BACKGROUND:Aim of this study was to evaluate whether the A736V TMPRSS6 polymorphism, a major genetic determinant of iron metabolism in healthy subjects, influences serum levels of hepcidin, the hormone regulating iron metabolism, and erythropoiesis in chronic hemodialysis (CHD). METHODS:To this end, we considered 199 CHD patients from Northern Italy (157 with hepcidin evaluation), and 188 healthy controls without iron deficiency, matched for age and gender. Genetic polymorphisms were evaluated by allele specific polymerase chain reaction assays, and hepcidin quantified by mass spectrometry. RESULTS:Serum hepcidin levels were not different between the whole CHD population and controls (median 7.1, interquartile range (IQR) 0.55-17.1 vs. 7.4, 4.5-17.9 nM, respectively), but were higher in the CHD subgroup after exclusion of subjects with relative iron deficiency (p = 0.04). In CHD patients, the A736V TMPRSS6 polymorphism influenced serum hepcidin levels in individuals positive for mutations in the HFE gene of hereditary hemochromatosis (p < 0.0001). In particular, the TMPRSS6 736 V variant was associated with higher hepcidin levels (p = 0.017). At multivariate analysis, HFE and A736V TMPRSS6 genotypes predicted serum hepcidin independently of ferritin and C reactive protein (p = 0.048). In patients without acute inflammation and overt iron deficiency (C reactive protein <1 mg/dl and ferritin >30 ng/ml; n = 86), hepcidin was associated with lower mean corpuscular volume (p = 0.002), suggesting that it contributed to iron-restricted erythropoiesis. In line with previous results, in patients without acute inflammation and severe iron deficiency the "high hepcidin" 736 V TMPRSS6 variant was associated with higher erythropoietin maintenance dose (p = 0.016), independently of subclinical inflammation (p = 0.02). CONCLUSIONS:The A736V TMPRSS6 genotype influences hepcidin levels, erythropoiesis, and anemia management in CHD patients. Evaluation of the effect of TMPRSS6 genotype on clinical outcomes in prospective studies in CHD may be useful to predict the outcomes of hepcidin manipulation, and to guide treatment personalization by optimizing anemia management.

to those with eGFR0 >= 60, were 1.0 (0.8-1.3), 1.9(1.5-2.6), and 3.6(2.0- 6.4), respectively. Diabetic men and women had greater age-adjusted eGFR decline, 1.6 (95% confidence interval, 0.9;2.3) ml/min/1,73m 2 /yr and 1.2 (0.3;2.1) than their nondiabetic counterparts, 0.6 (0.4;0.9) and 0.1 (0.1;+0.2), respectively. The lower the eGFRm, the lower the decline: 0.6, 0.7, 1.5, 1.5 ml/min/1,73m2/yr, for eGFRm >60, 45-59, 30-44, <30, respectively. In nondiabetic participants, proteinuria (>300 mg/g creatinine) was present in 7% of those with mean GFR > 60 as well as in those with a mean GFR in 45-59 and stable renal function defined as a GFR decline < 4%/yr, but in more than 20% of those with either lower mean GFR or rapidly declining GFR, defined as a GFR decline > 4%/yr. Anemia was present in less than 7% of the participants with mean GFR > 60 and in those with a mean GFR in 45-59 and stable renal function, but in 19% of their counterparts with rapidly declining GFR and in more than 50% of those with a mean GFR < 30. Conclusions: A cut-off value of 60 ml/min/1.73m 2 tends to label a large number of elderly individuals with CKD in whom only a small fraction is at risk for mortality and/or CKD progression and complication. These results suggest that in nondiabetic elderly screened for CKD, clinical evaluation may be limited to those with eGFR <45 ml/min/1.73m 2 .

Background and objectives: Increased serum hepcidin has been reported in patients receiving chronic hemodialysis, and hypothesized to contribute to the alterations of iron metabolism of end-stage renal disease. However, no quantitative assessment is available to date; the clinical determinants are still under definition; and the role of genetic factors, namely HFE mutations, has not yet been evaluated. The aim of this study was to quantitatively assess serum hepcidin-25 in hemodialysis patients versus controls, and analyze the relationship between hepcidin, iron indices, HFE genotype, and erythropoietic parameters. Design, setting, participants & measurements: Sixty-five hemodialysis patients and 57 healthy controls were considered. Hepcidin-25 was evaluated by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry, HFE genotype by restriction analysis. Results: Serum hepcidin-25 was higher in hemodialysis patients compared with controls. In patients, hepcidin-25 correlated positively with ferritin and C reactive protein, and negatively with serum iron after adjustment for confounders. Hepcidin/ferritin ratio was lower in patients with (n = 25) than in those without (n = 40) HFE mutations. At multivariate analysis, hepcidin-25 was independently associated with ferritin and HFE status. In a subgroup of 22 “stable” patients, i.e., with Hb levels on target, normal CRP levels, and absence of complications for at least 1 yr, hepcidin-25 was negatively correlated with Hb levels independently of confounders. Conclusions: Serum hepcidin-25 is increased in hemodialysis patients, regulated by iron stores and inflammation, and relatively reduced in subjects carrying frequent HFE mutations. Hepcidin-25 may contribute to the pathogenesis of anemia by decreasing iron availability.

Myśliwiec M. The periodontal status of pre-dialysis chronic kidney disease and maintenance dialysis patients. Nephrol Dial Transplant 2007; 22: 457–464 3. Trzonkowski P, Mysliwska J, De bska-S?lizień A et al. Longterm therapy with recombinant human erythropoietin decreases percentage of CD 152þ lymphocytes in primary glomerulonephritis haemodialysis patients. Nephrol Dial Transplant 2002; 17: 1070–1080 4. Tyrzyk S, Sadlak-Nowicka J, Ke dzia A, Bochniak M, Szumska-Tyrzyk B, Rutkowski P. Clinical and mycological examinations of oral mucosa in cyclosporine A treated patients after renal transplantation. Przegl Lek 2004; 61: 467–472 5. Tyrzyk S, Sadlak-Nowicka J, Ke dzia A, Bochniak M, Rutkowski P. Proposal of a periodontal preventive and treatment scheme for patients before and after renal transplantation receiving cyclosporine A. Dent Med Probl 2006; 43: 483–491 6. Stellingsma C, Vissink A, Meijer HJA, Kuiper C, Raghoebar GM. Implantology and the severely resorbed edentulous mandible. Crit Rev Oral Biol Med 2004; 15: 240–248 7. Wojtowicz A, Grabowska K, Kukula K et al. Densitometric examination of male patients with renal osteodystrophy. Prot Stom 2002; 52: 195–201 8. Kukula K, Wojtowicz A, Dijakiewicz M et al. The linear rediometric analysis of the jaws in renal osteodystrophy: introduction to implanto-prosthodontic treatment. Prot Stom 2005; 55: 336–343 9. Wojtowicz A, Dijakiewicz M, Wandzel B et al. The evaluation of mineral crystallinity of mandibular bone tissue using electron paramagnetic resonance (EPR) in patients suffering from renal osteodystrophy. Przegl Lek 2006; 63: 759–761 10. Dijakiewicz M, Wojtowicz A. Problems and algorithm of dental procedures in patients on renal replacement therapy. In: Rutkowski B, ed. Dialysis in Medical Practice, MAKmedia, Gdańsk: 2004

(r1⁄4 0.495; P1⁄4 0.024). There were no relationships between IL-6 changes and the main mineral metabolism related parameters. Our results agree with previous experimental findings [4] and point to the efficacy of calcimimetic drugs for the control of uraemic SHP. It was unexpected that 6 months of cinacalcet treatment resulted in highly significant increases in OPG and decreases in Fetuin-A serum levels. OPG, a cytokine produced and secreted mainly by osteoblasts, has been claimed to play an as yet undefined role in the vascular calcification process. Although a protective effect of increased OPG levels on vascular calcification has been suggested, higher OPG serum levels have been linked to an increased extent of arterial wall calcification, increased mortality rates in uraemic patients, and most importantly, with increased mortality in dialysis patients [3,5]. The clinical significance of the OPG increase observed in our patients and its potential effects on the vascular calcification process cannot be drawn from our data. Interestingly, OPG increases were significantly correlated with the degree of reduction in c-Ca levels. In association with the OPG increases, cinacalcet treatment also caused significant decreases in Fetuin-A levels without changes in IL-6, indicating no change in the inflammatory state in our patients. The Fetuin-A reduction was significantly related to PTH decreases. Previous studies have emphasized an association between low Fetuin-A levels with both increased vascular calcification and cardiovascular mortality [2,6]. From our data, we cannot determine whether the Fetuin-A decrease represents a real increase in risk for the calcification process, or whether it is the consequence of a reduced demand for a feedback defence mechanism, which may be secondary to improved mineral metabolism, by cinacalcet, that reduces the pro-calcification burden. This possibility was proposed in non-dialysed diabetic nephropathy patients [7]. Although we are aware of the main limitation of this preliminary study, the highly significant changes in both OPG and Fetuin-A levels observed in our patients provide a stimulus and starting point for further research in this field.

Background/Aims: HFE protein controls iron absorption and cycling, and HFE mutations influence iron status. The aim was to evaluate the effect of the HFE genotype on the need for iron and erythropoietin in Italian hemodialysis patients. Methods: Ninety-six prevalent patients were evaluated at the time of enrolment and prospectively followed for 3 years. Patients were given r-HuEPO and Fe3+-gluconate according to guidelines. The HFE genotype was determined by restriction analysis. Results: Three patients (3%) carried the C282Y mutation, 4 (4%) were homozygous and 18 (19%) heterozygous for the H63D mutation, and 71 (74%) were negative for both. At enrolment, subjects positive for HFE mutations had higher iron stores (ferritin 617 ± 663 vs. 423 ± 386 ng/ml, p = 0.05), were receiving less iron (82.5 ± 66 vs. 110 ± 154 mg/month, p = 0.05) and a lower r-HuEPO dosage (98 ± 83 vs. 142 ± 138 U/kg/week, p = 0.03). Consistently during the study period, patients positive for HFE mutations received a lower amount of r-HuEPO (94.5 ± 63 vs. 186 ± 344 U/kg/week, p = 0.01) and iron (97 ± 63 vs. 121 ± 68 mg/month, p = 0.07). Upon Cox regression analysis, after adjustment for confounding variables, the presence of HFE mutations was associated with a reduced risk of death (HR 0.6, 95% CI 0.34–1.03, p = 0.06). Conclusion:HFE mutations reduce the amount of r-HuEPO and iron necessary to support erythropoiesis in hemodialysis.

Background/Aims: Hyperferritinemia has been associated with cardiovascular mortality in hemodialysis patients. The aim of this study was to evaluate whether serum ferritin was affected by iron and oxidative status and by genetic factors (HFE mutations and the Ala9Val MnSOD polymorphism), and to assess the association between ferritin and cardiovascular damage evaluated by ecocolor-Doppler. Methods: 63 hemodialysis patients were tested for HFE and MnSOD genotype by restriction analysis and oxidative status; vascular damage was assessed by measuring intima-media thickness, and by detecting plaques at carotid and femoral arteries. Results: Ferritin was correlated with transferrin saturation (p = 0.003), decreased iron-specific serum antioxidant activity (p = 0.01), age (p = 0.03), and C282Y and H63D HFE mutations (p = 0.05), but not with the MnSOD polymorphism. Ferritin was associated with advanced vascular damage, as evaluated by the presence of plaques, both at carotid (p = 0.03) and femoral arteries (p = 0.001), the other risk factors being age and low albumin. Low iron-specific antioxidant activity was associated with carotid plaques (p = 0.03). Conclusion: In hemodialysis patients, hyperferritinemia reflects a relative increase in iron availability and a decrease in iron-specific antioxidant activity, is favored by HFE mutations, and represents a risk factor for advanced cardiovascular damage.