Characteristics of traditional Chinese medicine use in children with asthma: a nationwide population-based study.

Asthma is a chronic inflammatory airway disease accounting for severe morbidity and mortality in children. To determine the characteristics of traditional Chinese medicine (TCM) used to treat pediatric asthma, we conducted a nationwide population-based study by analyzing a cohort of one million randomly sampled patients from the beneficiaries of the National Health Insurance Program in Taiwan from 2002 to 2010. Children under 18 years of age with newly diagnosed asthma (ICD-9-CM code: 493, N = 45 833) were enrolled, and 57.95% (N = 26 585) of them had used TCM. The number of TCM users was significantly more than that of non-TCM users in school-age children. The most commonly prescribed TCM formula is Ding-chuan-tang, or Xing-ren (Semen Armeniacae Amarum) for the single herb. Our study is the first to reveal characteristics and prescription patterns of the use of TCM in children with asthma. Further research is needed to elucidate the efficacy and safety of these Chinese herbal products.

Thiamine deficiency and unexplained encephalopathy in hemodialysis and peritoneal dialysis patients.

Patients with end-stage renal disease undergoing regular dialysis are prone to encephalopathy, but the cause is often unclear. Dialysis patients are at risk for thiamine deficiency, which may mimic many uremic complications, including encephalopathy. To determine whether unexplained encephalopathy in regular dialysis patients is associated with thiamine deficiency, we conducted a prospective study that enrolled 30 consecutive dialysis patients with altered mental status admitted to a referred hospital during a 1-year period. A complete history, physical and neurological examinations, laboratory investigations, and computed tomographic scans or magnetic resonance imaging of the brain were obtained for each subject. In 10 of the 30 patients, diagnoses remained obscure after the initial workup. Manifestations included confusion, chorea, acute visual loss, rapidly progressive dementia, myoclonus, convulsions, and coma. Intravenous thiamine was administered to these 10 patients. All 10 patients had thiamine deficiency confirmed by a marked response to thiamine supplementation and/or a low serum thiamine concentration (35.3 +/- 6.0 nmol/L; normal, >50 nmol/L). Nine patients recovered, but one patient failed to respond because of delayed treatment. We conclude that in regular dialysis patients, unexplained encephalopathy can be mainly attributed to thiamine deficiency. This condition is fatal if unrecognized and can be successfully treated with prompt thiamine replacement.

Erythropoietin and iron: the role of ascorbic acid.

Provision of sufficient available iron is a prerequisite to ensure the optimal response to recombinant human erythropoietin (rHuEpo). Functional iron deficiency (a state when iron supply is reduced to meet the demands for increased erythropoiesis) is the common cause of rHuEpo hyporesponsiveness in dialysis patients who have normal iron status, even when they are iron-overloaded. Iron supplementation is not justified for this hyporesponsiveness in patients with iron overload due to the potential hazards of iron overload aggravated by intravenous iron therapy. Furthermore, in vivo studies indicated that the promising effect of intravenous iron medication to overcome iron-deficient erythropoiesis is not observed in iron-overloaded haemodialysis (HD) patients. Ascorbic acid, a water-soluble antioxidant as well as a reducing agent, has a number of associations with iron metabolism. Recent research highlights that ascorbic acid can potentiate the mobilization of iron from inert tissue stores and facilitates the incorporation of iron into protoporphyrin in iron-overloaded HD patients being treated with rHuEpo. Interest has turned towards the use of ascorbic acid as an adjuvant therapy in this field. This review focuses on the improvement of rHuEpo response by administration of ascorbic acid and discusses its clinical implications and potential issues for nephrologists.

Intravenous ascorbic acid as an adjuvant therapy for recombinant erythropoietin in hemodialysis patients with hyperferritinemia.

BACKGROUND: Inadequate iron mobilization and defective iron utilization may cause recombinant erythropoietin (rEPO) hyporesponsiveness in hemodialysis (HD) patients with iron overload. We have demonstrated that intravenous ascorbic acid (IVAA), but not intravenous iron medication, can effectively circumvent the functional iron-deficient erythropoiesis associated with iron overload in HD patients. However, it is uncertain whether all HD patients with hyperferritinemia will consistently respond to IVAA and which index may indicate functional iron deficiency in the special entity. Therefore, a prospective study was conducted to establish the guidelines for IVAA adjuvant therapy. METHODS: Sixty-five HD patients with serum ferritin levels of more than 500 microgram/liter were recruited and divided into the control (N = 19) and IVAA (N = 46) groups. IVAA patients with a hematocrit (Hct) of less than 30% received 300 mg of ascorbic acid three times per week for eight weeks. Controls had a Hct of more than 30% and did not receive the adjuvant therapy. Red blood cell and reticulocyte counts, iron metabolism indices, erythrocyte zinc protoporphyrin (E-ZPP), and the concentrations of plasma ascorbate and oxalate were examined before and following the therapy. RESULTS: Thirteen patients (four controls and nine IVAA patients) withdrew by the end of the study. Eighteen patients had a dramatic response to IVAA with a significant increase in their hemoglobin and reticulocyte index and a concomitant 24% reduction in rEPO dose after eight weeks. This paralleled a significant rise in serum iron and transferrin saturation (TS) and a fall in E-ZPP and serum ferritin (baselines vs. 8 weeks, serum iron 68 +/- 37 vs. 124 +/- 64 microgram/dl, TS 27 +/- 10 vs. 48 +/- 19%, E-ZPP 123 +/- 44 vs. 70 +/- 13 micromol/mol heme, and serum ferritin 816 +/- 435 vs. 587 +/- 323 microgram/liter, P < 0. 05). Compared with responders, mean values of hemoglobin, rEPO dose, iron metabolism parameters, and E-ZPP showed no significant changes in controls (N = 15) and in non-responders (N = 19). Thirty-seven patients (18 responders and 19 non-responders) were further analyzed by receiver operating characteristic curves to seek the criteria for prediction of a response to IVAA treatment. The results showed that E-ZPP at a cut-off level of more than 105 micromol/mol heme and TS at a level of less than 25% were more specific to confirm the status of functional iron deficiency in iron-overloaded patients. The two criterion values had the highest accuracy to predict a response to treatment. CONCLUSIONS: Functional iron-deficient erythropoiesis plays a role in rEPO-hyporesponsive anemia in HD patients with hyperferritinemia. IVAA may be an adjuvant therapy for rEPO in these patients, and E-ZPP of more than 105 micromol/mol heme and TS of less than 25% should be used to guide the IVAA treatment.

Erythropoietin hyporesponsiveness: from iron deficiency to iron overload.

Iron deficiency is the most frequently encountered cause of suboptimal response to recombinant human erythropoietin (rHuEPO). Carefully assessing iron status is of paramount importance in chronic renal failure patients prior to or during rHuEPO therapy. Because there is great need for iron in the EPO-stimulated erythroid progenitors, it is essential that serum ferritin and transferrin saturation levels should be maintained over 300 microg/liter and 30%, respectively. Investigators have shown that oral iron is unlikely to keep pace with the iron demand for an optimal rHuEPO response in uremics. Therefore, patients with iron deficiency will always require intravenous iron therapy. The early and prompt iron supplementation can lead to reductions in rHuEPO dose and hence cost. After the iron deficiency has been corrected or excluded, we must remember all of the possible causes of hyporesponsiveness in every rHuEPO-treated patient. As dose requirements vary, it is not clear which dose of rHuEPO causes this hyporesponsiveness. However, if the patient with iron repletion does not respond well after the induction period, the major causes blunting the response to rHuEPO should be investigated. Most factors are reversible and remediable, except resistant anemia associated with hemoglobinopathy or bone marrow fibrosis, which requires a further increase in the rHuEPO dose. By means of early detection and correction of the possible causes, the goal of increasing therapeutic efficacy can be achieved. Iron overload may lead to an enhanced risk for infection, cardiovascular complication, and cancer. Over-treatment with iron should be avoided in dialysis patients, despite the fact that the safe upper limit of serum ferritin to avoid iron overload is not clearly defined. On the other hand, functional iron deficiency may develop even when serum ferritin levels are increased. Controversy remains as to whether intravenous iron therapy can overcome this form of hyporesponsiveness in iron-overloaded patients. Moreover, a treatment option of iron supplementation is not warranted in these patients, as the potential hazards of iron overload will be worsened. We demonstrated that the mean hematocrit significantly increased from 25.1+/-0.9% to 31+/-1.2% after eight weeks of intravenous ascorbate therapy (300 mg three times a week) in 12 hemodialysis patients with serum ferritin levels of more than 500 microg/liter. The enhanced erythropoiesis paralleled with a rise in transferrin saturation (27.8+/-2.5% vs. 44.8+/-9.5%, P < 0.05) and reductions in erythrocyte zinc protoporphyrin (130+/-32 vs. 72+/-19 micromol/mol heme, P < 0.05) and monthly rHuEPO dose (24.2+/-4.5 vs. 16.8+/-3.4 x 10(3) units, P < 0.05) at the end of study. It is speculated that ascorbate supplementation not only facilitates the iron release from storage sites and its delivery to hematopoietic tissues, but also increases iron utilization in erythroid cells. Our study provides a more complete understanding of the pathogenesis of iron overload-related anemia and the development of an adjuvant therapy, intravenous ascorbic acid, to the existing treatments.

A parallel, comparative study of intravenous iron versus intravenous ascorbic acid for erythropoietin-hyporesponsive anaemia in haemodialysis patients with iron overload.

BACKGROUND: Functional iron deficiency may develop and cause erythropoietin resistance in haemodialysis patients with iron overload. Controversy remains as to whether intravenous iron medication can improve this hyporesponsiveness due to decreased iron availability, or whether iron therapy will aggravate haemosiderosis. Intravenous administration of ascorbic acid has been shown to effectively circumvent resistant anaemia associated with iron overload in a small preliminary study. To elucidate further the possible mechanisms of this resistance, a parallel, comparative study was conducted to compare the effects of intravenous iron and ascorbate therapies in iron-overloaded haemodialysis patients. METHODS: Fifty haemodialysis patients with serum ferritin of > 500 microg/l were randomly divided into two protocols. They were further stratified into controls (Control I, n = 11) and intravenous iron group (IVFE, n = 15) in protocol I; and into controls (Control II, n = 12) and intravenous ascorbic acid group (IVAA, n = 12) in protocol II. Controls had a haematocrit of > 30% and did not receive any adjuvant therapy. IVFE and IVAA patients were hyporesponsive to erythropoietin and functionally iron deficient. Ferric saccharate (100 mg dose) was administered intravenously postdialysis on five consecutive dialysis sessions in the first 2 weeks; and ascorbic acid (300 mg dose) thrice a week for 8 weeks. Red cell and iron metabolism indices were examined before and following therapy. RESULTS: Mean values of haematocrit and transferrin saturation were significantly lower, and erythropoietin dose was higher in IVFE and IVAA patients compared to controls. Intravenous iron therapy neither improved erythropoiesis nor reduced erythropoietin dose during 12 weeks. Iron metabolism indices significantly increased at 2 and 6 weeks, but decreased at 12 weeks returning to the baselines. In contrast, mean haematocrit significantly increased from 25.8+/-0.5 to 30.6+/-0.6% with a concomitant reduction of 20% in erythropoietin dose after 8 weeks of ascorbate therapy. Serum ferritin modestly fell but with no statistical significance. The enhanced erythropoiesis paralleled a rise in transferrin saturation from 27+/-3 to 48+/-6% and serum iron from 70+/-11 to 107+/-19 microg/dl (P<0.05). CONCLUSIONS: Short term intravenous iron therapy cannot resolve the issue of functional iron deficiency in haemodialysis patients with iron overload. Intravenous administration of ascorbic acid not only facilitates iron release from storage sites, but also increases iron utilization in the erythron. Our study draws attention to a potential adjuvant therapy, intravenous ascorbic acid, to treat erythropoietin-hyporesponsive anaemia in iron-overloaded patients.

Improvement of nutritional status in patients receiving maintenance hemodialysis after correction of renal anemia with recombinant human erythropoietin.

Despite a large body of evidence showing the beneficial effects of successful treatment of anemia with recombinant human erythropoietin (EPO) in patients with end-stage renal disease, controversy remains as to whether EPO treatment of anemia can improve the nutritional status in patients on maintenance hemodialysis. This prompted us to conduct a prospective study in 41 hemodialysis patients with basal hemoglobin less than 9 g/dl. The dose of EPO was increased for 12 weeks to achieve the target hemoglobin concentration of 10 g/dl and then titrated in the following 12 weeks to maintain the target value. Nutritional status was assessed at baseline and after 6 months of follow-up, using the global protein-calorie malnutrition (PCM) index proposed by Bilbrey and Cohen. A low global PCM score indicates better nutrition. The results showed that hemoglobin values significantly increased from 8.7 +/- 0.8 g/dl at baseline to 10.7 +/- 0.5 g/dl in the 6th month (p < 0.001). No significant changes were observed in the normalized protein catabolic rate and Kt/V during the study period. Global PCM scores improved from 30.0 +/- 7.5 to 23.6 +/- 3.1 (p < 0.001) and paralleled the correction of anemia by EPO treatment. The data were consistent with a major improvement in the nutritional markers of relative body weight, triceps skinfold, midarm circumference, midarm muscle circumference, serum albumin, serum transferrin and total lymphocyte count in the 6th month as compared to baseline. The percentages of mild and moderate-severe PCM at baseline were 32 and 58%, respectively. These percentages were significantly reduced during the 6th month to 20 and 30%, respectively (p = 0.0004). In summary, correction of renal anemia with EPO improves the nutritional status in hemodialysis patients. A postulated mechanism is that EPO may exhibit anabolic effects, with a better utilization of ingested protein.

Mathematical approach for estimating iron needs in hemodialysis patients on erythropoietin therapy.

Functional iron deficiency occurs when recombinant human erythropoietin (rHuEPO) accelerates erythropoiesis to an extent that the iron availability cannot meet the anticipated demand. Such a phenomenon will reduce the optimal response to rHuEPO. To estimate the iron needs of functional iron deficiency in hemodialysis patients on rHuEPO therapy, we utilized a mathematical method. Forty hemodialysis patients were examined in the study, and all had a baseline serum ferritin (SF) level > 100 microg/l. They were stratified into patients with a transferrin saturation (TfS) value > or = 25% (group I) and those below this value (group II). The treatment protocol consisted of rHuEPO therapy in the two groups for 6 months and iron supplement only in group II. The target hemoglobin level was 10.5 g/dl, and iron metabolism indices were analyzed prior to and following therapy. The results showed (1) in group I (n = 20) hemoglobin rose from 7.5 +/- 0.9 to 10.7 +/- 0.7 g/dl (p < 0.01) and the mean SF level declined from 1,583 +/- 997 to 968 +/- 664 mg (p < 0.01); (2) in group II (n = 20) hemoglobin also increased from 7.8 +/- 0.9 to 10.6 +/- 0.8 g/dl (p < 0.01) following iron supplement, while the SF rose from 183 +/- 70 to 326 +/- 125 mg (p < 0.01); (3) TfS was significantly elevated in group II following iron therapy (18.9 +/- 4.8 vs. 34.5 +/- 9.1%, p < 0.01), and (4) the nomogram showed a sensitivity of 80%, a specificity of 100%, a positive predictive value of 100%, and a negative predictive value of 83% in estimating the iron status before rHuEPO therapy. We conclude that SF levels reflect iron stores and that TfS < 25% is an index of functional iron deficiency. Iron supplementation is not necessary in patients with SF > 100 microg/l and TfS > or = 25%. It seems rational to provide intravenous iron in EPO-resistant patients with functional iron deficiency (SF > 100 microg/l, TfS < 25%). This paper illustrates the importance that accurate assessment of iron needs by a mathematical method would enhance treatment efficacy and avoid iron overload in hemodialysis patients on rHuEPO therapy.

Hemodialysis-related pruritus: a double-blind, placebo-controlled, crossover study of capsaicin 0.025% cream.

Pruritus is a significant symptom among patients receiving hemodialysis. However, its underlying mechanisms remain obscure. Substance P, a neuropeptide, has been implicated in the mediation of pain and some itch sensations. Local application of capsaicin depletes the peripheral neurons of substance P and may block the conduction of pain or pruritus. This study aims to assess the efficacy and safety of capsaicin 0.025% cream in the treatment of hemodialysis-related pruritus and to further explore the underlying pathomechanism. Nineteen hemodialysis patients with idiopathic, moderate (n = 5) to severe (n = 14) pruritus were examined in a double-blind, placebo-controlled, crossover study and 17 of them completed the study. Topical agent of capsaicin or placebo base cream was applied to localized areas of pruritus 4 times a day. The severity of pruritus and treatment-related side effects (cutaneous burning/stinging sensations, dryness, or erythema) were evaluated weekly. The results showed (1) that 14 of 17 patients reported marked relief and 5 of these 14 patients had complete remission of pruritus during capsaicin treatment (Wilcoxon signed-ranks test, 2p < 0.001); (2) capsaicin was significantly more effective than placebo (Mann-Whitney rank sum test, 2p < 0.001) and a prolonged antipruritic effect was observed 8 weeks posttreatment; (3) no serious side effects were noted during the study and (4) there were no significant changes in serum concentrations of albumin, calcium, phosphorus, alkaline phosphatase, or intact parathyroid hormone during the treatment with either capsaicin or placebo. In summary, the present study indicates indirectly that idiopathic pruritus in some patients on maintenance hemodialysis may be transmitted by substance P from the peripheral sensory neurons to the central nervous system. Topical capsaicin with the unique pharmacological effect is demonstrated to markedly improve the pruritus of these patients.

Iron metabolism indices for early prediction of the response and resistance to erythropoietin therapy in maintenance hemodialysis patients.

A prospective study with 65 maintenance hemodialysis (MHD) patients on recombinant human erythropoietin (rHuEPO) therapy was conducted to assess the effect of iron balance on responsiveness. An attempt to define the predictors of erythropoietin (EPO) response and identify the specific causes of EPO resistance was undertaken in the present study. The treatment protocol consisted of two stages, the first was rHuEPO therapy for 6 months and the second was iron supplementation plus rHuEPO therapy in patients without response to EPO for the next 6 months. According to the hemoglobin (Hb) changes (increment exceeded 30% of baseline or did not exceed 15% of baseline for 3 consecutive months) and whether or not there was an achievement of target Hb level (>10.5 g/dl), all patients (n = 65) were divided into EPO-responsive (n = 20) and EPO-resistant (n = 45) groups. The EPO-resistant patients were then further stratified into iron-responsive (n = 29) and iron-irresponsive (n=16) groups. Iron metabolism and red cell indices were analyzed prior to and following rHuEPO therapy and iron supplementation.(ABSTRACT TRUNCATED AT 250 WORDS)

Enhancement of ionized calcium and 1,25-dihydroxycholecalciferol loss from peritoneal fluid during peritonitis in patients treated with continuous ambulatory peritoneal dialysis.

This study was to evaluate whether peritoneal loss of vitamin D metabolites during peritonitis leads to more depletion of 1,25-hydroxycholecalciferol [1,25(OH)2D3] and 25-hydroxycholecalciferol [25(OH)D] in continuous ambulatory peritoneal dialysis (CAPD) patients, especially in the high peritonitis occurrence group (HPOG). A series of ionized calcium, pH values, 1,25(OH)2D3 and 25(OH)D levels in dialysate during peritonitis were studied in 30 CAPD patients. In addition, bone mineral content (BMC) was determined during peritonitis. On the basis of peritonitis occurrence, 14 patients were in the low peritonitis occurrence group (LPOG) and 6 patients in the HPOG. Increase in peritoneal loss of ionized calcium, 1,25(OH)2D3, 25(OH)D and a decrease of pH value in dialysate may appear in the early period of peritonitis in both groups. When peritonitis occurs too frequently in a short period, the peritoneal membrane function cannot recover completely. Frequent peritonitis may impair peritoneal function and cause persistent loss of calcium. 1,25(OH)2D3 amd 25(OH)D loss is also higher in the HPOG than in the LPOG. The persistent loss of calcium, low plasma vitamin D levels and increased parathyroid hormone level with hyperparathyroidism in the HPOG are the important factors contributing to renal osteodystrophy. The lower BMC in the bone study confirmed this. Therefore, adequate calcium and vitamin D supplementation is necessary in the HPOG.

Effects of low-protein diet on experimental diabetic nephropathy in the rat.

To evaluate the role of glomerular hyperfiltration in the development and progression of diabetic nephropathy, we performed clearance and histopathologic studies in 24 rats with streptozocin-induced diabetes after 3 months of diets with different protein compositions. Calcium phosphate was added to an 8% protein diet in group I (nine rats), and calcium carbonate to a 24% protein diet in group II (nine rats) to equalize calcium and phosphate contents in these diets. Group I and II rats also received small doses of insulin to reduce the excessive hyperglycemia induced by the high sucrose content of the diets. In group III, six rats given an 8% protein diet, no calcium, phosphate, or insulin was added. In groups I and III, low dietary protein significantly reduced glomerular filtration rate and renal plasma flow per gram of kidney weight as compared with rates observed in group II rats with a higher protein intake. Features of diabetic glomerulopathy including mesangial hypercellularity and mesangial matrix expansion were also significantly milder in the groups with a low protein diet. On the other hand, medullary calcification and interstitial changes were most prominent in group I, given calcium phosphate supplement; the increase in the kidney weight was greater in groups I and II, which received insulin, than in group III, which did not. It was concluded that low protein diet significantly ameliorates diabetic glomerulopathy but that supplementation with inorganic phosphate in an amount equal to organic phosphate contained in the higher protein diet causes medullary calcification and interstitial nephritis. Also, administration of suboptimal doses of insulin in diabetic animals greatly enhances renal growth, more than that induced by diabetes alone.