy actually leads to a comprehensive benefit for the patient, especially as ESAs are potentially associated with increased cerebro-cardiovascular events. Recently, new developments offer interesting options not only via stimulating erythropoeisis but also by employing additional mechanisms. The inhibition of activin, a member of the transforming growth factor superfamily, has the potential to correct anemia by stimulating liberation of mature erythrocyte forms and also to mitigate disturbed mineral and bone metabolism as well. Hypoxia-inducible factor prolyl hydroxylase inhibitors also show pleiotropic effects, which are at the focus of present research and have the potential of reducing mortality. However, conventional ESAs offer an extensive body of safety evidence, against which the newer substances should be measured. Carbamylated EPO is devoid of Hb augmenting effects whilst exerting promising tissue protective properties. Additionally, the role of hepcidin antagonists is discussed. An innovative new hemodialysis blood tube system, reducing blood contact with air, conveys a totally different and innocuous option to improve renal anemia by reducing mechanical hemolysis.

A prospective observational study of effectiveness and safety of iron isomaltoside in patients with chronic renal failure and iron deficiency anemia
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AIMS: The aim of this study was to investigate the effectiveness, safety, and tolerability of iron isomaltoside in routine practical care of iron deficiency anemia (IDA) in patients with chronic renal failure. METHODS: The study included 698 patients with IDA on dialysis or with nondialysis chronic kidney disease (CKD) stages 3 - 5 designated by their physicians for treatment with iron isomaltoside. Data were recorded at baseline and after 3 and 9 months. Effectiveness data included measurement of hemoglobin (Hb), hematocrit, i-iron, transferrin saturation (TSAT), and i-ferritin. Safety data included adverse events and safety laboratory variables. RESULTS: Following administration of a mean cumulative dose of 2,574 mg isomaltoside over 9 months, initial average Hb increased from 11.0 g/dL to 11.6 g/dL, TSAT from 19.4% to 28.3%, and i-ferritin from 320 µg/L to 642 µg/L, demonstrating a positive effect of iron isomaltoside on iron deficiency. In addition, there was a significant reduction in the use of erythropoiesis-stimulating agents (ESAs) (regarding epoetin α, initial mean dose 40,688 IU/month, final dose 35,665 IU/month, -13.7%, p < 0.001). No drug-related adverse events were reported. Furthermore, safety parameters including i-phosphate indicated no abnormal changes. CONCLUSIONS: Iron isomaltoside demonstrated very good effectiveness and tolerability in patients with stage 3 - 5 CKD, including an ESA saving effect.
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Treating hyperphosphatemia - current and advancing drugs.

INTRODUCTION: Hyperphosphatemia is a hallmark of advanced chronic kidney disease (CKD) and associated with adverse outcomes. Preclinical and epidemiological studies strongly support a causal relationship between hyperphosphatemia and mortality as well as cardiovascular complications, especially including vascular, valvular and soft-tissue calcifications. Thus, appropriate phosphate lowering is considered to play a major role in health and longevity of CKD patients. In this respect, phosphate binders are the most powerful therapeutic option, while dietary phosphate restriction and intensified dialysis are valuable supportive approaches. AREAS COVERED: Pubmed was the primary research platform. This search focused on novel phosphate lowering compounds, including iron-containing binders and phosphate transport inhibitors, which have just become available or are in the approval process. Further, additional reports on effective strategies to counteract the adverse consequences of resistant hyperphosphatemia were also collected. EXPERT OPINION: New iron-containing drugs may offer advantages, including iron supplementation, low pill burden and high efficacy. Phosphate transport inhibitors possess a high potential as add-on compounds in patients with insufficient phosphate binder therapy. One unsolved question remains at what CKD stage to start therapeutically counteracting phosphate retention.

Paricalcitol treatment of secondary hyperparathyroidism in hemodialysis patients: a German-Austrian, single-arm, open-label, prospective, noninterventional, observational study.

BACKGROUND: Safety and efficacy of paricalcitol in hemodialysis patients with secondary hyperparathyroidism (sHPT) was investigated under routine clinical practice in German and Austrian dialysis centers. METHODS: Hemodialysis patients with sHPT initiating intravenous paricalcitol were enrolled in this noninterventional study regardless of concomitant sHPT treatment. Prior active vitamin D therapy was discontinued. Clinical laboratory values, including intact parathyroid hormone (iPTH), total serum calcium (Ca), phosphorus (P), Ca × P product, and alkaline phosphatase (AP), were recorded for 6 months following initiation of paricalcitol treatment. RESULTS: 1,313 patients (Austria, n = 280; Germany, n = 1,033) from 169 dialysis centers were enrolled. Most patients (n = 932; 79.1%) had received dialysis for ≥1 year. Median iPTH fell from 518.9 pg/ml [55.0 pmol/l] at baseline to 264.0 pg/ml [28.0 pmol/l] after 6 months (p < 0.0001). After 6 months of treatment, ≥30 and ≥60% reductions in iPTH were observed in 63.0 and 35.9% of patients, respectively. At 6 months, 27.2% of patients achieved iPTH levels between 150 and <300 pg/ml [15.9 and <31.8 pmol/l] compared with 9.7% at baseline. Ca, P, and Ca × P levels remained stable in the majority of patients. AP levels declined from a median of 98 U/l at baseline to 83 U/l (p < 0.0001) at 6 months. Monitoring of adverse events and clinical laboratory assessments identified no unexpected safety signals for paricalcitol. CONCLUSIONS: Paricalcitol is an effective and well-tolerated treatment option for the control of iPTH levels in hemodialysis patients with sHPT. The results of this study support the results of previous trials under real-time clinical practice conditions in Austria and Germany.

Treatment of phosphate retention: The earlier the better?

Over the last 15 years, our knowledge and understanding of the underlying mechanisms involved in the regulation of calcium and phosphate homeostasis in chronic kidney disease have advanced dramatically. Contrary to general opinion in the 20(th) century that moderate hypercalcemia and hyperphosphatemia were acceptable in treating secondary hyperparathyroidism, the calcium and phosphate load is increasingly perceived to be a major trigger of vascular and soft tissue calcification. The current treatment options are discussed in view of historical developments and the expectations of the foreseeable future, focusing on the early treatment of hyperphosphatemia. At present, we lack indisputable evidence that active intervention using currently available drugs is of benefit to patients in chronic kidney disease stages 3 and 4.

Use of phosphate binders in chronic kidney disease.

PURPOSE OF REVIEW: Hyperphosphatemia is a paradigmatic finding in late-stage chronic kidney disease (CKD) and consistently associated with adverse outcomes. Preclinical and epidemiological studies strongly support a causative role of hyperphosphatemia for cardiovascular complications, especially with regard to vascular, valvular and soft-tissue calcifications, and for subsequent mortality. Therefore, phosphate management is thought to play a pivotal role in health and longevity of CKD patients. In this regard, phosphate binders are considered the prime option; however, dietary phosphate restriction and intensified dialysis are also valuable supportive tools. RECENT FINDINGS: Studies on available calcium-free phosphate binders demonstrate potential to interfere with phosphate regulatory factors, such as fibroblast growth factor-23 (FGF23). Magnesium-containing phosphate binding may possess a pleiotropic potential due to its calcification inhibitory properties. Novel phosphate lowering compounds, including colestilan, iron-containing binders and nicotinamide, are underway to extend the armamentarium of phosphate-lowering strategies. An open question remains when to therapeutically counteract phosphate retention by binders. A recent prospective randomized trial in patients with moderate CKD (stages 3b-4) and phosphate levels in the upper normal range demonstrated only moderate reductions in serum phosphate levels, no effects on FGF23, but increased vascular calcification progression with active treatment versus placebo. Another small trial in patients with similar renal function given diets containing approximately 1 g of calcium and 1.4 g of phosphate per day showed neutral calcium and phosphate balances, whereas addition of calcium carbonate as a phosphate binder only caused a positive calcium, but no negative phosphate balance. SUMMARY: Adequate phosphate management in end-stage CKD remains a mainstay of our therapeutic approaches in this population, and additional promising drugs are in development and may shortly be available. The timing and indication for phosphate-lowering strategies in predialysis CKD is currently unclear.

ESA therapy - the quest continues: anemia treatment following recent national and international recommendations 2011 and 2012.

The development of ESA (Erythropoiesis Stimulating Agents) revolutionized the treatment of renal anemia. However, the initial euphoria has abated and, in the last few years, studies have shown that ESAs should not be administered without caution as the rate of cardiovascular events and possibly tumor related deaths may increase with over-augmented hemoglobin levels. Renal anemia therapy is discussed against the background of recent decisions to lower the recommended hemoglobin target ranges in chronic kidney disease (CKD) patients on ESAs, thus, necessitating a redefinition of treatment quality criteria and exposing areas requiring further research.

FGF23 antagonism: the thin line between adaptation and maladaptation in chronic kidney disease.

For more than 10 years, we have been convinced by overwhelming epidemiological evidence with a high biological plausibility that hyperphosphataemia imposes one of the most sustained cardiovascular and mortality risks on patients suffering from chronic kidney disease (CKD). With the discovery of the fibroblast growth factor-23 (FGF23)/klotho axis, we not only gained a new and mechanistic understanding of phosphate handling of the body, we also felt that novel therapeutic strategies may arise counteracting the deleterious consequences of phosphate retention, dysregulation and maldistribution. Two recent experimental studies shed additional and important light on what we can expect from such new insights. Faul et al. showed us that FGF23 excess may directly induce left ventricular hypertrophy (LVH) and that FGF-receptor antagonism ameliorates CKD-induced LVH in rats. Shalhoub et al. demonstrated that FGF23 antibodies successfully ameliorated the development and progression of most features of secondary hyperparathyroidism in a rat model of CKD, however, at the expense of hyperphosphataemia, progressive vascular calcification and death. Such studies not only help to continuously improve our understanding, but also especially sharpen our perception of how thin the line may be between adaptation and maladaptation in chronic disease scenarios.

Mechanisms and treatment of extraosseous calcification in chronic kidney disease.

Strong and unidirectional associations exist between the severity of cardiovascular calcifications and mortality in patients with advanced chronic kidney disease. In the past 10 years, a wealth of experimental and clinical information has been published on the key pathophysiological events that contribute to the development and progression of vascular and soft-tissue calcifications. These processes involve a sensitive balance of calcification inhibition, induction and removal. The traditional view of regarding secondary hyperparathyroidism and elevated calcium × phosphate product as the pivotal risk factors for calcification has been challenged by data demonstrating a role for other, more subtle and complex pathomechanisms. These mechanisms include the loss of endogenous calcification inhibitors, deficient clearance of calcified debris, effects of vitamin K and vitamin D, and the action of calcification inducers as in osteogenic transdifferentiation. In this Review, we describe our current knowledge of the factors involved in the passive and active regulation of extraosseous calcification processes, with an assessment of their importance as targets for future diagnostic and therapeutic interventions.

Vitamin D, chronic kidney disease and survival: a pluripotent hormone or just another bone drug?

It is now about 40 years ago that the mechanism of renal 1-α-hydroxylation of vitamin D was discovered and characterized. After this seminal observation, the key role of the active vitamin D derivative 1, 25-(OH)2-vitamin D (calcitriol) in calcium homeostasis and bone mineralization, and its specific role in the course of chronic kidney disease (CKD) and renal osteopathy, was unraveled step by step, while the precursor 25-OH-vitamin D (calcidiol) was gradually ignored. Calcitriol and its synthetic analogue alfa-calcidol became the first-line standard drug to tackle secondary hyperparathyroidism (sHPT) in CKD. Potential side-effects, including hypercalcemia, hyperphosphatemia, and vascular calcification, were partly abrogated by developing less calcemic substances such as paricalcitol or maxacalcitol. Thus, TIME Magazine surprised when nominating vitamin D, with regard to its newly discovered pleiotropic actions, as one of the "top medical breakthroughs" in the December issue of 2007. This vote was driven by novel and spectacular insights into the pivotal regulatory role of vitamin D with regard to autoimmune diseases, immune defense, cancer development and progression, and cardiovascular function and disease. More than 30 cell types express the vitamin D receptor (VDR), and more than ten organs in addition to the kidney are capable of paracrine 1-α-hydroxylation. More than 200 genes are under the control of calcitriol. A MEDLINE search performed in December 2009 focusing on the keywords "vitamin D-and-kidney-and-2009" yielded 523 hits. This review intends to give a subjective and CKD-related update on novel biological and clinical insights with relevance to the steroid hormone vitamin D.

Sevelamer carbonate for the treatment of hyperphosphatemia in patients with kidney failure (CKD III - V).

IMPORTANCE OF THE FIELD: Altered mineral metabolism in chronic kidney disease (CKD) is associated with increased morbidity, mortality, hospitalization, cost of care and reduced quality of life. Phosphorus control, one component of CKD metabolic derangements, is potentially related to impaired outcomes and has significant room for improvement. AREAS COVERED IN THIS REVIEW: Historical, present and future aspects of treatment of hyperphosphatemia focusing on sevelamer hydrochloride and sevelamer carbonate. WHAT THE READER WILL GAIN: Comprehensive insight into the background and controversies regarding phosphate binders. TAKE HOME MESSAGE: While calcium-free phosphate binders with a sevelamer backbone may offer therapeutic advantages for CKD patients at risk, more studies comprising significant patient numbers are warranted to answer compelling clinical questions.

Relation of recurrence of atrial fibrillation after successful cardioversion to renal function.

Angiotensin II exerts proinflammatory effects leading to atrial fibrosis that is associated with persistence of atrial fibrillation (AF). Renal function plays a major role in activation of the renin-angiotensin-aldosterone system. We examined whether the level of impaired renal function, defined by glomerular filtration rate (GFR), would influence the maintenance of sinus rhythm after successful external electric cardioversion (ECV). One hundred two consecutive patients with persistent AF underwent successful ECV. Patients were prospectively followed for recurrence of AF by telephone interviews, Holter electrocardiograms, and electrocardiograms sent by primary care providers. Repeated GFR assays were performed before and 1 month after ECV. Patients were divided into 4 groups according to baseline GFR (I >90 ml/min, II 60 to 90 ml/min, III 30 to 59 ml/min, IV <30 ml/min). AF recurrence rate was significantly higher in patients with moderately or severely decreased renal function (GFR <60 ml/min, p = 0.003). Patients with moderately (GFR 30 to 59 ml/min, p = 0.02) or only mildly (GFR 60 to 90 ml/min, p = 0.01) decreased renal function showed an increase in GFR if sinus rhythm was maintained at 1 month follow-up. In conclusion, impaired renal function was associated with an increased risk of AF recurrence after successful ECV.