Serum levels of intact parathyroid hormone is a prognostic indicator of dialyzed patients: the Nishinomiya study.

Patients with chronic kidney disease on dialysis are at higher risk for cardiovascular disease (CVD), which is the greatest cause of mortality. The target range of serum intact parathyroid hormone (iPTH) for prognosis, 60 to 240 pg/mL, was recommended by the Japanese Society for Dialysis Therapy guidelines. To investigate the impact of this iPTH target on CVD, dialysis patients were enrolled. A total 287 participants were observed. At the start of the study, serum iPTH levels, routine laboratory parameters, and certain factors related to CVD were evaluated. A survival analysis (Kaplan-Meier curve) was used. After 10 years of follow-up, 19.2% of patients had CVD. The subjects were divided into three groups according to their iPTH level at baseline based on the target range of 60 to 240 pg/mL: Low, Middle, and High groups. CVD was more common in the High and Low groups compared to the Middle group. A lower risk of CVD was evident in the extended dialysis patients with a range of 60 to 240 pg/mL iPTH. Further studies are needed to evaluate the impact of the iPTH level on poor outcome.

The mitochondrial protein frataxin is downregulated in hemodialysis patients.

BACKGROUND: The mitochondrial protein frataxin regulates iron metabolism for heme and iron sulfur cluster synthesis in the mitochondria and could be associated with the regulation of oxidative stress. To clarify the expression of frataxin and its association with uremia, we evaluated the mRNA and protein levels of frataxin in the polymorphonuclear leukocytes (PMNLs) of patients on hemodialysis (HD). METHODS: Uremic patients on HD (n = 18) and healthy control subjects (n = 18) were investigated. PMNLs were isolated by differential centrifugation. The mRNA levels of frataxin in isolated leukocytes were quantified by TaqMan real-time polymerase chain reaction. Frataxin protein expression in the cell lysate was evaluated using SDS-polyacrylamide gel electrophoresis and Western blotting. RESULTS: The frataxin/glyceraldehyde-3-phosphate dehydrogenase mRNA ratio in PMNLs from uremic patients was significantly lower than that in control subjects. Frataxin protein expression in uremic patients was also significantly lower than that in controls. Multiple regression analysis showed that frataxin mRNA levels were independently associated with the serum levels of both the oxidative stress marker malondialdehyde and the proinflammatory cytokine tumor necrosis factor-α. CONCLUSION: The downregulation of frataxin seems to be linked with uremic status, which is usually associated with chronic inflammation and the acceleration of oxidative stress. Mitochondrial iron regulation may play a role in several comorbidities and in the poor prognosis in uremic patients. Further investigation is needed to elucidate whether reduced frataxin levels are linked to the pathological status of uremic patients and whether uremic substances affect frataxin expression.

Should we reconsider iron administration based on prevailing ferritin and hepcidin concentrations?

The results of recent randomized, controlled trials in patients with chronic kidney disease and anemia have suggested that hyporesponsiveness to erythropoiesis stimulating agents (ESA) is a significant predictor of poor patient outcomes. Functional iron deficiency (FID) is the most common cause of suboptimal ESA response, and intravenous iron administration (IVFe) efficiently raises hemoglobin (Hb) concentrations even under the condition of FID. Consequently, renal anemia correction has conceptually shifted from 'higher Hb values with high ESA doses' to 'prevention of ESA hyporesponsiveness with IVFe'. The discovery of hepcidin has profoundly changed our understanding of the place of FID in renal anemia therapy. Hepcidin reduces the abundance of iron transport proteins which facilitate iron absorption from the gut and iron mobilization from macrophages. Serum hepcidin is mainly modulated by iron stores, as is serum ferritin. High hepcidin or ferritin levels block intestinal iron absorption and iron recycling in macrophages and decrease iron availability for erythropoiesis, leading to FID. Iron administration, especially IVFe, increases hepcidin levels and concomitantly inhibits iron supply to erythroid cells. This in turn could lead to a vicious circle, exacerbating FID and increasing iron demand. Therefore, physicians should be cautious with unrestricted IVFe to chronic kidney disease patients with FID.

High levels of tumor necrosis factor-α downregulate antimicrobial iron transport protein, Nramp1, in chronic hemodialysis patients: a key factor for infection risk.

BACKGROUND/AIMS: The susceptibility of patients on maintenance hemodialysis (MHD) to infections is a major cause of mortality and morbidity. Natural resistance-associated macrophage protein 1 (Nramp1) regulates intracellular pathogen proliferation, and its mRNA expression is highest in polymorphonuclear leukocytes (PMNLs). The purpose of this study was to determine the level of Nramp1 in PMNLs from MHD patients and the factors affecting its expression. METHODS: Twenty MHD patients and 24 healthy volunteers (controls) were recruited. Relative quantitative PCR was used to measure Nramp1 mRNA, and protein levels were semiquantified by means of real-time PCR and Western blot analysis or immunohistochemistry. The effect of tumor necrosis factor-α (TNF-α) or interleukin-6 (IL-6) on Nramp1 expression in PMNLs from controls was also examined. RESULTS: Nramp1 mRNA and protein levels were substantially lower in PMNLs from MHD than control subjects. Serum TNF-α levels were significantly higher in the MHD group and were inversely correlated with Nramp1 mRNA levels. The addition of TNF-α to PMNLs from control subjects decreased mRNA and protein levels of Nramp1. IL-6 did not alter Nramp1 mRNA or protein expression. CONCLUSION: We found that Nramp1 was downregulated in the PMNLs of MHD patients, which constitute the first defense barrier against bacterial challenges. High levels of TNF-α may be associated with the downregulation of Nramp1. Our findings indicate that the susceptibility to infection observed in MHD patients could be partly due to the impairment of the intracellular handling of iron and the donation of more iron to the bacteria.

A sinus of Valsalva-right atrium fistula without aneurysm formation.

A 61-year-old man was admitted to the hospital because of orthopnea and was diagnosed with heart failure with a continuous heart murmur. A transthoracic echocardiogram revealed turbulent flow from the right coronary sinus of Valsalva to the right atrium throughout the cardiac cycle. Aortography confirmed the presence of a shunt jet from the right coronary sinus of Valsalva to the right atrium. Cardiac catheterization revealed a left-right shunt rate of 47% and a pulmonary to systemic blood flow ratio of 1.81. Transesophageal echocardiography confirmed the existence of the shunt jet and revealed no deformity of the sinus of Valsalva. We report a rare case of sinus of Valsalva-right atrium fistula without typical aneurysmal formation.

High index of microcirculatory resistance level after successful primary percutaneous coronary intervention can be improved by intracoronary administration of nicorandil.

BACKGROUND: Although microvascular dysfunction following percutaneous coronary intervention (PCI) can be evaluated with the index of microcirculatory resistance (IMR), no method of treatment has been established. We hypothesized that intracoronary administration of nicorandil can improve IMR after successful primary PCI in patients with ST-segment elevation myocardial infarction (STEMI). METHODS AND RESULTS: In 40 patients with first STEMI after successful primary PCI, IMR was measured using PressureWire(TM) Certus (St. Jude Medical, MN, USA). In 20 of the patients (Group N), IMR was measured at baseline and after intracoronary nicorandil (2 mg/10 ml). In the other 20 patients (Control), IMR was measured at baseline, after intracoronary saline (10 ml) and after intracoronary nicorandil (2 mg/10 ml). In Group N, IMR significantly decreased after intracoronary nicorandil (median IMR, 27.7-18.7 U, P<0.0001). In the Control group, IMR did not change after saline administration (median IMR, 24.3-23.8 U, P=0.8193), but was significantly decreased after intracoronary nicorandil (median IMR, 23.8-14.9 U, P<0.0001). Next, all 40 patients were divided into subgroups by tertile of baseline IMR. In those with intermediate to high IMR (baseline IMR > or =21), intracoronary nicorandil significantly decreased IMR, although it did not change IMR in those with low IMR (baseline IMR <21). CONCLUSIONS: High IMR levels in patients with STEMI after successful primary PCI can be improved by intracoronary administration of nicorandil.