Long-term safety and efficacy of ferric citrate in phosphate-lowering and iron-repletion effects among patients with on hemodialysis: A multicenter, open-label, Phase IV trial.

BACKGROUND: We explored the long-term safety and efficacy of ferric citrate in hemodialysis patients in Taiwan, and further evaluated the iron repletion effect and change of iron parameters by different baseline groups. METHODS: This was a 12-month, Phase IV, multicenter, open-label study. The initial dose of ferric citrate was administered by patients' clinical condition and further adjusted to maintain serum phosphorus at 3.5-5.5 mg/dL. The primary endpoint was to assess the safety profiles of ferric citrate. The secondary endpoints were to evaluate the efficacy by the time-course changes and the number of subjects who achieved the target range of serum phosphorus. RESULTS: A total of 202 patients were enrolled. No apparent or unexpected safety concerns were observed. The most common treatment-emergent adverse events were gastrointestinal-related with discolored feces (41.6%). Serum phosphorus was well controlled, with a mean dose of 3.35±1.49 g/day, ranging from 1.5 to 6.0 g/day. Iron parameters were significantly improved. The change from baseline of ferritin and TSAT were 227.17 ng/mL and 7.53%, respectively (p-trend<0.001), and the increase started to slow down after 3-6 months of treatment. In addition, the increase trend was found only in patients with lower baseline level of ferritin (≤500 ng/mL) and TSAT (<30%). CONCLUSIONS: Ferric citrate is an effective phosphate binder with favorable safety profile in ESRD patients. The iron-repletion by ferric citrate is effective, and the increase is limited in patients with a higher baseline. In addition to controlling hyperphosphatemia, ferric citrate also shows additional benefits in the treatment of renal anemia. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT03256838; 12/04/2017.

Aberrant serum parathyroid hormone, calcium, and phosphorus as risk factors for peritonitis in peritoneal dialysis patients.

Identifying modifiable risk factors of peritoneal dialysis (PD)-related peritonitis is of clinical importance in patient care. Mineral bone disease (MBD) has been associated with mortality and morbidity in end-stage kidney disease (ESKD) patients. However, its influence on PD related peritonitis due to altered host immunity remains elusive. This study investigated whether abnormal biomarkers of MBD are associated with the development of peritonitis in patients undergoing maintenance PD. We conducted a retrospective observational cohort study, analysing data derived from a nationwide dialysis registry database in Taiwan, from 2005 to 2012. A total of 5750 ESKD patients commencing PD therapy during this period were enrolled and followed up to 60 months or by the end of the study period. The patients were stratified based on their baseline serum parathyroid hormone (PTH) levels, calcium (Ca) levels or phosphorus (P) levels, respectively or in combinations. The primary outcome was the occurrence of first episode of peritonitis, and patient outcomes such as deaths, transfer to haemodialysis or receiving renal transplantation were censored. Peritonitis-free survival and the influence of PTH, Ca, P (individual or in combination) on the peritonitis occurrence were analysed. A total of 5750 PD patients was enrolled. Of them, 1611 patients experienced their first episode of peritonitis during the study period. Patients with low PTH, high Ca or low P levels, respectively or in combination, had the lowest peritonitis-free survival. After adjusting for age, sex and serum albumin levels, we found that the combinations of low PTH levels with either high Ca levels or low/normal P levels were significant risk factors of developing peritonitis. Abnormal mineral bone metabolism in maintenance PD patients with low serum PTH levels, in combination with either high Ca levels or low/normal P levels, could be novel risk factors of PD-related peritonitis.

Therapeutic Targeting of Aristolochic Acid Induced Uremic Toxin Retention, SMAD 2/3 and JNK/ERK Pathways in Tubulointerstitial Fibrosis: Nephroprotective Role of Propolis in Chronic Kidney Disease.

The nephrotoxicity of aristolochic acids (AAs), p-cresyl sulfate (PCS) and indoxyl sulfate (IS) were well-documented, culminating in tubulointerstitial fibrosis (TIF), advanced chronic kidney disease (CKD) and fatal urothelial cancer. Nonetheless, information regarding the attenuation of AAs-induced nephropathy (AAN) and uremic toxin retention is scarce. Propolis is a versatile natural product, exerting anti-oxidant, anti-cancer and anti-fibrotic properties. We aimed to evaluate nephroprotective effects of propolis extract (PE) in a murine model. AAN was developed to retain circulating PCS and IS using C57BL/6 mice, mimicking human CKD. The kidney sizes/masses, renal function indicators, plasma concentrations of PCS/IS, tissue expressions of TIF, α-SMA, collagen IaI, collagen IV and signaling pathways in transforming growth factor-ß (TGF-ß) family were analyzed among the control, PE, AAN, and AAN-PE groups. PE ameliorated AAN-induced renal atrophy, renal function deterioration, TIF, plasma retention of PCS and IS. PE also suppressed α-SMA expression and deposition of collagen IaI and IV in the fibrotic epithelial-mesenchymal transition. Notably, PE treatment in AAN model inhibited not only SMAD 2/3-dependent pathways but also SMAD-independent JNK/ERK activation in the signaling cascades of TGF-ß family. Through disrupting fibrotic epithelial-mesenchymal transition and TGF-ß signaling transduction pathways, PE improves TIF and thereby facilitates renal excretion of PCS and IS in AAN. In light of multi-faced toxicity of AAs, PE may be capable of developing a new potential drug to treat CKD patients exposed to AAs.

The association between chronic musculoskeletal pain and clinical outcome in chronic kidney disease patients: a prospective cohort study.

BACKGROUND AND OBJECTIVES: Chronic musculoskeletal (MS) pain is common in chronic kidney disease (CKD) patients. The association of chronic MS pain and CKD progression has not yet been established. METHOD: We conducted a prospective cohort study to evaluate the association of chronic MS pain and CKD progression of pre-dialysis CKD patients. RESULT: A total of 53.2% of pre-dialysis CKD patients had chronic MS pain. Patients classified as progression and non-progression had a similar prevalence of chronic MS pain at baseline, and similar baseline use of NSAIDs and Chinese herbal medicines. Univariate Cox analysis indicated that chronic MS pain and baseline NSAID or Chinese herbal medicine use were not significantly associated with progression of CKD. But multivariate Cox regression found chronic MS pain was independently significantly associated with all-cause mortality (HR, 2.912, 95% CI, 1.004-8.444; p = .049). However, serum levels of hs-CRP were similar between those chronic MS pain patients and without chronic MS pain patients (4.96 ± 9.4 vs. 4.25 ± 13.3 mg/L, p = .535). CONCLUSION: The CKD patients with chronic MS pain was independently and significantly associated with all-cause mortality, but not independently and significantly associated with CKD progression and composite endpoints. The inflammatory marker-hs-CRP was similar between CKD patients with and without chronic MS pain.

Different Effects of Iron Indices on Mortality in Patients With Autosomal Dominant Polycystic Kidney Disease After Long-Term Hemodialysis: A Nationwide Population-Based Study.

OBJECTIVE: Iron supplementation and erythropoietin stimulating agents (ESAs) are essential for maintaining hemoglobin levels in hemodialysis patients. However, patients with autosomal-dominant polycystic kidney disease (PKD) have higher endogenous erythropoietin levels, so their recommended iron indices for hemodialysis patients may differ. This study evaluated iron profiles, including ferritin levels and transferrin saturation (TSAT) to identify factors affecting mortality in patients on dialysis, and those associated with mortality in patients with and without PKD. DESIGN: This cohort study from the Taiwan Renal Registry Data System stratified mortality risk by the presence of PKD recorded as the underlying disease. SUBJECTS: We enrolled 1346 hemodialysis patients with PKD and 82,873 hemodialysis patients without PKD. MAIN OUTCOME MEASURE: The primary outcome was 3-year all-cause mortality. Predictors included time-averaged and baseline serum ferritin levels and TSAT. Multivariate Cox regression analysis adjusting for age, comorbidities, and relevant laboratory parameters was used to estimate the all-cause hazard ratios (HRs) for mortality. RESULTS: The mean ages of patients with and without PKD were 56.2±13.2 and 61.7±13.5 years and the median follow-up time was 37 (15-76) months. The adjusted mortality risks for time-averaged ferritin levels >800 ng/mL (HR=1.52; 95% confidence interval: 1.40-1.65) or TSAT levels >50% (HR=1.46; 95% confidence interval: 1.30-1.65) were significantly higher among patients without PKD than those for patients with normal iron indices. However, a U-shaped curve of mortality against ferritin/TSAT levels was not observed in patients with PKD. In the sensitivity test, there was no difference among PKD patients who underwent regular ESA therapy and those who did not. CONCLUSION: Iron indices have different effects on mortality among patients with and without PKD. Iron supplementation, recommended serum ferritin levels, or TSAT should be monitored in hemodialysis patients, especially those without PKD. Clinicians should consider treating anemia in hemodialysis patients individually, especially in PKD.

Taiwan renal care system: A learning health-care system.

Taiwan renal care system is an evolving learning health-care system. There are four facets of this system. From the early history of dialysis and Taiwan Renal Registry Data System, it facilitates the generation of data to knowledge. National multidisciplinary pre-end-stage renal disease care project and outcome enhances knowledge to practice. Early chronic kidney disease (CKD) programs and 2015 Taiwan CKD clinical guidelines implicate the practice to customer, and then explore the causes of CKD help to resume customer to data. A learning health-care system allows better and safer care at lower cost, enhancement of public health and patient empowerment. The successful development of a learning health-care system was to collect, accumulate and analyze data, interpret results, deliver tailored message and take action to change practice. Through the established database and data analysis, an integrated care system would be able to improve clinical outcomes and achieve the most cost-effectiveness care. Acute kidney injury, CKD with unknown origin, palliative care and kidney transplant are our new focuses to struggle.

Roles of Serum Calcium, Phosphorus, PTH and ALP on Mortality in Peritoneal Dialysis Patients: A Nationwide, Population-based Longitudinal Study Using TWRDS 2005-2012.

Biomarkers of chronic kidney disease-mineral and bone disorder (CKD-MBD) correlate with morbidity and mortality in dialysis patients. However, the comparative roles of each CKD-MBD biomarker remained undetermined on long-term peritoneal dialysis (PD) patients. This retrospective study, employing a population-based database, aimed to evaluate the performance and provide the best evidence of each biomarker of CKD-MBD as predictor of all-cause mortality. Throughout the 8-year study period, total 12,116 PD patients were included in this study. Cox proportional regression and Kaplan-Meier method were used for survival analysis. For Cox regression model, baseline measurements and time-varying covariates were used for analysis. In Cox regression model using time-dependent covariates, serum calcium level of ≧9.5 mg/dL was associated with increased mortality. For phosphorus, serum levels of either ≧6.5 mg/dL or <3.5 mg/dL were associated with increased mortality. For parathyroid hormone (PTH), higher serum levels were not associated increased mortality. For alkaline phosphatase (ALP), mortality increased at levels ≧100 IU/L. Our findings suggested that the detrimental effect of ALP on survival was more consistent, while serum calcium, phosphorus and PTH may have a less prominent effect on mortality. This study provided additional information for manipulating CKD-MBD biomarkers in PD patients.

Health policies on dialysis modality selection: a nationwide population cohort study.

OBJECTIVES: In Taiwan, peritoneal dialysis (PD) and haemodialysis are fully accessible to patients with end-stage renal disease. However, the usage of PD is considered low in Taiwan. Since 2005, 4 major policies have been implemented by Taiwan's Ministry of Health and Welfare, namely a multidisciplinary predialysis care programme and usage increasing the PD incidence as a key performance indicator (KPI) for hospital accreditation, both of which were implemented in 2006; reimbursement of the glucose-free dialysate, icodextrin that was implemented in 2007; and insurance reimbursement for renting automated PD machines that was implemented in 2008. The aim of this study was to analyse the associations between the PD promotional policies and the actual PD selection rates. SETTING: We analysed data within the Taiwan Renal Registry Data System from 2006 to 2013, focusing on the PD incidence in relation to the timings of the 4 PD promotional policies; then we stratified the results according to age, sex and the presence of diabetes mellitus. PARTICIPANTS: From 2006 to 2013, 115 565 patients were enrolled in this study. The mean (SD) age of patients on PD was 54.6 (15.7) years. RESULTS: During the time frame in which the 4 PD promotional policies were implemented, the PD incidence increased from 12.8% in 2006 to 15.1% in 2009. The PD incidence started to decline in 2010 (13.8%) when the hospital accreditation policy was repealed. The 3 remaining policies were weakly associated with the PD incidence. The observational analysis determined that the patients' ages, sexes and diabetes mellitus incidence rates were relatively stable from 2006 to 2013. CONCLUSIONS: Of the 4 health policies intended to promote PD usage, using increasing the PD incidence as a KPI for hospital accreditation had the strongest association with the PD incidence.

Effect of oral ferric citrate on serum phosphorus in hemodialysis patients: multicenter, randomized, double-blind, placebo-controlled study.

BACKGROUND: Hyperphosphatemia is a common complication in dialysis patients that can be treated by oral phosphate binders. We investigated the efficacy and safety of oral ferric citrate as a phosphate binder for Taiwanese patients with end stage renal disease and with hyperphosphatemia who were undergoing hemodialysis. METHODS: This was a prospective, double-blind, placebo-controlled, randomized trial carried out in 5 hospitals in Taiwan. Ferric citrate (4 or 6 g/day) or placebo was administered for 56 days. Serum calcium, phosphorous levels, calcium × phosphorus product, serum ferritin level, transferrin saturation, and adverse events were recorded. RESULTS: A total of 166 patients completed the trial. The placebo group had relatively constant serum data. Serum phosphorus declined significantly in the 6 g/day group (p < 0.05 for 4 and 8 weeks) and the 4 g/day group (p < 0.05 for 4 and 8 weeks). There were similar changes in the calcium × phosphorus product. The serum ferritin level increased significantly in the 6 g/day group (p < 0.05) and the 4 g/day group (p < 0.05). There were similar changes in transferrin saturation. Most adverse events were mild to moderate and were comparable among the three groups. CONCLUSIONS: A 56-day treatment with ferric citrate effectively controlled hyperphosphatemia and was well tolerated in maintenance hemodialysis patients. There were also moderate increases in serum ferritin and transferrin saturation.

Anaemia management in patients with chronic kidney disease: Taiwan practice guidelines.

The introduction of erythropoiesis-stimulating agents (ESAs) markedly improved the lives of many anaemic patients with chronic kidney disease (CKD). In Taiwan, the strategy of management of anaemia in patients with CKD was different from many other parts of the world. In 1996, the National Health Insurance Administration of Taiwan applied a more restrictive reimbursement criteria for ESA use in patients with CKD. ESA is to be initiated when non-dialysis CKD patients have a serum creatinine >6 mg/dL and a hematocrit <28% to maintain a hematocrit level not exceeding 30%. The maximal dose of epoetin-α or ß was 20 000 U per month. The target haemoglobin range and dose limitation for ESAs were the same for dialysis CKD patients. Thus, long before randomized controlled trials showing an increased risk for cardiovascular events at nearly normal haemoglobin concentrations and higher ESA doses in CKD, nephrologists in Taiwan had avoided the use of disproportionately high dosages of ESAs to achieve a haemoglobin level of 10-11 g/dL. Moreover, intravenous iron supplementation was encouraged earlier in Taiwan in 1996, when we reached consensus on the diagnostic criteria for iron deficiency (serum ferritin <300 ng/mL and/or transferrin saturation <30%). The experience of CKD anaemia management in Taiwan demonstrated that a reasonable haemoglobin target can be achieved by using the lowest possible ESA dose and intravenous iron supplementation.

Successful hemoperfusion and plasma exchange in acute hepatic failure due to snake bile intoxication.

Snake gallbladder is a traditional Chinese medicine that has been used for treating arthritis and detoxification for more than two thousand years. Sporadic cases of toxic hepatic and renal injury from snake gallbladder have been reported. The toxic effects are dose related and there is a high mortality rate after delayed renal failure. We present a 35 year-old man who was a hepatitis B surface antigen carrier who developed acute hepatic failure after ingestion of snake gallbladder capsules for 6 weeks. The serologic study for hepatitis C antibody, hepatitis B e antigen and hepatitis B virus-deoxyribonucleic acid (HBV-DNA) were negative. Progressively elevated liver enzymes were noted during lamivudine treatment, so blood purification therapy was done to remove possible toxins. The patient recovered after hemoperfusion preceding a series of plasma exchanges. We feel that blood purification can remove toxins and block disease progression to renal failure. In summary, we suggest that blood purification procedures should be done as soon as possible for snake gallbladder-related fulminant hepatitis due to its high mortality rate.

Extreme hyperphosphatemia and hypocalcemic coma associated with phosphate enema.

Fleet enema (sodium phosphate, C.B. Fleet Co., Inc., Lynchburg, Virginia) is widely used for bowel preparation or constipation relief in the hospital and over the counter. The potential risks, including hyperphosphatemia and hypocalcemic coma should be kept in mind of primary care physician. The patients with older age, bowel obstruction, small intestinal disorders, poor gut motility, and renal disease are contraindicated or should be administered with caution. We present a patient with old age and chronic renal failure who developed severe hyperphosphatemia and hypocalcemic tetany with coma after sodium phosphate enema. We recommend the use of alternative enema preparations, such as simple tap water or saline solution enemas, which can prevent fatal complications in high risk patients.

Patient education: an efficient adjuvant therapy for hyperphosphatemia in hemodialysis patients.

BACKGROUND: Hemodialysis and phosphate (P) binder therapy are the major methods to reduce the phosphate level in dialysis patients. However, dietary P restriction is necessary for adequate control. The successful dietary control is based on patient compliance. Patient education is the best method to assure the knowledge and drive of dietary control, which are the key features for patient compliance. The aim of the study is to investigate quantitatively the effect of patient education on serum P levels in hyperphosphatemic hemodialysis patients. METHODS: We conducted a prospective self-control study. Fifty hemodialysis patients with a pre-dialysis serum P level greater than 6.0 mg/dL were studied. Intensified patient education was given. Serum P, calcium (Ca), and intact parathyroid hormone (iPTH) were evaluated before and one month after patient education. RESULTS: Thirty-six (72%) patients had improved pre-dialysis P level (pre-education: 7.50 +/- 1.33; post-education: 5.85 +/- 1.20 mg/dL, p < 0.001) and Ca x P product (pre-education: 68.17 +/- 12.70; post-education: 54.70 +/- 11.87 mg(2)/dL(2), p < 0.001). The effect lasted for at least three months. There is no significant change on calcium levels. The only predictor of a successful patient education is the iPTH level (improved: 348.8 +/- 277.6; non-improved: 668.0 +/- 674.1 ng/mL, p = 0.021). CONCLUSIONS: Patient education could be helpful and efficient in hyperphosphatemic control in dialysis patients. The patient education should be given before the serum iPTH level getting high.

Therapeutic effect of topical gamma-linolenic acid on refractory uremic pruritus.

BACKGROUND: Pruritus is a bothersome symptom affecting up to 80% of dialysis patients. Lymphocyte and cytokine interaction has an important role in the pathogenesis of uremic pruritus. Gamma-linolenic acid (GLA) is associated with immune modulation of T lymphocytes and lymphokines. The aim of this study is to determine whether topical GLA can attenuate uremic pruritus. METHODS: Seventeen dialysis patients with refractory uremic pruritus who passed the screening criteria entered a prospective, randomized, double-blind, placebo-controlled, crossover study. They stopped all antipruritic therapy at least 2 weeks before the study and were randomly assigned to treatment with either GLA 2.2% cream or placebo-based cream applied to the entire body after taking a bath once a day and to pruritic sites 3 times a day for 2 weeks, and then the reverse treatment after a 2-week washout period. Severity of pruritus was evaluated by using a traditional visual analogue scale (VAS) and a modified questionnaire method (pruritus score [PS]). Hemogram, aspartate and alanine aminotransferases, bilirubin, albumin, blood urea nitrogen, creatinine, calcium, phosphate, and intact parathyroid hormone were measured. RESULTS: Sixteen patients completed the study; 1 patient was withdrawn because of an allergic skin reaction. There were no significant differences between groups except for sex distribution. Median VAS and PS values between groups did not differ significantly at baseline. There is a greater antipruritic effect of GLA based on evaluation with both the VAS and PS. There is persistence of a residual effect into the second treatment period after GLA treatment. CONCLUSION: GLA-rich cream is better than placebo-based cream for alleviating uremic pruritus. It is a useful adjuvant in the management of refractory uremic pruritus.