Median CSA Research Articles

Median Nerve Affection in Hypertensive Patients with and without Diabetes High-Resolution Ultrasound Assessment.

PurposeDiabetes is a documented risk factor for peripheral neuropathy. It was reported that associated hypertension could increase this risk. The present study aimed to assess the effect of hypertension and diabetes on median nerve using high-resolution ultrasound.MethodsThe study includes 50 hypertensive patients (HTN group), 50 diabetic patients (DM group), 50 patients with coexisting diabetes and hypertension (HTN + DM group) and 50 healthy controls. Median nerve affection in the studied groups was studied by vibration perception thresholds (VPT). The median nerve cross-sectional area was determined at the nerve cross-sectional area of the median nerve at the carpal tunnel by high-resolution ultrasound. Clinical symptoms were assessed using Toronto Clinical Severity Score (TCSS).ResultsThere was significantly higher median nerve CSA in all patient groups in comparison to controls. HTN + DM group had significantly higher median nerve CSA when compared with DM group. Patients with peripheral neuropathy in HTN + DM and DM groups had significantly higher median nerve CSA than patients without. Using ROC curve analysis, it was shown that median CSA could successfully distinguish patients with peripheral neuropathy from patients without in HTN + DM group [AUC (95% CI): 0.71 (0.54–0.89)] and in DM group [AUC (95% CI): 0.86 (0.72–0.99)].ConclusionHypertensive patients with and without diabetes have significantly higher median nerve CSA when compared with controls.

Relationship between blood glucose variability and muscle composition in ICU patients receiving nutrition support: A pilot study.

Many critically ill patients experience increased blood glucose variability (BGV). The objective of the current pilot study was to assess the relationship between muscle composition (defined as average Hounsfield units (HU)) among ICU patients with an abdominal CT scan within seven days of intubation, and BGV (defined as coefficient of variation (CV)) calculated from blood glucose levels measured each morning while intubated. The first serum blood glucose measurement obtained each day during intubation was recorded, blood glucose CV ((mean/SD)∗100) was calculated. Cross-sectional muscle area (CSA; cm2) at the third lumbar region was identified using the-29 to+150 HU range; muscle composition was calculated as the average HU. BGV predictors were determined using linear regression. Eighty-two patients were included (53% female), with a median age of 64 (25th, 75 percentile (IQR): 51, 70) years. The median CV was 29% (IQR: 20, 37); 40% of subjects required insulin. The median CSA was 100.4cm2 (IQR: 84.0, 120.8) and muscle composition was 20.4 HU (IQR: 12.2, 29.4). Patients received only 36% of estimated calorie requirements. Insulin administration, history of diabetes, and muscle composition were significant BGV predictors. Among these adult intubated ICU patients, higher muscle composition was associated with lower BGV. Future research is needed to corroborate these findings, determine other factors associated with poor muscle quality, and identify methods to describe muscle composition for all ICU patients.

A longitudinal histologic evaluation of vitamin D receptor expression in the skeletal muscles of patients with a distal radius fracture.

Vitamin D supplementation is known to enhance muscle mass and function, but whether the VDR is essential in this process remains unknown. We evaluated the change in VDR expression and CSA in the forearm muscles following vitamin D supplementation in patients with a DRF. We prospectively recruited 18 women with a median age of 63.5 years who have a DRF. We obtained two biopsies of the forearm muscle, first at the time of fracture repair and then during hardware removal. We supplemented 1000 IU of vitamin D per day during a median interval of 8 months. We examined the changes in VDR expression and CSA by immunohistochemistry. The median serum 25-hydroxyvitamin D [25(OH)D] increased from 14.3 to 32.1 ng/mL (P = 0.001). The median VDR expression increased from 0.72 to 0.78 (P = 0.002), and the median CSA increased from 1290.0 to 1685.8 μm2 (P = 0.022). Significant increases in VDR expression and CSA were observed in vitamin D-deficient patients [25(OH)D] < 20 ng/mL, but not in vitamin D-non-deficient patients. The changes in VDR expression and CSA were in the same direction in 13 patients, but in the opposite direction in 5 patients. Vitamin D supplementation may increase muscle VDR expression and CSA in patients with a DRF, especially in vitamin D-deficient patients. The increase in CSA without an increase in VDR expression in some patients indicates that the effect of vitamin D supplementation on muscle mass could be mediated by indirect effect of serum vitamin D restoration and by VDR.

Higher Starting Dose of Ciclosporin Optimized Therapeutic Levels in Patients Receiving Phenytoin for Busulfan-induced Seizure Prophylaxis.

Despite understanding the drug-drug interaction between phenytoin and ciclosporin (CsA), there is no recommended CsA dosing in patients receiving phenytoin as seizure prophylaxis in busulfan-based conditioning regimens. This drug-drug interaction has resulted in patients with sub-therapeutic levels at day 0 (D0) of allogeneic hematopoietic stem cell transplantation (alloHSCT) and at risk for acute graft-versus-host disease (aGVHD). A single-center historical-control study was conducted at Singapore General Hospital between March 2010 and July 2019 to evaluate a new dosing strategy. Patients with phenytoin received a higher starting dose of intravenous CsA (4 mg/kg/dose twice daily instead of 3 mg/kg/dose twice daily). The primary endpoint of this study was to determine the proportion of patients with therapeutic CsA levels at D0. Secondary endpoints included median CsA level on D-1 and D0, time to the therapeutic target, incidence and severity of aGVHD, and safety profile. A total of 91 patients were included in this study. Patients with therapeutic CsA at D0 was higher (66.7%) in the study arm than in the control arm (24.7 %) (p = 0.006). The median CsA concentration at D0 in the study arm was 284 ng/mL (range, 144-441 ng/mL) as compared to the control arm, 255 ng/mL (range, 104-580). There was no difference in the time to therapeutic range and the cumulative incidence of aGVHD. There were no significant differences in the safety outcomes. The new strategy with higher dosing based on the actual body weight should be adopted as it resulted in a higher proportion of patients with therapeutic CsA at D0, without an increase in CsA-related adverse events.

Making community-supported agriculture accessible to low-income families: findings from the Farm Fresh Foods for Healthy Kids process evaluation.

A randomized trial of Farm Fresh Foods for Healthy Kids (F3HK) was initiated across 4 states and 12 farms to test whether cost-offset community-supported agriculture (CO-CSA) could improve diet quality among children in low-income families. Intervention households purchased a 50% subsidized share of local produce and were invited to nine complimentary nutrition classes. The purpose of this study was to assess F3HK reach, dose, and fidelity via a mixed methods process evaluation. Screening and enrollment records indicated reach; study records and postlesson educator surveys tracked dose delivered; CSA pickup logs, lesson sign-in sheets, postseason participant surveys, and postlesson caregiver surveys assessed dose received; and coordinator audits and educator surveys tracked fidelity. Educator interviews contextualized findings. The results of this study were as follows. Reach: enrolled caregivers (n = 305) were older (p = .005) than eligible nonenrollees (n = 243) and more likely to be female (p < .001). Dose: mean CSA season was 21 weeks (interquartile range [IQR]: 19-23). Median CSA pickup was 88% of the weeks (IQR: 40-100). All sites offered each class at least once. Most adults (77%) and children (54%) attended at least one class; few attended all. Eighty-two percent of caregivers indicated that their household consumed most or all produce. Median lesson activity ratings were 5/5 ("very useful"). Fidelity: CSA locations functioned with integrity to project standards. Educators taught 92% of activities but frequently modified lesson order. This study demonstrates the feasibility of pairing a CO-CSA intervention with nutrition education across geographically dispersed sites. Greater integration of intervention elements and clearer allowance for site-level modifications, particularly for educational elements, may improve intervention dose and, ultimately, impact.

Diagnostic utility of median nerve CSA to ulnar nerve CSA ratio in the diagnosis of mild idiopathic carpal tunnel syndrome

BackgroundUltrasonography (US) measurement of median nerve cross-sectional area (m-CSA) at pisiform is increasingly utilized in identification of carpal tunnel syndrome (CTS), but there is still no agreement about the ideal cut-off value to employ. The aim of the study was to explore whether the median CSA to ulnar CSA ratio at the level of pisiform may yield a more accurate diagnosis of CTS. The study included 50 patients with mild idiopathic CTS (ICTS), assessed clinically and by nerve conduction studies, and 50 matched controls. M-CSA, median nerve flattening ratio and swelling ratio (m-SR), palmer bowing, and median CSA to ulnar CSA ratio (m-CAS:u-CSA) were measured for patients and controls. The cutoff values for the US parameters for the diagnosis of ICTS were evaluated.ResultsCompared to the control group, the ICTS group had significantly higher m-CSA (p < 0.001), higher m-CSA:u-CSA ratio (p < 0.001), higher m-SR (p = 0.012, and higher palmar bowing (p < 0.001). Use of m-CSA cutoff value of 11.78 mm2 and CSA:u-CSA ratio cut-off point of 2.97 yielded the greatest sensitivity and specificity for the diagnosis of ICTS.ConclusionThe m-CSA:u-CSA ratio is slightly superior to the m-CSA in the diagnosis of CTS in terms of sensitivity and specificity.

Effect of Indirect Neural Decompression Through Oblique Lateral Interbody Fusion for Degenerative Lumbar Disease

Prospective consecutive clinical study to assess the decompressive benefit and outcome of oblique lateral interbody fusion for lumbar degenerative diseases. To evaluate radiologically the effect of interbody distraction upon neural patency via an anterolateral retroperitoneal approach for the treatment of lumbar degenerative diseases. Traditional treatment for symptomatic lumbar stenosis uses direct posterior decompression with or without fusion. Symptoms of radiculopathy and neurological claudication may also be alleviated indirectly through restoration of intervertebral and foraminal heights and correction of spinal alignment. Twenty-eight consecutive patients presenting with degenerative conditions that included concomitant lumbar stenosis underwent oblique lateral interbody fusion combined with percutaneous pedicle screw fixation at 52 lumbar levels without neuromonitoring. Magnetic resonance images were obtained successfully for 48 of 52 levels. The cross-sectional area of the thecal sac (CSA) was measured preoperatively and postoperatively on T2-weighted axial magnetic resonance images. Differences in CSA were compared, and the relationship between the ratio of CSA extension and that of the preoperative CSA was assessed. The change in disc height and segmental disc angle were measured. The relationships between CSA, disc height, segmental disc angle, and clinical results were assessed by correlational analysis. Twenty-eight oblique lateral interbody fusions were performed successfully without neural complications. There was clinical improvement in all cases. The mean CSA increased from 99.6 mm preoperatively to 134.3 mm postoperatively (P<0.001). The median CSA extension ratio was 30.2% and this correlated inversely with preoperative CSA. Disc height, segmental disc angle, and clinical results improved significantly. Multivariate regression analysis demonstrated that the preoperative CSA was the only independent factor that correlated inversely with the CSA extension ratio (corrected R=0.361; P<0.001). Spinal stenosis was resolved successfully by indirect decompression through a miniopen anterolateral retroperitoneal approach without the need for neuromonitoring. 3.

Impact of Cyclosporine Levels on the Development of Acute Graft versus Host Disease after Reduced Intensity Conditioning Allogeneic Stem Cell Transplantation

We analyze the impact of cyclosporine (CsA) levels in the development of acute graft-versus-host disease (aGVHD) after reduced intensity conditioning allogeneic hematopoietic transplantation (allo-RIC). We retrospectively evaluated 156 consecutive patients who underwent HLA-identical sibling allo-RIC at our institution. CsA median blood levels in the 1st, 2nd, 3rd and 4th weeks after allo-RIC were 134 (range: 10–444), 219 (54–656), 253 (53–910) and 224 (30–699) ng/mL; 60%, 16%, 11% and 17% of the patients had median CsA blood levels below 150 ng/mL during these weeks. 53 patients developed grade 2–4 aGVHD for a cumulative incidence of 45% (95% CI 34–50%) at a median of 42 days. Low CsA levels on the 3rd week and sex-mismatch were associated with the development of GVHD. Risk factors for 1-year NRM and OS were advanced disease status (HR: 2.2, P = 0.02) and development of grade 2–4 aGVHD (HR: 2.5, P < 0.01), while there was a trend for higher NRM in patients with a low median CsA concentration on the 3rd week (P = 0.06). These results emphasize the relevance of sustaining adequate levels of blood CsA by close monitoring and dose adjustments, particularly when engraftment becomes evident. CsA adequate management will impact on long-term outcomes in the allo-RIC setting.

The Role of Musculoskeletal USG as Diagonostic Tool of CTS

Abstract Introduction Over the years NCS has been used to diagnose and monitor the patients with CTS though USG has several advantages as diagnostic tool. This study has been done to find out the diagnostic accuracy of USG in CTS and to compare the efficacy of USG with standard NCS in CTS. Prospective cross-sectional analytical study was conducted at Dept. of PM&amp;R, IPGME&amp;R, Kolkata from 1st March, 2012 to 31st August 2012 (6 months). Patient with clinical diagnosis of CTS of age &gt;18 year of both sexes were included in this study and on the other hand patient with previous wrist surgery /injury, wrist deformity, diabetes mellitus, anatomical variants of median nerve on ultrasound were excluded from the study. Methodology After getting institutional ethical committee clearance, all patients who fulfil the above criteria were included in the study and further diagnostic conformation done by the standard diagnostic criteria of NCS. The same group of patients have been also screened by ultrasonography (USG). Results At the end of the study, data analysis showed that sensitivity and specificity were 92.3 and 70.0% respectively. Predictive value of +test, predictive value of -test were 88.9 and 77.8% respectively. Kappa value was 0.64 (between 0.5 and 0.7). It signifies that there is good correlation between NCS and USG as diagnostic tool of CTS. The comparison of the numerical values of median latency, amplitude and CSA USG within the groups with the help of ANOVA followed by Tukey's test showed that there was good correlation between latency and amplitude in mild, moderate, severe and profound CTS but unfortunately it was not correlated with the CSA measured by USG. Conclusion USG can be used for screening large population of patients as it is simple, easily available, non-invasive test and has relatively low cost and useful in evaluating and excluding local causes of nerve compression.

Higher CSA Levels After Umbilical Cord Blood Transplant For Acute Leukemia Result In Improved Survival

BackgroundCyclosporine A (CSA) is commonly used after bone marrow transplantation for graft versus host disease (GVHD) prophylaxis. There have been conflicting reports regarding dosing of CSA and its effects on relapse and GVHD. Higher doses of CSA after bone marrow transplantation have been associated with greater leukemia relapse. Because it was unknown whether umbilical cord blood transplantation (UCBT) has a similar risk, we studied the impact of CSA levels on UCBT outcomes in patients with acute leukemia. Patients and MethodsWe reviewed the records of 242 consecutive patients with acute leukemia who received UCBT and CSA for GVHD prophylaxis at our institution from 2004-2011. Eighty (33%) patients had acute lymphoblastic leukemia and 162 (67%) had acute myelogenous leukemia. Fifty-seven patients (24%) had a single UCBT; one hundred fifty-four patients (64%) underwent myeloablative conditioning. The median age at transplant was 30 (1-71) years and median follow-up 4.95 (0.56-10.29) years. Serum CSA levels were collected at least once a week around day -1 and continuing through ∼day 180. We hypothesized that early CSA levels would have the greatest impact on both graft vs. host disease (GVHD) and graft vs. leukemia (GVL) reactions. For the purpose of this study, we examined CSA levels during the first 6 weeks of administration and determined the median CSA level both early (day -3-20) and late (day 21-42). A median of 13 (range was 4-28) CSA levels were drawn during this time period. The median CSA level determined from day-3-20 was 273.5 and the median CSA from days 21-42 was 249.5. Based on the medians in each three week period, patients were divided into four different groups based CSA level and whether it was above or below the median (low-low; low-high; high-low and high-high). ResultsIn multivariate analysis for patients with ALL, disease free survival (DFS) at one year and three years was significantly improved in patients that maintained high levels of CSA from days 21-42 (p=0.02 for low-high and p=0.01 for high-high). Overall survival (OS) was improved at one year for patients with high CSA levels late (p=<0.01 for low-high and high-high) but at three years was improved in only patients that had maintained high CSA levels throughout the entire 6 weeks (p=0.03 for high-high). Patients with high levels of CSA from days 21-42 were also associated with less transplant related mortality (TRM) (p=0.04 for low-high and p=0.01 for high-high). There was no association of CSA levels and relapse or acute GVHD grades II-IV for ALL patients. In multivariate analysis of AML patients, we found that DFS at one year was significantly improved in patients that maintained high CSA levels at any time during the six weeks (p=0.01 for high-low, low-high and high-high) whereas at 3 years, patients that maintained high CSA levels early had a better chance of DFS (p=0.02 for high-low and high-high). OS at three years was also significantly greater in patients with high levels of CSA early (p=0.05 for high-low and high-high). TRM was decreased in patients that had high levels of CSA early (p=0.02 for high-low and high-high). Interestingly, in multivariate analysis, relapse was improved in patients that maintained initially low levels and then high levels of CSA (p=0.05). Acute GVHD grades II-IV was significantly improved in AML patients with high CSA levels for the entire 6 weeks (p=0.04 for high-high). ConclusionsTaken together, these data suggest that high median CSA levels in the first six weeks is critical to ensure improved DFS and OS in patients with acute leukemia undergoing UCBT. Interestingly, in ALL patients, the improvement was seen in patients that maintained high CSA levels late, whereas in AML patients, it was seen in those that maintained high CSA levels early. This implies that the interaction between CSA dose and GVL may be different between myelogenous and lymphoid leukemia following UCBT. Disclosures:Wagner:Novartis: Research Funding.

Racial Disparities after Heart Transplant: Evidence from IMAGE

Purpose The basis for increased mortality after heart transplant in non-Caucasians is poorly defined. We hypothesized that increased risk of adverse events is due to biological factors related to the alloimmune response. To test this hypothesis in the IMAGE study, we determined whether the event rate of the primary outcome (rejection with hemodynamic compromise, graft dysfunction, death, or retransplantation) varied by race in heart transplant recipients. We explored whether racial differences may be due to differences in levels of calcineurin inhibitors (CNI) or gene expression profile (GEP) scores. Methods and Materials We studied the event rate of the primary outcome, comparing racial groups in the IMAGE population, stratified by time post-transplant. We assessed whether differences in event rate varied as a function of CNI levels and GEP score. Logistic regression was used to compute the relative risk across racial groups and linear modeling was used to measure the dependence of GEP score and CNI on race. Results We found increased incidence of the primary endpoint in African Americans and other non-Caucasians, compared to Caucasians (18.3% and 22.2% vs. 8.5% respectively). African Americans had higher GEP score than Caucasians on CSA (p=0.01) despite similar levels. GEP score was higher, albeit tacrolimus blood level was lower, for other non-Caucasians than Caucasians. Conclusions Non-Caucasian heart transplant patients are 2.5-3 times more likely than Caucasians to experience rejection with hemodynamic compromise or death. Our data suggest that the increased risk of adverse outcomes may be due to the biology of the alloimmune response, which is less effectively abrogated by immunosuppression in non-Caucasians. Group Month post-tx Events/pt/yr Tac median trough CSA median trough GEP score mean (Tac) GEP score mean (CSA) Caucasian 7-12 0.09 8.8 167 28.8 26.1 13-36 0.07 8.2 144 30 30.1 >36 0.05 7.0 118 30 30 African American 7-12 0.27 9.3 141 30.5 32.2 13-36 0.18 8.4 120 29.8 32.2 >36 0.14 7.1 111 29.4 30.5 Other non-Caucasian 7-12 0.87 8.2 183 29.7 28.5 13-36 0.21 7.0 173 31.8 29.4 >36 0.07 5.7 122 29.6 28.0

Hepatitis C virus viral kinetics during α-2a or α-2b pegylated interferon plus ribavirin therapy in liver transplant recipients with different immunosuppression regimes

BackgroundPredictors of sustained virological response (SVR) to antiviral therapy post-liver transplantation (LT) for chronic hepatitis C are needed. In non-transplanted patients, viral kinetics can predict SVR. ObjectivesTo determine the early viral kinetics in LT recipients with different immunosuppression (tacrolimus – Tac- vs. cyclosporine – CsA-) during treatment with peg-IFN+RBV. Study designProspective pilot study in HCV-1b infected patients: (LT CsA n=8; Tac n=8; non-LT n=4), treated with IFN α-2a vs. α-2b (180μg or 1.5μg/kg, respectively) once weekly plus weight-based RBV. Median CsA or Tac baseline trough levels were 141 and 7.70ng/mL, respectively. HCV-RNA was quantified before treatment and after 3, 6, 12h; days 1–6; and weeks 4, 12, 24, 48 and 78 (follow-up). ResultsDifferent kinetics were observed: early viral load declines with shoulder phase (n=12), delayed monophasic without first phase (n=5, all CsA), and biphasic (n=1) or flat (n=1), without influence of IL28B rs12979860 donor/recipient alleles. In LT, median declines (log10UI/mL) at week 4 were −3.62 and −1.49 for Tac vs. CsA; and −2.10 vs.−1.50 for IFN α-2a vs. α-2b (NS), with a trend for faster declines in Tac patients. Generalized additive models suggested a cut-off for predicting response in LT patients of 30 days for Tac, but beyond day 40 for CsA. ConclusionIn LT, the viral kinetics during peg-IFN+RBV treatment is delayed. HCV-RNA at 48h. may not be predictive of response, and CsA-immunosupressed patients with delayed monophasic declines may potentially achieve ETVR and SVR despite unfavourable or absent early viral load declines.

Antibody-Directed Myostatin Inhibition Improves Diaphragm Pathology in Young but not Adult Dystrophic mdx Mice

Duchenne muscular dystrophy (DMD) is characterized by progressive skeletal muscle wasting and weakness, leading to premature death from respiratory and/or cardiac failure. A clinically relevant question is whether myostatin inhibition can improve function of the diaphragm, which exhibits a severe and progressive pathology comparable with that in DMD. We hypothesized that antibody-directed myostatin inhibition would improve the pathophysiology of diaphragm muscle strips from young mdx mice (when the pathology is mild) and adult mdx mice (when the pathology is quite marked). Five weeks treatment with a mouse chimera of anti-human myostatin antibody (PF-354, 10 mg/kg/week) increased muscle mass (P < 0.05) and increased diaphragm median fiber cross-sectional area (CSA, P < 0.05) in young C57BL/10 and mdx mice, compared with saline-treated controls. PF-354 had no effect on specific force (sPo, maximum force normalized to muscle CSA) of diaphragm muscle strips from young C57BL/10 mice, but increased sPo by 84% (P < 0.05) in young mdx mice. In contrast, 8 weeks of PF-354 treatment did not improve muscle mass, median fiber CSA, collagen infiltration, or sPo of diaphragm muscle strips from adult mdx mice. PF-354 antibody-directed myostatin inhibition completely restored the functional capacity of diaphragm strips to control levels when treatment was initiated early, but not in the later stages of disease progression, suggesting that such therapies may only have a limited window of efficacy for DMD and related conditions.

Achievement of Target Cyclosporine Concentrations as a Predictor of Severe Acute Graft Versus Host Disease in Children Undergoing Hematopoietic Stem Cell Transplantation and Receiving Cyclosporine and Methotrexate Prophylaxis

This study evaluates our institution's target trough cyclosporine (CSA) concentrations as predictors of severe acute graft versus host disease (aGvHD) in children receiving either matched related or unrelated hematopoietic stem cell transplantation (HSCT). The outcomes of 87 consecutive children who underwent allogeneic HSCT and received CSA and methotrexate as prophylaxis against aGvHD between October 1, 1999 and September 30, 2002 were retrospectively evaluated. The proportion of time that each patient maintained a whole blood CSA concentration within or above the initial target range (105-155 ng/mL or 155-210 ng/mL) was calculated for each of the following time periods: in each week after HSCT from day 0 to +28; in the week preceding engraftment; and in the week preceding the onset of aGvHD. Patients were prospectively evaluated twice weekly for the presence and severity of aGvHD by senior attending physicians. The relationship between potential predictors and the development of severe aGvHD was examined using univariate logistic regression. The main variables of interest were the proportion of time that therapeutic or supratherapeutic CSA concentrations were maintained; median CSA concentrations; the number of methotrexate doses received; and the use of folinic acid rescue. Mean follow-up time was 3.0+/-1.9 years among children who survived beyond day +100. Three variables were significantly associated with the development of severe aGvHD on univariate analysis: initial CSA target concentration [odds ratio (OR), 0.24; P=0.03], proportion of time the target CSA concentration was achieved during the second week after transplant (OR, 0.16; P=0.02), and proportion of time the target CSA concentration was achieved during the week before engraftment (OR, 0.22; P=0.0489). Multivariable analysis demonstrated an inverse relationship between the median CSA concentration during the week before engraftment and the development of severe aGvHD (OR, 0.99; P=0.045). These results suggest that achievement of our CSA target concentrations is important to aGvHD outcomes.

Single daily dose of cyclosporine in patients with primary glomerulonephritis and nephrotic syndrome

Single daily dose cyclosporine (SDD-CsA) might be a new option providing comparable efficacy, increased compliance and less nephrotoxicity compared to standard twice-daily dose cyclosporine (TDD-CsA). The aim of this trial was to prove the feasibility of SDD-CsA as primary and secondary maintenance therapy in patients with nephrotic syndrome. We treated 25 adult patients with nephrotic syndrome and chronic primary glomerulonephropathy with SDD-CsA for a period of 12 months or more. 12 patients were pre-treated with twice-daily dose cyclosporine (TDD-CsA) and were then switched secondarily to a single daily dose after a median period of 8 months (sSDD-CsA). 13 patients were treated primarily with single daily dose cyclosporine (pSDD-CsA). In primary SDD-CsA patients, proteinuria decreased significantly from 9.2 - 0.8 g/l (p = 0.02) and serum protein increased significantly from 54 - 71 g/l (p = 0.03) during the study period. In secondary SDD-CsA patients, serum protein increased further (64 - 69, p = 0.04) after switching to SDD-CsA. In secondary SDD-CsA patients, the median total daily CsA dose was significantly lower (200 mg) with SDD-CsA compared to previous twice-daily dosing (300 mg, p = 0.01). Serum creatinine did not differ significantly before and after therapy and between the groups. SDD-CsA is effective in patients with nephrotic syndrome as primary and secondary maintenance therapy. SDD-CsA allows for significantly lower total daily doses, probably with less nephrotoxicity.

Everolimus and reduced cyclosporine trough levels in maintenance heart transplant recipients

Background Long-term survival of patients after oHTX significantly increased over the last years, but CAV and chronic renal failure due to nephrotoxic side-effects of CNIs still remain unsolved problems. Everolimus has shown to reduce acute cellular rejection and may allow CsA dosage reduction. In this study the effectiveness of Everolimus in combination with CsA dosage reduction in maintenance oHTX immunosuppression and the influence on renal function was tested. Methods 37 patients (30 male, 7 female) after oHTX were divided into group A ( n = 20) receiving Everolimus in combination with CsA and prednisolone and group B ( n = 17) under standard immunosuppression with CsA, MMF and prednisolone. Patients received 1.0 mg to 1.5 mg Everolimus per day and target Everolimus trough levels were between 3 and 8 ng/ml. Death, safety, side effects, BPAR, trough levels, and routine laboratory values especially creatinine levels were monitored over a follow-up period of 8 months retrospectively and statistically evaluated. Results A significant reduction of CsA dosage ( p < 0.001) and a significant CsA trough level reduction ( p < 0.001) to a median CsA trough level of 68.5 ng/ml were achieved in group A. Mean Everolimus trough levels were reached within 1 week and 2 months. Renal function was stable in both groups. No statistical differences in BPAR, hospitalization rates or triglyceride levels were observed. Cholesterol levels significantly increased in group B ( p = 0.024). Conclusion CsA trough levels and dosage can be significantly reduced in combination with Everolimus without higher rejection rates and with stable kidney function in oHTX patients.

Daily Monitoring of Cyclosporine (Csa) Allows Better Control of Graft vs. Leukaemia Effect (GvL): Single Centre Experience.

The most important consideration in modern SCT practices is the fine balance that is required to achieve adequate immunosuppression and stable engraftment thus allowing the platform to mount an effective GVL response. Though CsA facilitates this objective, it is associated with several adverse clinical manifestations due to its narrow therapeutic index (TI) and wide variability in the absorption kinetics. Weekly monitoring of trough CsA levels are used to adjust the dose. The aim of this study is to determine whether daily monitoring of CsA levels enables better achievement of these goals and yet reduce the serious toxicities.Patients & methods: Twenty three patients (M=15, F=8, median age 46yrs range 19–63) received an allogeneic transplant (sibling-15, MUD-7 mismatched unrelated-1) since March 2004 when we started to monitor daily CsA levels (Biostat TDX analyser using fluorescent immunoassay) from the day of first administration until the time of discharge. The transplants included full intensity (FI=11), reduced intensity (RI=11) or customised (1) for various haematolymphoid malignancies. Patients received uniform GVHD prophylaxis with IV CsA (RI+FI) and methotrexate (FI) as per standard loading doses. The CsA target level was adjusted to 200–220 ng/ml from Day-1 onwards and was later modified according to the treatment strategy. Oral CsA administration was started when patients were able to switch over. Results Nine of 23 (40%) patients developed acute GVH (n=7 grade1–2, n=2 grade 3–4) at a median of 23.5 days (10–28). Two of 9 patients required addition of steroids by Day+30. The median CsA level at the first occurrence of GVH was 247ng/ml (113–333) and the median CsA level during hospitalisation was 207 ng/ml (136–291). Only one patient who received T cell addback required increased dose of IV CsA to manage Grade 4 GVH. Twenty two/22 patients engrafted with a median day to neutrophil recovery being 13 days (8–35). One patient lost his graft due to a low initial cell dose and the inability of the MUD donor to donate any further cells. There was no significant difference in the baseline and Day30 creatinine levels (median highest creatinine 108μmol/l range 58–267) or bilirubin levels (median highest bilirubin 27μmol/l, range15–251). Five/22 patients developed CMV reactivation/infection and 1 developed RSV infection. No patients developed seizures and in one patient pre-existent neuropathy was exacerbated which was directly attributable to CsA. Twenty one/22 patients (95.5%) switched to oral CsA by Day+25. In 8/22 (36.36%) patients, the target CsA levels was around 100–150 ng/ml at the time of discharge. The median duration of hospital stay was 35days (24–130).Conclusions: These observations suggests that daily monitoring of CsA is safe and successful. This allowed successful engraftment and a more liberal management of Grade 1–2 GVH thus allowing us to maximise the GVL effect. Despite concomitant use of other toxic drugs, side effects were minimal and reversible. Close observation of early clinical manifestations enabled us to modify the immunosuppressive strategy at later time periods. This approach also allowed us to better manage patients suffering from CMV and EBV/PTLD (patient number 10 on day+88) by reducing the dose during active infections.

New concepts in cyclosporine pharmacokinetic and dynamic monitoring: the impact of concomitant immunosuppression on target C 2 concentrations

Background There is a correlation between cyclosporine (CsA) pharmacokinetics (PK) and pharmacodynamics (PD), especially 2 hours after drug administration. Aim To evaluate the relationship between CsA PK and PD profiles in two groups of stable renal transplant patients treated with CsA alone or CsA plus mycophenolate mofetil (CsA+MMF), so as to define the best target for C 2 and clarify the impact of concomitant immunosuppression. Methods Thirty-eight stable renal transplant recipients were treated with CsA ( n = 20) or CsA+MMF ( n = 18). Twelve nontreated normal healthy controls (NHC) were also included. Calcineurin activity (CNa), IL-2 production, and CsA levels were measured at 0 and 2 hours postdose. Results There were no significant differences in median CsA C 2 values and CNa between the CsA alone and the CsA+MMF groups (388 μg/L and 497.5 μg/L and CNa 2h; 3.92% alkaline phosphatase [AP]; 3.94% AP, respectively). In vitro production of IL-2 was significantly lower in the CsA+MMF group than in the CsA group (median IL-2 2h: 280.52 ng/L, 169.48 ng/L, P < .001). The correlations ( r) between C 2 and CNa 2h were: CsA r = 0.74; CsA+MMF r = 0.84 ( P < .001 in both cases). Conclusions In stable renal transplant patients, median CsA C 2 values below 500 μg/L were associated with inhibition of CNa and IL-2 synthesis. CNa and IL-2 production may be good biological markers of CsA immunosuppression. The measurement of CNa depends mainly on CsA concentration, whereas in vitro IL-2 production reflects the effect of both CsA and MMF. Further studies are necessary to define the optimal C 2 target concentration and the possible impact of concomitant immunosuppression.

Angiotension converting enzyme inhibition and calcium channel blockage improves cyclosporine induced glucose intolerance in rats

The aim of this study was to evaluate the effects of quinapril, valsartan, and amlodipin on glucose tolerance in cyclosporine (CsA)-toxic rats. Among 40 male Wistar rats 32 were administered cyclosporine (CsA) (15 mg/kg) intraperitoneally for 6 weeks. Quinapril (10 mg/kg per day) (group Q), valsartan (40 mg/kg per day) (group V), and amlodipine (10mg/kg per day) (group A) were administered to individual sets of eight CsA-treated animals via the drinking water with the remaining untreated hosts followed as a control group (group C) and 8 healthy controls (group H). A Glucose-tolerance test was performed by administering oral glucose (2 g/kg) followed by blood samples obtained from the tail vein at baseline as well as 30,60,90, and 120 minutes after the glucose load. Glucose area under the curve (AUC) was calculated according to the trapezoidal rule. CsA levels were determined using an immunofluorescence method. Kruskal Wallis ANOVA test was used for statistical analysis. Median CsA levels were 1968 ng/mL, 1982 ng/mL, 1580 ng/mL, 1600 ng/mL; and glucose AUC, 232.4 ± 130 mg/min per dL, 63.1 ± 25 mg/min per dL, 115.0 ± 90 mg/min per dL, 47.4 ± 34 mg/min per dL 53.4 ± 38 mg/min per dL for groups C,Q,V,A and H, respectively. Quinapril-treated and amilodipine-treated rats displayed a lower glucose AUC than group C (P < .01), which had higher glucose levels than healthy controls (P < .001). In summary, CsA treated rats show impaired glucose tolerance, which is improved by quinapril or amlodipine treatment. Angiotensin converting enzymes inhibitors and calcium channel blockers affect beta cell function rather than insulin sensitivity.

Effect of cyclophosphamide on serum cyclosporine levels at the conditioning of hematopoietic stem cell transplantation.

We retrospectively analyzed the factors that affect serum cyclosporine (CsA) concentrations up to day 14 after allogeneic hematopoietic stem cell transplantation (HSCT). In all, 103 transplant recipients who received MTX and CsA for acute GVHD prophylaxis were analyzed. No significant relationships between serum CsA concentrations and gender, age, serum creatinine levels, AST/ALT levels, or antibiotic/fluconazole administration were found by comparing median CsA concentrations or by using longitudinal or regression multivariate analyses. However, the mean of the median serum CsA concentration in patients (n=54) receiving the regimen containing cyclophosphamide (CY) (149.7 ng/ml; 95% confidence interval (CI): 132.1-167.4) was significantly (P<0.0001) lower than that in patients (n=49) receiving the non-CY regimen (217.3 ng/ml; 95% CI: 198.9-235.6). Longitudinal analysis and regression multivariate analysis showed that only administration of CY had a significant effect on the serum CsA concentration. Our results suggest that administration of CY during conditioning can reduce the effects on serum CsA concentrations during the 2 weeks following HSCT. The mechanism of this effect is not clear, but it may be due to the autoinduction of CY.