Oral Iron Absorption of Ferric Citrate Hydrate and Hepcidin-25 in Hemodialysis Patients: A Prospective, Multicenter, Observational Riona-Oral Iron Absorption Trial.

Oral ferric citrate hydrate (FCH) is effective for iron deficiencies in hemodialysis patients; however, how iron balance in the body affects iron absorption in the intestinal tract remains unclear. This prospective observational study (Riona-Oral Iron Absorption Trial, R-OIAT, UMIN 000031406) was conducted at 42 hemodialysis centers in Japan, wherein 268 hemodialysis patients without inflammation were enrolled and treated with a fixed amount of FCH for 6 months. We assessed the predictive value of hepcidin-25 for iron absorption and iron shift between ferritin (FTN) and red blood cells (RBCs) following FCH therapy. Serum iron changes at 2 h (ΔFe2h) after FCH ingestion were evaluated as iron absorption. The primary outcome was the quantitative delineation of iron variables with respect to ΔFe2h, and the secondary outcome was the description of the predictors of the body's iron balance. Generalized estimating equations (GEEs) were used to identify the determinants of iron absorption during each phase of FCH treatment. ΔFe2h increased when hepcidin-25 and TSAT decreased (-0.459, -0.643 to -0.276, p = 0.000; -0.648, -1.099 to -0.197, p = 0.005, respectively) in GEEs. FTN increased when RBCs decreased (-1.392, -1.749 to -1.035, p = 0.000) and hepcidin-25 increased (0.297, 0.239 to 0.355, p = 0.000). Limiting erythropoiesis to maintain hemoglobin levels induces RBC reduction in hemodialysis patients, resulting in increased hepcidin-25 and FTN levels. Hepcidin-25 production may prompt an iron shift from RBC iron to FTN iron, inhibiting iron absorption even with continued FCH intake.

A comparison of the utility of the urine dipstick and urine protein-to-creatinine ratio for predicting microalbuminuria in patients with non-diabetic lifestyle-related diseases -a comparison with diabetes.

BACKGROUND: The utility of dipstick proteinuria for predicting microalbuminuria in non-diabetic lifestyle-related diseases compared with the urine protein-to-creatinine ratio (uPCR) and the effect of dipstick proteinuria on the cut-off value (CO) and accuracy of uPCR are unclear. METHODS: The subjects included Japanese patients ≥ 18 years old with lifestyle-related diseases who had an estimated glomerular filtration rate of ≥ 15 ml/min/1.73 m2 and uPCR of < 0.5 g/gCr at initiation. Urine dipstick, uPCR and urine albumin-to-creatinine ratio (uACR) were measured three times per case. Microalbuminuria was defined as uACR of 30-299 mg/gCr for at least 2 of 3 measurements. Youden's Index was used as the optimal CO. Factors associated with microalbuminuria were analyzed using a logistic regression model. RESULTS: In 313 non-diabetic cases (median 70.8 years old), 3 dipstick proteinuria measurements were independently useful for detecting microalbuminuria, and the CO was set when a trace finding was obtained at least 1 of 3 times (sensitivity 0.56, specificity 0.80, positive predictive value [PPV] 0.73, negative predictive value [NPV] 0.65). A single uPCR measurement was more useful than 3 dipstick measurements, and was useful for detecting microalbuminuria even in cases with three consecutive negative proteinuria findings, indicating that the CO of the second uPCR with G1-3a (n = 136) was 0.06 g/gCr (sensitivity 0.76, specificity 0.84. PPV 0.68, NPV 0.89), while that with G3-b4 (n = 59) was 0.10 g/gCr (sensitivity 0.56, specificity 0.91. PPV 0.83, NPV 0.71). The sum of 3 uPCRs was useful for detecting microalbuminuria in cases with G1-3a (sensitivity 0.67, specificity 0.94, PPV 0.82, NPV 0.86) and G3b-4 (sensitivity 0.78, specificity 0.94, PPV 0.91 NPV 0.83), with both COs being 0.23 g/gCr. These COs of microalbuminuria did not change when trace or more proteinuria was included, although the sensitivity increased. A high uPCR and low urine specific gravity or creatinine level were independent factors for uACR ≥ 30 mg/gCr in cases with negative proteinuria, although the uPCR was a major predictive factor of a uACR ≥ 30 mg/gCr. CONCLUSIONS: The uPCR (preferably determined using early-morning urine), including in dipstick-negative proteinuria cases with non-diabetic lifestyle-related diseases, can aid in the early detection of microalbuminuria. TRIAL REGISTRATION: Retrospectively registered.

Prediction of microalbuminuria from proteinuria in chronic kidney disease due to non-diabetic lifestyle-related diseases: comparison with diabetes.

BACKGROUND: To suppress increases in kidney failure and cardiovascular disease due to lifestyle-related diseases other than diabetes, early intervention is desirable. We examined whether microalbuminuria could be predicted from proteinuria. METHODS: The participants consisted of adults who exhibited a urinary protein-to-creatinine ratio (uPCR) of < 0.5 g/gCr and an eGFR of ≥ 15 ml/min/1.73 m2 in their spot urine at their first examination for lifestyle-related disease. Urine was tested three times for each case, with microalbuminuria defined as a urinary albumin-to-creatinine ratio (uACR) of 30-299 mg/gCr, at least twice on three measurements. Youden's Index was used as an index of the cut-off value (CO) according to the ROC curve. RESULTS: A single uPCR was useful for differentiating normoalbuminuria and micro- and macroalbuminuria in patients with non-diabetic lifestyle-related diseases. Regarding the GFR categories, the CO of the second uPCR was 0.09 g/gCr (AUC 0.89, sensitivity 0.76, specificity 0.89) in G1-4 (n = 197) and 0.07 g/gCr (AUC 0.92, sensitivity 0.85, specificity 0.88) in G1-3a (n = 125). Using the sum of two or three uPCR measurements was more useful than a single uPCR for differentiating microalbuminuria in non-diabetic lifestyle disease [CO, 0.16 g/gCr (AUC 0.91, sensitivity 0.85, specificity 0.87) and 0.23 g/gCr (AUC 0.92, sensitivity 0.88, specificity 0.84), respectively]. CONCLUSION: Microalbuminuria in Japanese individuals with non-diabetic lifestyle-related diseases can be predicted from the uPCR, wherein the CO of the uPCR that differentiates normoalbuminuria and micro- and macroalbuminuria was 0.07 g/gCr for G1-3a, while that in G3b-4 was 0.09 g/gCr.

The oxalate level in ultrafiltrate fluid collected from a dialyzer is useful for estimating the plasma oxalate level in hemodialysis patients.

BACKGROUND: Patients on chronic hemodialysis are likely to develop secondary hyperoxalemia. It is, however, difficult to measure plasma oxalate levels. To measure plasma oxalate levels, rapid plasma separation, deproteinization, and acidification are essential in preventing the formation of oxalate and the deposition of calcium oxalate within the test tube. The present study was undertaken to examine whether the oxalate level in dialyzer ultrafiltrate is potentially useful for estimating plasma oxalate levels. METHODS: In nine patients on chronic hemodialysis, the plasma, after deproteinization with a filter, and the ultrafiltrate from the dialyzer before hemodialysis were acidified to a pH level of less than 3, followed by the measurement of oxalate levels by ion chromatography. Also, oxalate levels were compared between acidified and non-acidified ultrafiltrates from the dialyzer. In the second part of the study, seven patients on chronic hemodialysis receiving erythropoietin therapy, in whom the ferritin level was more than 300 ng/ml and transferrin saturation was less than 25%, were intravenously administered ascorbic acid, 100 mg, three times a week, after each dialysis session to facilitate the utilization of stored iron. This treatment was continued until the serum ferritin level decreased to a level below 300 ng/ml (for 3 months, at a maximum). The oxalate level in the dialyzer ultrafiltrate after this treatment was compared with that before treatment. RESULTS: The mean +/- SE oxalate level in the dialyzer ultrafiltrate was 45 +/- 6 micromol/l, essentially equal to the plasma oxalate level (46 +/- 7 micromol/l). The plasma oxalate level had a significant positive correlation with the dialyzer ultrafiltrate oxalate level (plasma oxalate level = 0.99 x dialyzer ultrafiltrate oxalate level + 1.5; r = 0.95; P < 0.0001). The oxalate level in the acidified ultrafiltrate (45 +/- 6 micromol/l) did not differ significantly from that in the non-acidified ultrafiltrate (45 +/- 6 micromol/l). The mean +/- SE duration of ascorbic acid administration was 64 +/- 13 days. The hemoglobin level remained unchanged at 9.6 +/- 0.4 g/dl, whereas the serum iron level increased significantly, from 34 +/- 2 microg/dl to 43 +/- 4 microg/dl (P < 0.05), and serum ferritin levels decreased significantly, from 645 +/- 219 ng/ml to 231 +/- 30 ng/ml after the treatment (P < 0.05). The oxalate level in the acidified ultrafiltrate showed no significant change after ascorbic acid administration (31 +/- 8 micromol/l vs 47 +/- 7 micromol/l). CONCLUSIONS: In patients on chronic hemodialysis, the oxalate level in acidified ultrafiltrate from the dialyzer was found to be useful for estimating the plasma level of non-protein-bound oxalate. When administering ascorbic acid to hemodialysis patients, the plasma oxalate level can be monitored using this method.

[Comparison of intravenous ascorbic acid versus intravenous iron for functional iron deficiency in hemodialysis patients].

The effect of intravenous ascorbic acid was compared with that of intravenous iron in the treatment of functional iron deficiency, as defined as serum ferritin levels over 300 ng/ml and serum iron levels below 50 microg/dl, in patients on chronic hemodialysis. Thirteen patients on chronic hemodialysis with functional iron deficiency received intravenous injections of ascorbic acid, 100 mg, three times a week, after hemodialysis. The therapy was continued until serum ferritin decreased to below 300 ng/ml (3 months at the maximum). The iron and control group were composed of patients who had serum iron levels below 50 microg/dl within 3 months after serum ferritin rose to over 300 ng/ml. Seven patients with the iron group received more than a total of 10 intravenous injections of saccharated ferric oxide (40 mg/dose) after hemodialysis, and seven patients with the control group received no iron preparation during the 3 months. In the ascorbic acid group, while hemoglobin did not change from 10.9 +/- 0.5 g/dl (mean +/- SE) during the three-month period, serum iron increased significantly from 37 +/- 4 microg/dl to 49 +/- 4 microg/dl after one month (p<0.01), and remained elevated until the end of the three-month period. Serum ferritin decreased significantly from 607 +/- 118 ng/ml to 354 +/- 30 ng/ml after 3 months (p<0.01). In the iron group, hemoglobin and serum iron increased significantly from the respective pre-treatment levels during the 2-month period, and serum ferritin rose significantly after 3 months. In the control group, hemoglobin, serum iron and ferritin levels decreased significantly from the respective pre-treatment levels during the 3 months. The recombinant erythropoietin dose remained stable for three months in the ascorbic acid, iron, and control groups, respectively. These results suggest that in hemodialysis patients with a functional iron deficiency, treatment with intravenous ascorbic acid can prevent iron overload due to treatment with intravenous iron, and provide a useful adjuvant means of maintaining hemoglobin and serum iron levels.

A single-nucleotide mutation in a gene encoding S-adenosylmethionine synthetase is associated with methionine over-accumulation phenotype in Arabidopsis thaliana.

Met-overaccumulating mutants provide a powerful genetic tool for examining both the regulation of the Met biosynthetic pathway and in vivo developmental responses of gene expression to altered Met levels. We have previously reported the identification of two Arabidopsis thaliana Met over-accumulation (mto) mutants, mto1-1 and mto2-1, that carry mutations in the genes encoding cystathionine gamma-synthase (CGS) and threonine synthase (TS), respectively. A third mutant, mto3-1, has recently been reported to carry a mutation in the gene encoding S-adenosylmethionine synthetase 3 (SAMS3). Here, we report the isolation of a new ethionine-resistant A. thaliana mutant that over-accumulates soluble Met approximately 20-fold in young rosettes. The causal mutation was determined to be a single, recessive mutation that was mapped to chromosome 3. Sequence analysis identified a single nucleotide change in the gene encoding SAMS3 that was distinct from the mto3-1 mutation and altered the amino acid sequence of the enzyme active site. This mutation was therefore referred to as mto3-2. Although Met over-accumulation in the mto3-2 mutant was similar to that in the mto2-1 mutant, CGS mRNA levels did not respond to the mto3-2 mutation and were similar to that in equivalent wild-type plants.