Achievement of renal anemia KDIGO targets by two different clinical strategies - a European hemodialysis multicenter analysis.

BACKGROUND: The optimal treatment algorithm for iron therapy and the use of erythropoiesis-stimulating agents (ESA) in anemic hemodialysis (HD) patients has not been established. Hemoglobin (Hb) target levels can be achieved through more frequent intravenous (IV) iron use with lower ESA dose, or with less iron dosing but higher ESA. ESA therapy to correct anemia may result in severe arterial and venous thrombotic complications and the evidence base evaluating hard clinical outcomes related to the use of IV iron is sparse. METHODS: A total of 1247 maintenance HD patients from 12 dialysis centers in Portugal (n = 730) and Poland (n = 517) were considered. We assessed achievement of KDIGO renal anemia targets with focus on treatment strategies, which typically differ between countries. In Poland the use and dose of IV iron was 35-72% higher than that in Portugal (p <  0.001) during three consecutive months; use and dose of ESA was 61% higher in Portugal (5034 vs 3133 IU (adjusted)/week, p <  0.001). RESULTS: Mean Hb concentration was similar (11.0 vs 11.0 g/dL) in patients treated in both countries and the proportion of patients within KDIGO anemia target was 69.5% in Poland vs 65.8% in Portugal (NS). Ferritin and TSAT levels and the proportion of patients with TSAT > 20 and > 50% were both significantly higher in patients in Poland (88.8 and 14.6%) than in Portugal (76.3 and 5.7% respectively, p <  0.001). Significantly more patients in Poland had a ferritin concentration > 800 µg/L (35.6%) compared to Portugal (15.8%, p <  0.001). The ESA resistance index (ERI) was significantly higher in patients treated in Portugal (p <  0.001). Correlation analyses showed confounding by treatment indication in unadjusted models. Multiple and logistic regression analyses showed that with ferritin within KDIGO recommended range of 200-800 µg/L the odds for Hb within guidelines increased significantly. Annual gross mortality was 16% in Poland and 13% in Portugal (NS); there were no differences in cause-specific mortality. CONCLUSIONS: Administration of high doses of IV iron in routine clinical HD practice may not be associated with considerable harm. However, large randomized controlled trials are needed to provide absolute evidence of iron safety.

Influence of gender and age on haemodialysis practices: a European multicentre analysis.

BACKGROUND: Women of all ages and elderly patients of both genders comprise an increasing proportion of the haemodialysis population. Worldwide, significant differences in practice patterns and treatment results exist between genders and among younger versus older patients. Although efforts to mitigate sex-based differences have been attempted, significant disparities still exist. METHODS: This retrospective cohort study included all 1247 prevalent haemodialysis patients in DaVita units in Portugal (five dialysis centres, n = 730) and Poland (seven centres, n = 517). Demographic data, dialysis practice patterns, vascular access prevalence and the achievement of a variety of Kidney Disease: Improving Global Outcomes (KDIGO) treatment targets were evaluated in relation to gender and age groups. RESULTS: Body weight and the prescribed dialysis blood flow rate were lower in women (P < 0.001), whereas treated blood volume per kilogram per session was higher (P < 0.01), resulting in higher single-pool Kt/V in women than in men (P < 0.001). Haemoglobin was significantly higher in men (P = 0.01), but the proportion of patients within target range (10-12 g/dL) was similar. Men more often had an arteriovenous fistula than women (80% versus 73%; P < 0.01) with a similar percentage of central venous catheters. There were no gender-specific differences in terms of dialysis adequacy, anaemia parameters or mineral and bone disorder parameters, or in the attainment of KDIGO targets between women and men >80 years of age. CONCLUSIONS: This large, multicentre real-world analysis indicates that haemodialysis practices and treatment targets are similar for women and men, including the most elderly, in DaVita haemodialysis clinics in Europe.

Cell type-specific tumor suppression by Ink4a and Arf in Kras-induced mouse gliomagenesis.

Homozygous deletion of the INK4a-ARF locus is one of the most frequent mutations found in human glioblastoma. We have previously shown that combined Ink4a-Arf loss can increase tumor incidence in both glial progenitor cells and astrocytes during mouse gliomagenesis. Here we have investigated the separate contribution of loss of each of the tumor suppressor genes in glial progenitor cells and astrocytes in Akt + Kras-induced gliomagenesis. We show that Arf is the major tumor suppressor gene in both cell types. Arf loss generated glioblastomas from both nestin-expressing glial progenitor cells and glial fibrillary acidic protein-expressing astrocytes, with a significantly higher incidence in astrocytes. Ink4a loss, on the other hand, could only significantly contribute to gliomagenesis from glial progenitor cells and the induced tumors were of lower malignancy than those seen in Arf-deficient mice. Thus, Ink4a and Arf have independent and differential tumor suppressor functions in vivo in the glial cell compartment.

Expression analysis of genes involved in brain tumor progression driven by retroviral insertional mutagenesis in mice.

Retroviral tagging previously identified putative cancer-causing genes in a mouse brain tumor model where a recombinant Moloney murine leukemia virus encoding the platelet-derived growth factor B-chain (MMLV/PDGFB) was intracerebrally injected in newborn mice. In the present study, expression analysis using cDNA arrays revealed several similarities of virus-induced mouse gliomas with human brain tumors. Brain tumors with short latency contained on average 8.0 retroviral insertions and resembled human glioblastoma multiforme (GBM) whereas long-latency gliomas were of lower grade, similar to human oligodendroglioma (OD) and had 2.3 insertions per tumor. Several known and novel genes of tumor progression or cell markers were differentially expressed between OD- and GBM-like tumors. Array and quantitative real-time PCR analysis demonstrated elevated expression similar to Pdgfralpha of retrovirally tagged genes Abhd2, Ddr1, Fos, Ng2, Ppfibp1, Rad51b and Sulf2 in both glioma types compared to neonatal and adult normal brain. The retrovirally tagged genes Plekhb1, Prex1, Prkg2, Sox10 and 1200004M23Rik were upregulated in the tumors but had a different expression profile than Pdgfralpha whereas Rap1gap, Gli1, Neurl and Camk2b were downregulated in the tumors. The present study accentuates the proposed role of the retrovirally tagged genes in PDGF-driven gliomagenesis and indicates that insertional mutagenesis can promote glioma progression.

Identification of candidate cancer-causing genes in mouse brain tumors by retroviral tagging.

Murine retroviruses may cause malignant tumors in mice by insertional mutagenesis of host genes. The use of retroviral tagging as a means of identifying cancer-causing genes has, however, almost entirely been restricted to hematopoietic tumors. The aim of this study was to develop a system allowing for the retroviral tagging of candidate genes in malignant brain tumors. Mouse gliomas were induced by a recombinant Moloney murine leukemia virus encoding platelet-derived growth factor (PDGF) B-chain. The underlying idea was that tumors evolve through a combination of PDGF-mediated autocrine growth stimulation and insertional mutagenesis of genes that cooperate with PDGF in gliomagenesis. Common insertion sites (loci that were tagged in more than one tumor) were identified by cloning and sequencing retroviral flanking segments, followed by blast searches of mouse genome databases. A number of candidate brain tumor loci (Btls) were identified. Several of these Btls correspond to known tumor-causing genes; these findings strongly support the underlying idea of our experimental approach. Other Btls harbor genes with a hitherto unproven role in transformation or oncogenesis. Our findings indicate that retroviral tagging with a growth factor-encoding virus may be a powerful means of identifying candidate tumor-causing genes in nonhematopoietic tumors.