Magnesium exposure increases hip fracture risks in patients with chronic kidney disease: a population-based nested case-control study.

This population-based study demonstrates a strong link between Mg-containing antacid exposure and hip fracture risk in nondialysis CKD and dialysis patients. As an Mg-containing antacid, MgO is also commonly used as a stool softener, which can be effortlessly replaced by other laxatives in CKD patients to maintain bone health. PURPOSE: Bone fracture is a severe complication in chronic kidney disease (CKD) patients, leading to disability and reduced survival. In CKD patients, blood magnesium (Mg) concentrations are usually above the normal range due to reduced kidney excretion of Mg. The present study examines the association between Mg-containing antacid exposure and the risk of hip fracture of CKD patients. METHODS: In this nationwide nested case-control study, we enrolled 44,062 CKD patients with hip fracture and 44,062 CKD matched controls, among which the mean age was 77.1 years old, and 87.9% was nondialysis CKD. RESULTS: As compared to non-users, Mg-containing antacid users were significantly more likely to experience hip fracture (adjusted odds ratio (OR) 1.36, 95% CI, 1.32 to 1.41; p < 0.001). Subgroup analysis showed that such risk exists in both nondialysis CKD patients and long-term dialysis patients. In contrast, aluminum or calcium-containing-antacid use did not reveal such association. Next, we examined the influence of Mg-containing antacid dosage on hip fracture risk, the adjusted ORs in the first quartile (Q1), Q2, Q3, and Q4 were 1.20 (95% CI, 1.15 to 1.25; p < 0.001), 1.35 (95% CI, 1.30 to 1.41; p < 0.001), 1.49 (95% CI, 1.43 to 1.56; p < 0.001), and 1.54 (95% CI, 1.47 to 1.61; p < 0.001), respectively, showing that such risk exists regardless of the antacid dosage. A receiver operating characteristic curve analysis demonstrated that the best cutoff value of the exposed Mg dose to discriminate the hip fracture is 532 mEq during the follow-up period. CONCLUSION: This population-based study demonstrates a strong link between Mg-containing antacid exposure and the hip fracture risk in both nondialysis CKD and dialysis patients.

Physician Scientist Training in the United States: A Survey of the Current Literature.

The declining number of physician scientists is an alarming issue. A systematic review of all existing programs described in the literature was performed, so as to highlight which programs may serve as the best models for the training of successful physician scientists. Multiple databases were searched, and 1,294 articles related to physician scientist training were identified. Preference was given to studies that looked at number of confirmed publications and/or research grants as primary outcomes. Thirteen programs were identified in nine studies. Eighty-three percent of Medical Scientist Training Program (MSTP) graduates, 77% of Clinician Investigator Training Program (CI) graduates, and only 16% of Medical Fellows Program graduates entered a career in academics. Seventy-eight percent of MSTP graduates succeeded in obtaining National Institute of Health (NIH) grants, while only 15% of Mayo Clinic National Research Service Award-T32 graduates obtained NIH grants. MSTP physician scientists who graduated in 1990 had 13.5 ± 12.5 publications, while MSTP physician scientists who graduated in 1975 had 51.2 ± 38.3 publications. Additionally, graduates from the Mayo Clinic's MD-PhD Program, the CI Program, and the NSRA Program had 18.2 ± 20.1, 26.5 ± 24.5, and 17.9 ± 26.3 publications, respectively. MSTP is a successful model for the training of physician scientists in the United States, but training at the postgraduate level also shows promising outcomes. An increase in the number of positions available for training at the postgraduate level should be considered.

Increased risk of bone fracture among patients with urinary calculi: a nationwide longitudinal population-based study.

UNLABELLED: Urinary calculi were associated with higher risk of vertebral and upper limb fracture. Therefore, patients with urinary calculi should be evaluated carefully because they may have a higher risk of subsequent fracture later in life. INTRODUCTION: The contribution of urinary calculi to reduced bone mineral density has been recognized. However, the association of urinary calculi with the risk of fracture remains inconclusive. The aim of the study was to determine the risk of overall fracture and fractures at different anatomic sites in patients with urinary calculi. METHODS: The records of inpatients and outpatients with urinary calculi were retrieved from the Taiwan National Health Insurance Database from 2000 to 2010. Among patients with urinary calculi at the cohort entry, controls were matched using propensity scores on a 1:1 ratio. All subjects were followed up from the date of enrollment until fracture occurrence, death, or December 31, 2010. There were 46,243 Medicare beneficiaries with a diagnosis of urinary calculi and 46,243 controls without calculi enrolled. RESULTS: Among these patients, 6005 patients with a diagnosis of urinary calculi and 5339 controls developed fractures during a median follow-up period of 5.3 years. Patients with urinary calculi had a higher incidence of fracture compared with controls (23.9 versus 22.1 per 1000 person-years) and a greater risk of overall fractures (adjusted hazard ratio [aHR] 1.08, 95 % confidence interval [CI], 1.04-1.12), mainly located at the vertebrae (aHR 1.15, 95 % CI, 1.06-1.25) and upper limb (aHR 1.07, 95 % CI, 1.01-1.14), but the risk for hip fracture was not increased (aHR 1.09, 95 % CI, 0.96-1.22). CONCLUSIONS: Urinary calculus is independently associated with higher risk of subsequent fracture. Patients with urinary calculi should pay attention to the future vertebral and upper limb fractures.

Hyperuricemia predicts kidney disease progression after acute allograft dysfunction.

BACKGROUND: Hyperuricemia is associated with the development of new cardiovascular events and chronic allograft nephropathy in patients with decreased allograft function. This study investigates whether hyperuricemia in kidney transplant recipients should be considered as an independent predictor of kidney disease progression after acute allograft dysfunction. METHODS: Between September 1, 2010, and December 31, 2012, 124 patients who underwent kidney graft biopsy for acute allograft dysfunction were enrolled. Participants were divided into 2 groups: A hyperuricemic group (n = 57) and a normouricemic group (n = 67). The mean serum uric acid (UA) level was obtained by averaging all measurements, once per month for 3 months, before the study began. Clinical and laboratory data were collected. We investigated the role of hyperuricemia on the composite end point (CEP) of doubling of serum creatinine and graft failure by using Cox regression and Kaplan-Meier plots. RESULTS: Over a mean follow-up of 14.27 months, the hyperuricemic group had a poor cumulative survival and easily reached the CEP of doubling of serum creatinine and graft failure (P = .025) with a first-year cumulative incidence of 29.84% and a second-year cumulative incidence of 35.09%. Cox regression models revealed that age at biopsy (unadjusted hazard ratio [HR], 1.03; 95% CI, 1.00-1.06), hyperuricemia (HR, 2.24; 95% CI, 1.13-4.46), and interstitial fibrosis and tubular atrophy (IF/TA), including <25% of parenchyma affected (HR, 3.71; 95% CI, 1.34-10.31) and ≥ 25% of parenchyma affected (HR, 5.10; 95% CI, 1.83-14.19), were highly associated with poor outcome. After adjusting different variables, hyperuricemia and IF/TA were still significant. CONCLUSION: Persistently high serum UA and IF/TA both contribute to the risk of kidney disease progression after acute allograft dysfunction.

Uric acid is highly associated with kidney allograft survival in a time-varying analysis.

BACKGROUND: Hyperuricemia may be associated with the development of new cardiovascular events and graft loss in renal transplant recipients. This study was conducted to clarify whether hyperuricemia is a persistently independent predictor of long-term graft survival and patient outcome. METHODS: Renal allograft recipients (n = 880) who underwent transplantation from December 1999 to March 2013 were included. Participants were divided into 2 groups: a hyperuricemic group (n = 389) and a normouricemic group (n = 491). The mean serum uric acid (UA) level was obtained by averaging all measurements, once per month for 3 months, before the study began. Clinical and laboratory data were collected. We investigated the role of hyperuricemia in the primary endpoint of graft failure by using time-varying analysis and Kaplan-Meier plots. All-cause mortality in renal transplant recipients was also surveyed. RESULTS: During a mean follow-up of 43.3 ± 26.3 months, the major predisposing factors in the 389 patients with hyperuricemia were male predominance (62.98%), high entry serum UA (7.70; range 6.70-8.80 mg/dL), more hypertension (92.29%), previous hemodialysis mode (29.56%), hepatitis C infection (24.42%), more frequent use of UA-lowering agents (43.44%), and use of more drugs for inducing high serum UA (17.74%). After 12 months, the hyperuricemic group had persistently high serum UA (7.66 ± 2.00 vs 6.17 ± 1.60 mg/dL, P < .001) and poor renal function (serum creatinine 2.96 ± 3.20 vs 1.61 ± 1.96 mg/dL, P < .001) compared with the normouricemic group. Survival analysis showed the hyperuricemic group had poorer graft survival (60.47%) than the normouricemic group (75.82%, P = .0069) after 13-year follow-up. However, there was no difference in all-cause mortality between the 2 groups. CONCLUSION: Persistently high serum UA seems to be implicated in elevation of serum creatinine, which could increase the risk for allograft dysfunction.

Gene polymorphisms are associated with posttransplantation diabetes mellitus among Taiwanese renal transplant recipients.

BACKGROUND: Genetic variations may affect posttransplantation metabolic syndrome and diabetes mellitus (PTDM), which is associated with greater morbidity and progressive impairment of both patient and graft survivals. The aim of this study was to evaluate several candidate gene polymorphisms for their association with the risk of developing PTDM. METHODS: In April 1999, we enrolled 278 renal transplant participants, including 251 subjects free of diabetes and 27 with PTDM. We studied several candidate gene polymorphisms associated with diabetes: 4G/5G polymorphism of plasminogen activator inhibitor 1 (PAI-1) at -675; C/T polymorphism of interleukin-1beta (IL-1ß) at -511; G/C polymorphism of IL-6 at 174; polymorphic XbaI of Glucose transporter 1 (GLUT1); and C/T polymorphism of methylenetetrahydrofolate redutase (MTHFR) at 677. RESULTS: The PTDM group had an older mean age (47.6 ± 9.8 years), greater predominance of men (77.8%), higher number of chronic diseases (CDN ≥2, 96.3%), and more patients using tacrolimus-based immunosuppression (44.4%; P < .05). Using model A, a simple logistic regression, we observed that patients with the IL-6 G/G genotype experienced a lower risk of developing PTDM (odds ratio [OR], 0.08; 95% confidence interval [CI] 0.01-0.86), and multiple logistic regression models B and C, after adjusting for different variables, confirmed this observation (model B: OR, 0.05; 95% CI, 0.00-0.66). The IL-6 G/G genotype showed a borderline effect in model C (OR, 0.02; 95% CI, 0.00-1.16). There were no significant differences between the 2 groups in genotype variations of PAI-1, IL-1ß, GLUT-1, and MTHFR. CONCLUSIONS: The G/G genotype of IL-6 may play an important role to lower the risk for PTDM development.

Epoetin alfa and darbepoetin alfa: effects on ventricular hypertrophy in patients with chronic kidney disease.

BACKGROUND: Anemia is very common in chronic kidney disease (CKD) and is commonly treated with recombinant human erythropoietin. The aim of this study was to analyze the efficacy of epoetin alfa and darbepoetin alfa on left ventricular parameters in patients with CKD. METHODS: Patients with CKD not yet dependent on dialysis were randomly assigned to treatment with epoetin alfa at weekly intervals (Epo group; baseline hemoglobin 8.5 +/- 0.8 mg/dL, creatinine clearance 10.0 +/- 2.0 ml/min per 1.73 m2) or darbepoetin alfa every 2 weeks (Dar group; baseline hemoglobin 8.2 +/- 0.8 mg/dL, creatinine clearance 10.8 +/- 2.4 ml/min per 1.73 m2). Patients not receiving erythropoietin served as a control group. Two-dimensional color Doppler echocardiography was performed at baseline and at 24 weeks to measure left ventricular mass index (LVMI) and ejection fraction. RESULTS: Hemoglobin in the 2 treatment arms was corrected to 10.6 +/- 0.6 mg/dL and 10.7 +/- 0.5 mg/dL for Epo and Dar groups, respectively. The LVMI decreased significantly in both the Epo (-5.7 +/- 14.2 g/m2) and the Dar group (-5.6 +/- 15.8 g/m2) but increased in the control group (9.0 +/- 15.1 g/m2; p=0.02, between the Epo and control groups, and between the Dar and control groups). The ejection fraction was increased in both treatment groups (Epo group: 2.45% +/- 2.28%, Dar group: 1.64% +/- 2.95%) and decreased in controls (-1.15% +/- 3.69%) (p=0.004 among groups). The 2 treatment groups showed similar efficacy. The degree and the change of renal function did not differ among the 3 groups at end of study. CONCLUSIONS: The 2 erythropoiesis-stimulating agents epoetin alfa and darbepoetin alfa, when given to patients with CKD in doses aimed at standard anemia correction are associated with a similar degree of LVMI reduction, in the absence of a concomitant enhancement of CKD progression.

Indwelled femoral vein non-cuffed, double-lumen hemodialysis catheter complicated by pulmonary thromboembolism.

Non-cuffed, double-lumen hemodialysis (HD) catheters can be inserted at the bedside in the femoral, internal jugular or subclavian position. The femoral route is less risky, and the incidence of life-threatening complications is lower for femoral cannulation than for internal jugular and subclavian cannulations. However, here we describe a life-threatening complication of an extensive deep vein thrombosis and subsequent pulmonary thromboembolism following femoral cannulation of a double-lumen HD catheter. The possible mechanisms and treatment for this potentially fatal thromboembolic event are discussed in this report.

Mechanical hemolysis in a hemodialysis patient with carotid-jugular arteriovenous fistula.

Renal anemia is mainly caused by inadequate synthesis of erythropoietin from diseased kidneys. At the present time, recombinant human erythropoietin (rHuEPO) is used to correct anemia successfully in most patients with end-stage renal diseases. Nevertheless, poor response to rHuEPO still exists in some hemodialysis patients and its mechanism in some cases remains obscure. Herein, we describe a rare case of rHuEPO hyporesponsiveness due to mechanical hemolysis induced by a traumatic carotid-jugular arteriovenous fistula (AVF) in the presence of subclinical aluminum intoxication. Following surgical resection of the traumatic AVF and 8 months of desferrioxamine treatment, the responsiveness to rHuEPO was restored and the rHuEPO dose requirements reduced.

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.

An occult cause of arteriovenous access failure: central vein stenosis from permanent pacemaker wire. Report of three cases and review of the literature.

Central vein stenosis is an indolent and underestimated complication of permanent pacemaker placement. It leads to serious problems in hemodialysis patients when arteriovenous (AV) fistulae/grafts were created at the ipsilateral arm. We, herein, reported 3 cases of AV access failure resulting from permanent pacemaker-related central vein stenosis. The pathogenesis, clinical manifestations, radiological findings, and therapeutic solution on this issue are discussed. It is mandatory to place the AV fistula/graft and permanent pacemaker wire on the opposite side for prevention of the high risk of AV access failure.

Renal disease in type 2 diabetes.

The prevalence of type 2 diabetes is rising in all Westernized societies. Presumably as a consequence of diminishing cardiovascular mortality, end-stage renal failure (ESRF) in patients with diabetes (mostly type 2) as a co-morbid condition has risen dramatically in the past decade. This constellation has become the single most common cause of ESRF in most countries. Such an epidemiological trend is particularly regrettable, since in uraemic diabetic patients, medical rehabilitation and survival are remarkably poor. Recent studies indicate that an interplay between genetic predisposition and factors, some of them susceptible to intervention, such as hyperglycaemia, blood pressure, smoking, age, gender and ethnicity, predispose to the development and progression of nephropathy. It has also become clear that trace albuminuria ('microalbuminuria') provides unique opportunities to recognize incipient renal involvement early on, although it is less specific in type 2 as compared with type 1 diabetes. Factors that promote progression include hypertension, proteinuria, smoking, glycaemic control and, less certainly, dietary protein intake and hyperlipidaemia. Cumulating evidence indicates that early intervention delays progression of nephropathy. The most important strategies to combat the medical catastrophe of increasing numbers of diabetic patients with ESRF include: (i) prevention of diabetes (mainly type 2); (ii) glycaemic control to prevent onset of renal involvement; and (iii) meticulous antihypertensive treatment to avoid progression of nephropathy.

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.

Chorea induced by thiamine deficiency in hemodialysis patients.

Thiamine deficiency is mainly encountered in alcoholics or food faddists, but it may complicate chronic dialysis because of low intake and accelerated loss of thiamine in dialysis patients. We report here 2 hemodialysis (HD) patients who developed chorea induced by thiamine deficiency. We propose that thiamine deficiency, with a consequent dysfunction of the basal ganglia, may induce chorea in HD patients.

8-hydroxy-2'-deoxyguanosine of leukocyte DNA as a marker of oxidative stress in chronic hemodialysis patients.

In contrast to proteins and lipids, oxidative damage to DNA has not been well studied in patients undergoing hemodialysis (HD). We hypothesized that phagocytes are activated after blood-membrane contact during HD, and oxidants from metabolic activation can damage leukocyte DNA. To test this hypothesis, the 8-hydroxy-2'-deoxyguanosine (8-OHdG) content of leukocyte DNA was measured by high-performance liquid chromatography electrochemical detection method in 35 age- and sex-matched healthy subjects, 22 undialyzed patients with advanced renal failure, and 109 HD patients to assess the relation between oxidative DNA damage and complement-activating membranes, blood antioxidants, and iron status. Dialysis membranes were classified into complement-activating (cellulose; n = 55) and non-complement-activating (polymethylmethacrylate [PMMA]; n = 35; polysulfone [PS]; n = 19) membranes. We found increased oxidative stress in undialyzed and HD patients based on a decrease in plasma levels of ascorbate and alpha-tocopherol adjusted for blood lipid (alpha-tocopherol/lipid), serum albumin, and reduced glutathione levels in whole blood and an increase in oxidized glutathione levels in whole blood compared with controls (P < 0.001). The greatest 8-OHdG level in leukocyte DNA was in HD patients, followed by undialyzed patients and healthy controls (P < 0.001), and was significantly greater in HD patients using cellulose membranes than those using PMMA or PS membranes (P < 0.001). 8-OHdG levels correlated with plasma alpha-tocopherol/lipid (r = -0.314; P < 0.005), serum iron (r = 0. 446; P < 0.001), and transferrin saturation values (r = 0.202; P < 0.05) in the analysis of all HD patients. In a 6-week crossover study, 8-OHdG levels significantly decreased after the switch from cellulose to synthetic membranes for 2 weeks and increased after the shift from synthetic to cellulose membranes (P < 0.05). Iron metabolism indices and plasma alpha-tocopherol/lipid values did not change significantly in the study period. We conclude that 8-OHdG content in leukocyte DNA is a biomarker of oxidant-induced DNA damage in HD patients. Oxidative DNA damage is a consequence of uremia, further augmented by complement-activating membranes.

Effect of vitamin E-bonded membrane on the 8-hydroxy 2'-deoxyguanosine level in leukocyte DNA of hemodialysis patients.

BACKGROUND: 8-Hydroxy 2'-deoxyguanosine (8-OHdG) of leukocyte DNA has been identified as a surrogate marker of oxidative stress in chronic hemodialysis (HD) patients. In this study, we focused on the determinants of the 8-OHdG level in leukocyte DNA of HD patients. We further investigated the influence of vitamin E-modified, regenerated cellulose (CL-E) membrane on the oxidative DNA damage, intracellular reactive oxygen species (ROS) production of granulocytes, and plasma alpha-tocopherol concentration. METHODS: 8-OHdG content in cellular DNA of leukocytes was measured by a high-performance liquid chromatography-electrochemical detection (HPLC-ECD) method. Intracellular production of ROS, H2O2 and O2-. were analyzed by flow cytometry in leukocytes with and without phorbol-12-myristate-13-acetate (PMA) stimulation before dialysis, as well as at 15 and 30 minutes of dialysis. Plasma alpha-tocopherol concentration was measured by a HPLC method, and the value of alpha-tocopherol was corrected by total blood lipid concentration. RESULTS: In the prospective cross sectional study, the mean 8-OHdG level in leukocyte DNA was equally lower in the patients of the CL-E, polymethylmethacrylate (PMMA), and polysulfone (PS) groups as compared with the cellulosic group (ANOVA, P < 0.001). The leukocyte 8-OHdG level correlated negatively with plasma alpha-tocopherol and blood lipid-adjusted plasma alpha-tocopherol, but correlated positively with serum iron and percentage of transferrin saturation. Forward stepwise multiple regression showed that dialysis membrane type, serum iron, and blood lipid-adjusted plasma alpha-tocopherol were the independent determinants of the leukocyte 8-OHdG level in HD patients. Like synthetic membranes, granulocyte ROS production was less augmented during dialysis with the CL-E membrane as compared with the cellulose membrane. Exposure to cellulose membrane impaired intracellular ROS production of granulocytes in response to PMA challenge, whereas the CL-E and synthetic membranes improved the granulocyte responsiveness to PMA. In the longitudinal cross-over study, the 8-OHdG level significantly decreased, and blood lipid-adjusted plasma alpha-tocopherol increased after switching the cellulose membrane to CL-E or synthetic membrane for eight weeks. In contrast, the 8-OHdG level dramatically rose, and blood lipid-adjusted plasma alpha-tocopherol declined after shift of CL-E or synthetic membrane to the cellulose membrane. CONCLUSIONS: CL-E membrane exhibited biocompatible and bioactive characteristics. Like synthetic membranes, treatment with a CL-E dialyzer effectively reduced the 8-OHdG content in leukocyte DNA, suppressed intracellular ROS production of granulocytes, and preserved the plasma level of vitamin E. It could further improve granulocyte responsiveness to a PMA challenge. Reduced DNA damage and improved immune function of leukocytes may reduce the cancer and infection risks in chronic HD patients.