[Anemia and iron deficiency - treatment options in chronic kidney disease and in chronic heart failure]. / Anämie und Eisenmangel ­ Behandlungsoptionen bei chronischer Nierenerkrankung und chronischer Herzinsuffizienz.

Anemia and iron deficiency are highly prevalent in chronic kidney disease (CKD) and in chronic heart failure. Both may epidemiologically predict future renal and/or cardiovascular events. However, anemia treatment with either erythropoietin or erythropoiesis-stimulating agents failed to induce a prognostic benefit in either CKD or chronic heart failure. Instead, in the subgroup of chronic dialysis patients, liberal intravenous iron supplementation was beneficial, and ongoing clinical trials are testing the prognostic implication of intravenous iron supplementation in chronic heart failure. Finally, HIF stabilizers are a new treatment option for anemia in chronic kidney disease, and safety studies are currently ongoing in CKD patients. Whether patients suffering from chronic heart failure might also benefit from this treatment is currently unknown.

Lipid management in patients with chronic kidney disease.

An increased risk of cardiovascular disease, independent of conventional risk factors, is present even at minor levels of renal impairment and is highest in patients with end-stage renal disease (ESRD) requiring dialysis. Renal dysfunction changes the level, composition and quality of blood lipids in favour of a more atherogenic profile. Patients with advanced chronic kidney disease (CKD) or ESRD have a characteristic lipid pattern of hypertriglyceridaemia and low HDL cholesterol levels but normal LDL cholesterol levels. In the general population, a clear relationship exists between LDL cholesterol and major atherosclerotic events. However, in patients with ESRD, LDL cholesterol shows a negative association with these outcomes at below average LDL cholesterol levels and a flat or weakly positive association with mortality at higher LDL cholesterol levels. Overall, the available data suggest that lowering of LDL cholesterol is beneficial for prevention of major atherosclerotic events in patients with CKD and in kidney transplant recipients but is not beneficial in patients requiring dialysis. The 2013 Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for Lipid Management in CKD provides simple recommendations for the management of dyslipidaemia in patients with CKD and ESRD. However, emerging data and novel lipid-lowering therapies warrant some reappraisal of these recommendations.

S-adenosylhomocysteine is associated with subclinical atherosclerosis and renal function in a cardiovascular low-risk population.

OBJECTIVE: Although homocysteine has been proposed as a cardiovascular risk factor, interventional trials lowering homocysteine have not consistently demonstrated clinical benefit. Recent evidence proposed the homocysteine metabolite S-adenosylhomocysteine (SAH) rather than homocysteine itself as the real culprit in cardiovascular disease. Of note, SAH is predominantly excreted by the kidneys, and cannot be lowered by vitamin supplementation. Due to its cumbersome measurement, data from large studies on the association between SAH, kidney function and cardiovascular disease are not available. METHODS: We recruited 420 apparently healthy subjects into our I Like HOMe FU study. Among all study participants, we assessed parameters of C1 metabolism (homocysteine, SAH and S-adenosylmethionine), renal function (estimated glomerular filtration rate [eGFR]) and subclinical atherosclerosis (common carotid intima-media-thickness [IMT]). eGFR was estimated by the CKD-EPIcreat-cys equation. RESULTS: Traditional cardiovascular risk factors and subclinical atherosclerosis were associated with SAH, but not with homocysteine (IMT vs SAH: r = 0.129; p = 0.010; IMT vs homocysteine: r = 0.009; p = 0.853). Moreover, renal function was more closely correlated with SAH than with homocysteine (eGFR vs SAH: r = -0.335; p < 0.001; eGFR vs homocysteine: r = -0.250; p < 0.001). The association between eGFR and SAH remained significant after adjustment for traditional cardiovascular risk factors. CONCLUSION: In summary, cardiovascular risk factors, subclinical atherosclerosis and eGFR are more strongly associated with SAH than with homocysteine in apparently healthy subjects. Thus, SAH might represent a more promising target to prevent cardiovascular disease than homocysteine.

Massive analysis of cDNA Ends (MACE) and miRNA expression profiling identifies proatherogenic pathways in chronic kidney disease.

Epigenetic dysregulation contributes to the high cardiovascular disease burden in chronic kidney disease (CKD) patients. Although microRNAs (miRNAs) are central epigenetic regulators, which substantially affect the development and progression of cardiovascular disease (CVD), no data on miRNA dysregulation in CKD-associated CVD are available until now. We now performed high-throughput miRNA sequencing of peripheral blood mononuclear cells from ten clinically stable hemodialysis (HD) patients and ten healthy controls, which allowed us to identify 182 differentially expressed miRNAs (e.g., miR-21, miR-26b, miR-146b, miR-155). To test biological relevance, we aimed to connect miRNA dysregulation to differential gene expression. Genome-wide gene expression profiling by MACE (Massive Analysis of cDNA Ends) identified 80 genes to be differentially expressed between HD patients and controls, which could be linked to cardiovascular disease (e.g., KLF6, DUSP6, KLF4), to infection / immune disease (e.g., ZFP36, SOCS3, JUND), and to distinct proatherogenic pathways such as the Toll-like receptor signaling pathway (e.g., IL1B, MYD88, TICAM2), the MAPK signaling pathway (e.g., DUSP1, FOS, HSPA1A), and the chemokine signaling pathway (e.g., RHOA, PAK1, CXCL5). Formal interaction network analysis proved biological relevance of miRNA dysregulation, as 68 differentially expressed miRNAs could be connected to 47 reciprocally expressed target genes. Our study is the first comprehensive miRNA analysis in CKD that links dysregulated miRNA expression with differential expression of genes connected to inflammation and CVD. After recent animal data suggested that targeting miRNAs is beneficial in experimental CVD, our data may now spur further research in the field of CKD-associated human CVD.

Influence of cholecalciferol supplementation in hemodialysis patients on monocyte subsets: a randomized, double-blind, placebo-controlled clinical trial.

BACKGROUND/AIMS: Although most hemodialysis patients share a significant 25-hydroxyvitamin D [25(OH)D] deficiency, supplementation is controversially discussed. A potential influence on monocyte and T lymphocyte dysfunction advocates blood level-adapted supplementation as recommended by K/DOQI guidelines. This was a prospective double-blind randomized placebo controlled trial examining immune effects of 12 weeks of cholecalciferol supplementation. METHODS: We initiated serum level-adapted de novo cholecalciferol supplementation in 38 hemodialysis patients. Outcome measures were: monocyte subset cell counts (CD14+CD16++ vs. CD14++CD16+ vs. CD14++CD16-), lymphocyte Th1/Th2 differentiation frequencies, serum inflammatory proteins CRP and TNFα, parathyroid hormone (PTH), FGF-23, and α-Klotho. RESULTS: At baseline, the mean 25(OH)D serum level in the study population was 31.7 ± 14.3 nmol/l, and only 3% of patients had levels within the normal range. At 12 weeks, 25(OH)D levels were normalized in the verum group (87.8 ± 22.3 vs. placebo 24.6 ± 8.0 nmol/l, p < 0.0001). In parallel, 1,25(OH)2D levels increased in the verum group. Monocyte subset cell counts as well as Th1 and Th2 lymphocyte frequencies did not change significantly after 12 weeks of cholecalciferol supplementation. There was also no significant difference in PTH, alkaline phosphatase, calcium, phosphate, TNFα, FGF-23, α-Klotho and CRP levels. CONCLUSIONS: Oral cholecalciferol supplementation according to the K/DOQI recommendations normalizes 25(OH)D levels without relevant side effects such as hyperphosphatemia or hypercalcemia. However, beneficial pleiotropic effects on monocyte subset cell counts, T cell differentiation, or cytokine production could not be confirmed at least at the used dosage. PTH and FGF23 levels were not affected during cholecalciferol administration.

FGF-23: the rise of a novel cardiovascular risk marker in CKD.

Elevated plasma levels of the phosphaturic hormone fibroblast growth factor 23 (FGF-23) are a hallmark of chronic kidney disease (CKD)-mineral and bone disorder. FGF-23 allows serum phosphate levels within physiological limits to be maintained in progressive CKD until end-stage renal disease is reached. Despite its seemingly beneficial role in phosphate homeostasis, several prospective studies in dialysis patients and in patients with less advanced CKD associated elevated FGF-23 with poor cardiovascular and renal outcome. Moreover, very recent evidence suggests an adverse prognostic impact of elevated FGF-23 even in subjects without manifest CKD. These epidemiological data are supplemented by laboratory findings that reveal a pathophysiological role of FGF-23 in the pathogenesis of myocardial injury. In aggregate, these clinical and experimental data identify FGF-23 as a promising target of novel therapeutic interventions in CKD and beyond, which should be tested in future clinical trials.