Comparison of Iron Dosing Strategies in Patients Undergoing Long-Term Hemodialysis: A Randomized Controlled Trial.

BACKGROUND AND OBJECTIVES: Whether iron supplementation in patients on hemodialysis could be delivered by less frequent but higher single doses compared with the currently more common higher-frequency schedules of lower single iron doses is unknown. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We carried out an open-label, randomized, controlled noninferiority trial over 40 weeks in patients on prevalent hemodialysis (n=142). We administered in total 2 g iron as 100 mg iron sucrose biweekly in a continuous (20 × 100 mg) fashion or 500 mg ferric carboxymaltose every 10 weeks in a periodic (4 × 500 mg) fashion. The primary end point was the change in hemoglobin at week 40 from baseline with a noninferiority margin of -0.8 g/dl. Secondary end points were changes in ferritin, transferrin, transferrin saturation, and erythropoiesis-stimulating agent use. RESULTS: In total, 108 patients completed the study. At 40 weeks, hemoglobin changed by -0.27 g/dl (95% confidence interval, -0.64 to 0.09) in the iron sucrose arm and by -0.74 g/dl (95% confidence interval, -1.1 to -0.39) in the ferric carboxymaltose arm compared with baseline. Noninferiority was not established in the per-protocol population as hemoglobin changes compared with baseline differed by -0.47 g/dl (95% confidence interval, -0.95 to 0.01) in the ferric carboxymaltose arm compared with the iron sucrose arm. Proportional changes from baseline to week 40 differed by -31% (98.3% confidence interval, -52 to -0.1) for ferritin, by 1% (98.3% confidence interval, -7 to 10) for transferrin, and by -27% (98.3% confidence interval, -39 to -13) for transferrin saturation in the ferric carboxymaltose arm compared with the iron sucrose arm. Erythropoiesis-stimulating agent dosing did not differ between groups. The overall number of adverse events was similar; however, more infections were observed in the iron sucrose arm. CONCLUSIONS: An equal cumulative dose of ferric carboxymaltose administered less frequently did not meet noninferiority for maintaining hemoglobin levels compared with iron sucrose administered more frequently. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Comparison Study of Two Iron Compounds for Treatment of Anemia in Hemodialysis Patients (COPEFER), NCT02198495.

Use of Calcium Channel Blockers is Associated with Mortality in Patients with Chronic Kidney Disease.

BACKGROUND/AIMS: The use of antihypertensive medicines has been shown to reduce proteinuria, morbidity, and mortality in patients with chronic kidney disease (CKD). A specific recommendation for a class of antihypertensive drugs is not available in this population, despite the pharmacodynamic differences. We have therefore analysed the association between antihypertensive medicines and survival of patients with chronic kidney disease. METHODS: Out of 2687 consecutive patients undergoing kidney biopsy a cohort of 606 subjects with retrievable medical therapy was included into the analysis. Kidney function was assessed by glomerular filtration rate (GFR) estimation at the time point of kidney biopsy. Main outcome variable was death. RESULTS: Overall 114 (18.7%) patients died. In univariate regression analysis the use of alpha-blockers and calcium channel antagonists, progression of disease, diabetes mellitus (DM) type 1 and 2, arterial hypertension, coronary heart disease, peripheral vascular disease, male sex and age were associated with mortality (all p<0.05). In a multivariate Cox regression model the use of calcium channel blockers (HR 1.89), age (HR 1.04), DM type 1 (HR 8.43) and DM type 2 (HR 2.17) and chronic obstructive pulmonary disease (HR 1.66) were associated with mortality (all p < 0.05). CONCLUSION: The use of calcium channel blockers but not of other antihypertensive medicines is associated with mortality in primarily GN patients with CKD.

Increased chemokine excretion in patients suffering from chronic kidney disease.

During chronic kidney disease (CKD) leukocytes attracted by chemokines can migrate into the kidney and further aggravate renal affliction by releasing proinflammatory and profibrotic factors. We therefore sought to investigate serum and urine chemokine levels of 114 patients with CKD and 21 healthy volunteers to examine their possible suitability as biomarkers for monitoring disease course and patient's risk assessment. Analyzed chemokines were CCL17, CCL20, CCL22, and CXCL11, which are especially involved in the development of chronic renal failure. Our results showed elevated fractional CCL22 excretion levels in patients with CKD stages 2-5 compared with healthy controls. Furthermore, fractional CCL22 excretion was increased in patients with CKD stages 4 and 5 compared with stages 1-3. Fractional CCL20 excretion showed a significant elevation in patients with CKD stage 5 compared with healthy individuals and patients with CKD stages 1-3. Fractional CXCL11 excretion was significantly elevated in patients with CKD stages 4 and 5 compared with healthy controls and patients with CKD stages 1-3. Moreover, receiver operating characteristic curve analysis showed the potential of chemokine excretion to predict various CKD stages (area under the curve [AUC] 0.835, P < 0.0001 for CCL22, stage 1 and higher; AUC 0.6887, P = 0.0007 for CCL20, stage 3 and higher; AUC 0.7549, P = 0.0003 for CXCL11, stage 3 and higher). Our results further uncovered trends in varying chemokine serum and excretion levels in different CKD etiologies. In conclusion, monitoring fractional chemokine excretion might be suitable for following CKD course and hence promoting individually adjusted treatment planning.

Correlations and time course of FGF23 and markers of bone metabolism in maintenance hemodialysis patients.

OBJECTIVE: Parathyroid hormone (iPTH) and fibroblast growth factor 23 (FGF23) are elevated in secondary hyperparathyroidism. In hemodialysis, higher dialysate calcium (1.5 mmol/L) induces intradialytic suppression of iPTH, whereas its impact on FGF23 and markers of bone metabolism is unknown. We assessed the time course of FGF23 and markers of bone metabolism in relationship to dialysate calcium. DESIGN AND METHODS: In this prospective cohort study of 19 patients on maintenance hemodialysis, we measured serum calcium (sCa), inorganic phosphate (iP), blood urea nitrogen (BUN), ß2-microglobulin (ßMG), iPTH, FGF23, aminoterminal propeptide type 1 procollagen (P1NP), C-telopeptide of type I collagen for bone degradation (CTX-I), osteocalcin (OC), bone specific alkaline phosphatase (BALP), and tartrate-resistant acid phosphatase (TRAP5b) during a single hemodialysis session at baseline, 1, 2, and 3h of dialysis. The time course of measured parameters was compared according to groups of prescribed dialysate calcium of 1.25 mmol/L and 1.5 mmol/L. RESULTS: iPTH declined in the 1.5 mmol/L dialysis group as serum calcium increased whereas it tended to increase in the 1.25 mmol/L group without significant changes in serum calcium. Patients on long-term dialysate calcium of 1.5 mmol/L had significantly lower CTX-I levels and tended to lower levels of iPTH, FGF23, OC, P1NP and TRAP5b at the start of dialysis compared to those on 1.25 mmol/L. CTX-I, FGF23 and OC but not BALP, P1NP and TRAP5b decreased during dialysis independent of dialysate calcium. CONCLUSIONS: In spite of immediate effects on iPTH, dialysate calcium does not acutely affect other parameters of bone and mineral metabolism. SHORT SUMMARY: Dialysate calcium concentration is known to have both immediate and longer-term impact on parathyroid hormone levels in hemodialysis patients. Little is known about the acute impact of dialysate calcium on bone metabolism. In this cross-sectional study of prevalent hemodialysis patients, we found no evidence of immediate short-term dialysate calcium-induced changes of fibroblast growth factor 23 or anabolic and catabolic markers of bone turnover during hemodialysis. However, differences in CTX-I and to a lesser extent other parameters between groups of higher and lower dialysate calcium suggest a longer-term effect that remains to be validated.

Kidney biopsy results versus clinical parameters on mortality and ESRD progression in 2687 patients with glomerulonephritis.

BACKGROUND: Physicians refer proteinuric patients to kidney biopsy in order to clarify the issue of underlying renal disease. We compared kidney biopsy results with classical outcome parameters in a large cohort of patients with biopsy proven glomerulonephritis (GN). METHODS: In a retrospective analysis, 2687 patients with different forms of GN from 123 Austrian centres were investigated. Patient characteristics, the diagnosis of GN and its respective subtype and clinical symptoms such as arterial hypertension, haematuria, amount of proteinuria and estimated glomerular filtration rate (eGFR) were tested for their association with all-cause mortality and progression to end-stage renal disease (ESRD). RESULTS: During a median follow-up of 129·9 months (IQR 89·6; 177·7), 688 patients (25·6%) died and 718 patients required dialysis (29·4%). In multivariate Cox's regression analysis age (HR 1·06), female sex (HR 0·71), eGFR (HR 0·74), the diagnosis of GN and its subtypes predicted patient survival (all P < 0·01), whereas the amount of proteinuria was not associated with patient survival. The incidence of progression to ESRD was associated with female sex (HR 0·71), eGFR (HR 0·65), amount of proteinuria (HR 1·15) and the diagnosis of GN and its subtypes (all P < 0·01). Nephrotic or nephritic syndromes were not associated with patient survival or progression to ESRD and did not add further predictive value to outcome of GN. CONCLUSIONS: Our study demonstrates histological diagnosis of GN and its specific subtype predicts patient survival and dialysis incidence. Therefore, kidney biopsy should be an integral part of routine diagnostic assessment in patients with any forms of suspected GN.

Independent or synergistic relationship of proteinuria and glomerular filtration rate on patient and renal survival in patients with glomerulonephritis?

BACKGROUND: Glomerular filtration rate (GFR) in patients with chronic kidney disease (CKD) identifies patients at risk for death or end-stage renal disease (ESRD). CKD staging by GFR should incorporate proteinuria to augment risk stratification. We therefore tested the predictive power of the combination of GFR with proteinuria in patients with different histologically-diagnosed types of glomerulonephritis (GN). METHODS: In a retrospective analysis, 2,687 patients with different forms of GN from 123 Austrian centres were investigated. Full data sets were available from 1,892 subjects. Classes of CKD on the basis of estimated GFR (eGFR) and of proteinuria grouped as <1, 1-3.5, and >3.5 g/24 h were tested for their association with all-cause mortality and ESRD. RESULTS: During a median follow-up of 130 months [interquartile range (IQR) 90; 178] 478 patients (25.3 %) died. Median eGFR was 49 ml/min/1.73 m(2) (IQR 24; 81) and proteinuria 3.8 g/24 h (IQR 1.7; 8.0). Adjusted multivariate Cox regression indicated that renal survival but not overall survival is related to proteinuria >3.5 g/24 h [as opposed to <1 g/24 h; hazard ratio (HR) 1.91] and shows progression to ESRD. However, subgroup analyses revealed that this risk with proteinuria >3.5 g/24 h exists only in patients with immunoglobulin (Ig)A GN (HR 4.93), miscellaneous GN (HR 1.74), and CKD stage 5 (HR 2.50). Additionally, proteinuria is a risk factor for renal survival in males more than in females with GN and proteinuria >3.5 g/24 h (HR 1.91). CONCLUSION: Proteinuria is a strong risk factor for renal survival particularly in patients with proteinuria >3.5 g/24 but not for all types of GN, nor for all CKD stages. Proteinuria is not a risk factor for overall survival in patients with GN.

Dialysate sodium prescription and blood pressure in hemodialysis patients.

BACKGROUND: Diffusive sodium removal has been recommended to control hypertension in hemodialysis patients. Recent evidence on hospitalizations and mortality, however, challenged the benefit of lower dialysate sodium prescriptions and ignited a debate in the dialysis community. We therefore studied the relationship between dialysate sodium and blood pressure over the longer term. METHODS: We used multiply adjusted linear mixed models to estimate the association between dialysate sodium and predialysis systolic blood pressure (SBP) as well as change in SBP (delta SBP; postdialysis minus predialysis) in 23,962 patients from the international Dialysis Outcomes and Practice Patterns Study. RESULTS: We found that 43% of hemodialysis facilities had variable (individualized) dialysate sodium prescriptions (125-155 mEq/L), whereas 57% had uniform dialysate sodium prescriptions (135-145 mEq/L) for ≥90% patients. Between-group comparisons of these 2 facility types suggested that dialysate sodium, when variably prescribed, might have been used to modify predialysis SBP (P interaction = 0.01) and perhaps delta SBP levels (P interaction = 0.08). Within facilities not prone to indication bias, because dialysate sodium was not variable, higher uniform dialysate sodium (per 2 mEq/L) was associated with slightly higher SBP (+0.9 mm Hg, 95% confidence interval (CI) = 0.1-1.6 among all patients; +1.7 mm Hg, 95% CI = 0.1-3.2 among patients not treated with blood pressure medication) and no increase in delta SBP. CONCLUSIONS: Patients assigned to hemodialysis facilities with uniformly higher dialysate sodium do not have markedly higher predialysis SBP, providing rather limited support for lowering dialysate sodium to control hypertension, particularly in view of hospitalization and mortality risks associated with lower dialysate sodium.

Low hepcidin triggers hepatic iron accumulation in patients with hepatitis C.

Persistent hepatitis C virus (HCV) infection is a major cause of chronic liver disease including fibrosis, cirrhosis and hepatocellular carcinoma (HCC). Chronic hepatitis C (CHC) is also a problem in patients with chronic kidney disease (CKD), particularly in those on haemodialysis. Excessive iron in the liver of CHC patients contributes to hepatic fibrosis, cirrhosis and finally HCC, while iron depletion is beneficial. In CHC patients without CKD, in HCV-infected experimental animals and in cell culture studies, serum hepcidin levels and/or cellular hepcidin expression are low and directly suppressed by HCV, radical oxygen species, growth factors and/or transcription factors. In contrast, antiviral therapy (e.g. with pegylated interferon-alpha combined with ribavirin) raises hepcidin levels and reduces iron overload in patients with CHC. Hepcidin directly inhibits HCV replication mediated by STAT3 activation. HCV circumvents hepatic innate antiviral defence by lowering hepcidin. If hepcidin is also low in CKD patients with CHC, iron supplementation should be avoided even in CKD patients with CHC treated with erythropoiesis-stimulating agents.

Fluid overload in hemodialysis patients: a cross-sectional study to determine its association with cardiac biomarkers and nutritional status.

BACKGROUND: Chronic fluid overload is associated with higher mortality in dialysis patients; however, the link with cardiovascular morbidity has not formally been established and may be influenced by subclinical inflammation. We hypothesized that a relationship exists between fluid overload and [i] cardiovascular laboratory parameter as well as between fluid overload and [ii] inflammatory laboratory parameters. In addition, we aimed to confirm whether volume status correlates with nutritional status. METHODS: We recorded baseline characteristics of 244 hemodialysis patients at three hemodialysis facilities in Vienna (Austria) and determined associations with volume measurements using the body composition monitor (Fresenius/Germany). In one facility comprising 126 patients, we further analyzed cardiovascular, inflammatory and nutritional parameters. RESULTS: We detected predialysis fluid overload (FO) in 39% of all patients (n = 95) with FO defined as ≥15% of extracellular water (ECW). In this subgroup, the absolute FO was 4.4 +/-1.5 L or 22.9 ± 4.8% of ECW. A sub-analysis of patients from one center showed that FO was negatively associated with body mass index (r = -0.371; p = <0.001), while serum albumin was significantly lower in fluid overloaded patients (p = 0.001). FO was positively associated with D-Dimer (r = 0.316; p = 0.001), troponin T (r = 0.325; p < 0.001), and N-terminal pro-B-type natriuretic peptide (r = 0.436; p < 0.001), but not with investigated inflammatory parameters. CONCLUSIONS: Fluid overload in HD patients was found to be lower in patients with high body mass index, indicating that dry weight was inadequately prescribed and/or difficult to achieve in overweight patients. The association with parameters of cardiovascular compromise and/or damage suggests that fluid overload is a biomarker for cardiovascular risk. Future studies should determine if this applies to patients prior to end-stage renal disease.

Effect of oral sodium bicarbonate supplementation on progression of chronic kidney disease in patients with chronic metabolic acidosis: study protocol for a randomized controlled trial (SoBic-Study).

BACKGROUND: Overt chronic metabolic acidosis in patients with chronic kidney disease develops after a drop of glomerular filtration rate to less than approximately 25 mL/min/1.73 m2. The pathogenic mechanism seems to be a lack of tubular bicarbonate production, which in healthy individuals neutralizes the acid net production. As shown in several animal and human studies the acidotic milieu alters bone and vitamin D metabolism, induces muscle wasting, and impairs albumin synthesis, aside from a direct alteration of renal tissue by increasing angiotensin II, aldosteron and endothelin kidney levels. Subsequent studies testing various therapeutic approaches in very selected study populations showed that oral supplementation of the lacking bicarbonate halts progression of decline of renal function. However, due to methodological limitations of these studies further investigations are of urgent need to ensure the validity of this therapeutic concept. METHODS/DESIGN: The SoBic-study is a single-center, randomized, controlled, open-label clinical phase IV study performed at the nephrological outpatient service of the Medical University of Vienna. Two-hundred patients classified to CKD stage 3 or 4 with two separate measurements of HCO3- of <21 mmol/L will be 1:1 randomized to either receive a high dose of oral sodium bicarbonate with a serum target HCO3- level of 24±1 mmol/L or receive a rescue therapy of sodium bicarbonate with a serum target level of 20±1 mmol/L. The follow up will be for two years. The primary outcome is the effect of sodium bicarbonate supplementation on renal function measured by means of estimated glomerular filtration rates (4-variable-MDRD-equation) after two years. Secondary outcomes are change in markers of bone metabolism between groups, death rates between groups, and the number of subjects proceeding to renal replacement therapy across groups. Adverse events, such as worsening of arterial hypertension due to the additional sodium consumption, will be accurately monitored. DISCUSSION: We hypothesize that sufficiently balanced acid-base homeostasis leads to a reduction of decline of renal function in patients with chronic kidney disease. The concept of an exogenous bicarbonate supplementation to substitute the lacking endogenous bicarbonate has existed for a long time, but has never been investigated sufficiently to state clear treatment guidelines. TRIAL REGISTRATION: EUDRACT Number: 2012-001824-36.

Significance of interdialytic weight gain versus chronic volume overload: consensus opinion.

Predialysis volume overload is the sum of interdialytic weight gain (IDWG) and residual postdialysis volume overload. It results mostly from failure to achieve an adequate volume status at the end of the dialysis session. Recent developments in bioimpedance spectroscopy and possibly relative plasma volume monitoring permit noninvasive volume status assessment in hemodialysis patients. A large proportion of patients have previously been shown to be chronically volume overloaded predialysis (defined as >15% above 'normal' extracellular fluid volume, equivalent to >2.5 liters on average), and to exhibit a more than twofold increased mortality risk. By contrast, the magnitude of the mortality risk associated with IDWG is much smaller and only evident with very large weight gains. Here we review the available evidence on volume overload and IDWG, and question the use of IDWG as an indicator of 'nonadherence' by describing its association with postdialysis volume depletion. We also demonstrate the relationship between IDWG, volume overload and predialysis serum sodium concentration, and comment on salt intake. Discriminating between volume overload and IDWG will likely lead to a more appropriate management of fluid withdrawal during dialysis. Consensually, the present authors agree that this discrimination should be among the primary goals for dialysis caretakers today. In consequence, we recommend objective measures of volume status beyond mere evaluations of IDWG.

Glucose metabolism after renal transplantation.

OBJECTIVE: We determined prevalence, risk factors, phenotype, and pathophysiological mechanism of new-onset diabetes after transplantation (NODAT) to generate strategies for optimal pharmacological management of hyperglycemia in NODAT patients. RESEARCH DESIGN AND METHODS: Retrospective cohort study comparing demographics, laboratory data, and oral glucose tolerance test (OGTT)-derived metabolic parameters from kidney transplant recipients versus subjects not receiving transplants. RESULTS: Among 1,064 stable kidney transplant recipients (≥ 6 months posttransplantation), 113 (11%) had a history of NODAT and 132 (12%) had pretransplant diabetes. In the remaining patients, randomly assigned OGTTs showed a high prevalence of abnormal glucose metabolism (11% diabetes; 32% impaired fasting glucose, impaired glucose tolerance, or both), predominantly in older patients who received tacrolimus as the primary immunosuppressant. Compared with 1,357 nontransplant subjects, stable kidney transplant recipients had lower basal glucose, higher glycated hemoglobin, lower insulin secretion, and greater insulin sensitivity in each of the three subgroups, defined by OGTT 2-h glucose (<140, 140-199, ≥ 200 mg/dL). These findings were reinforced in linear spline interpolation models of insulin secretion and sensitivity (all P < 0.001) and in another regression model in which the estimated oral glucose insulin sensitivity index was substantially higher (by 79-112 mL/min m(2)) for transplant versus nontransplant subjects despite adjustments for age, sex, and BMI (all P < 0.001). CONCLUSIONS: Glucose metabolism differs substantially between kidney transplant recipients and nontransplant controls. Because impaired insulin secretion appears to be the predominant pathophysiological feature after renal transplantation, early therapeutic interventions that preserve, maintain, or improve ß-cell function are potentially beneficial in this population.

Hereditary amyloidosis caused by R554L fibrinogen Aα-chain mutation in a Spanish family and review of the literature.

BACKGROUND: Hereditary amyloidosis with predominant renal disease can be caused by mutations in the gene encoding the fibrinogen Aα-chain (AFib). Here, we describe the clinical course of AFib amyloidosis associated with the rare R554L mutation, and the significance of extrarenal amyloid deposits and their possible influence on cardiovascular morbidity. METHODS: We report on 101 members of a family after having conducted patient interviews, chart review, genetic testing, renal biopsies and assessment for extrarenal amyloid deposition. RESULTS: Ten family members had chronic kidney disease with late-onset gross proteinuria and a variable course of declining renal function, starting in the fourth decade of life. In two affected living members, we identified the AFib R554L mutation. Renal biopsies from two affected members revealed almost complete obliteration of the mesangial glomerular architecture, although kidney function was only moderately impaired. There was neither evidence of extrarenal amyloidosis nor accelerated atherosclerosis. CONCLUSIONS: Renal amyloidosis associated with the R554L AFib variant dominated the clinical picture in this family, which was similar to that associated with the much more prevalent E526V mutation. Although it has been hypothesized that vascular deposits of fibrinogen amyloid may be associated with accelerated atherosclerosis, there was no suggestion of this in this particular kindred.

Cinacalcet effect on polymorphonuclear leucocytes of kidney transplant patients.

BACKGROUND: Polymorphonuclear leucocytes (PMNLs) play a key role in the nonspecific immune defence. Cinacalcet reduces serum calcium levels in kidney transplant recipients with mineral bone disorder associated with chronic kidney disease. We investigated essential functions of PMNLs of kidney transplant recipients with and without hypercalcaemia and with and without cinacalcet therapy. SUBJECTS AND METHODS: Oxidative burst, phagocytosis, apoptosis and intracellular calcium concentrations of PMNLs from normocalcaemic kidney transplant patients without (KT-NC) or with cinacalcet intake (KT-NC/CI), hypercalcaemic kidney transplant patients (KT-HC) and healthy subjects (HS) were investigated. RESULTS: Stimulation of oxidative burst of PMNLs from KT-HC patients by phorbol-12-myristate-13-acetate or Escherichia coli was significantly attenuated compared with PMNLs from KT-NC, KT-NC/CI and HS. Apoptosis of PMNLs from KT-HC patients was significantly decreased compared with cells from KT-NC, KT-NC/CI and HS. Apoptosis correlated significantly with serum calcium concentrations. Intracellular calcium concentrations and phagocytosis of PMNLs did not differ between groups. CONCLUSIONS: Our data indicate that stimulation of PMNL oxidative burst and apoptosis is significantly diminished in kidney transplant patients with hypercalcaemia, while kidney transplant patients with serum calcium levels normalized by cinacalcet have normal PMNL functions despite immunosuppressive therapy.

Anaemia management and mortality risk in chronic kidney disease.

Renal anaemia is a frequent complication in patients with chronic kidney disease (CKD). Severe anaemia (haemoglobin <90 g/l) is associated with increased risks of mortality and cardiac complications, such as left ventricular hypertrophy and cardiovascular disease, and impaired quality of life. Randomized controlled trials have tested the hypothesis that increasing haemoglobin level using erythropoiesis-stimulating agents (ESAs) lowers these risks and improves quality of life. Use of ESAs to normalize haemoglobin levels (to ≥130 g/l) versus the partial correction of anaemia (to haemoglobin levels of 90-110 g/l) has repeatedly been shown to have no cardiac benefit and to be associated with no incremental improvement in outcomes and quality of life (except fatigue), but has been shown to be associated with an increased risk of cardiovascular events and death. Use of more-intense iron dosing has been proposed in order to reduce ESA dosing but liberal intravenous iron therapy is also associated with complications, and its long-term safety has not yet been adequately investigated. For patients with CKD on dialysis, US medication labels recommend administering ESAs at doses sufficient to avoid transfusions, whereas European and Canadian labels recommend targeting haemoglobin levels of 100-120 g/l and 110-120 g/l, respectively. Treatment of anaemia to haemoglobin levels of 90-110 g/l in patients with CKD accomplishes what we want--a reduced need for transfusions and possible reductions in fatigue, while avoiding high doses of ESA or iron in order to achieve a specific haemoglobin goal.

Novel views on new-onset diabetes after transplantation: development, prevention and treatment.

New-onset diabetes after transplantation (NODAT) is associated with increased risk of allograft failure, cardiovascular disease and mortality, and therefore, jeopardizes the success of renal transplantation. Increased awareness of NODAT and the prediabetic states (impaired fasting glucose and impaired glucose tolerance, IGT) has fostered previous and present recommendations, based on the management of type 2 diabetes mellitus (T2DM). Unfortunately, the idea that NODAT merely resembles T2DM is potentially misleading, because the opportunity to initiate adequate anti-hyperglycaemic treatment early after transplantation might be given away for 'tailored' immunosuppression in patients who have developed NODAT or carry personal risk factors. Risk factor-independent mechanisms, however, seem to render postoperative hyperglycaemia with subsequent development of overt or 'full-blown' NODAT, the unavoidable consequence of the transplant and immunosuppressive process itself, at least in many cases. A proof of the concept that timely preventive intervention with exogenous insulin against post-transplant hyperglycaemia may decrease NODAT was recently provided by a small clinical trial, which is awaiting confirmation from a multicentre study. However, because early insulin therapy aimed at beta-cell protection seems to contrast the currently recommended, stepwise approach of 'watchful waiting' prior to pancreatic decompensation, we here aim at reviewing recent concepts regarding the development, prevention and treatment of NODAT, some of which seem to challenge the traditional view on T2DM and NODAT. In summary, we suggest a novel, risk factor-independent management approach to NODAT, which includes glycaemic monitoring and anti-hyperglycaemic treatment in virtually everybody after transplantation. This approach has widespread implications for future research and is intended to tackle NODAT and also ultimately cardiovascular disease.

Differentiating factors between erythropoiesis-stimulating agents: an update to selection for anaemia of chronic kidney disease.

Erythropoiesis-stimulating agents (ESAs) have become a hallmark of anaemia therapy in patients with chronic kidney disease (CKD). Although different ESAs are available for the treatment of renal anaemia, each nephrologist should select a single ESA for an individual patient. Epoetin alfa and epoetin beta have been used 1-3 times weekly but extended-interval dosing up to every 4 weeks is also effective in a substantial majority of CKD patients. However, the epoetin dose necessary to achieve or maintain target haemoglobin (Hb) levels increases substantially as the dosing interval increases. Subcutaneous administration of short-acting ESAs is more effective than the intravenous route of administration. Darbepoetin alfa and the continuous erythropoietin receptor activator (CERA) have been developed as a treatment for anaemia with extended administration intervals (every 2 weeks and every 4 weeks, respectively). Dose requirements for these long-acting ESAs are independent of the route of administration. Patents of short-acting ESAs have expired, which has opened the field for biosimilars. Epoetin biosimilars approved by the European Medicines Agency (EMA) or the US Food and Drug Administration (FDA) have been shown to have a comparable efficacy and safety profile to their originators. An alarming increase in pure red cell aplasia (PRCA) in Thailand with follow-on epoetins manufactured in Asia (but also those manufactured in Latin America) indicates that stringent country-specific approval and pharmacovigilance protocols for ESAs manufactured in non-North American and non-EU European countries are urgently needed. Two PRCA cases occurring with subcutaneous HX575 (one certain, one likely) indicate that chances of inducing a more immunogenic product are unpredictable, even with a biosimilar epoetin approved under the EMA biosimilar approval pathway. Phase III clinical trials with peginesatide, a pegylated synthetic peptide-based ESA without any homology to erythropoietin raised safety concerns in non-dialysis CKD patients but not in dialysis patients.