Prevalence and risk factors of pre-diabetes after renal transplantation: a single-centre cohort study in 200 consecutive patients.

BACKGROUND: After renal transplantation, patients are prone to develop impairments in glucose metabolism. In 2005, the American Diabetes Association published new guidelines on the diagnosis of pre-diabetes [plasma glucose levels from 100 to 125 mg/dL fasting or from 140 to 199 mg/dL 2 h after an oral glucose tolerance test (OGTT)]. This study sought to evaluate the prevalence and the potentially associated factors of pre-diabetes in a cohort of renal transplant patients on maintenance immunosuppressive medication. Furthermore, the diagnostic value of HbA1-c measurements in predicting pre-diabetes in transplant patients is undetermined. METHODS: Two hundred consecutive renal transplant patients of our outpatient transplant clinic were evaluated using a standard OGTT. On the day of testing, multiple factors presumably associated with pre-diabetes were assessed via a standardized questionnaire: daily steroid dosage, triglyceride levels, cholesterol levels, estimated glomerular filtration rate (eGFR) [abbreviated Modification of Diet in Renal Disease (MDRD) formula], systolic and diastolic blood pressure, pulse pressure, age, gender, body mass index (BMI), BMI <>30 and <>25, number of renal transplants, number of rejection episodes prior to testing, source of renal transplant, cause of renal failure and medications as related to the prescription of cyclosporine, tacrolimus, mycophenolate mophetil, angiotensin-converting enzyme inhibitors, AT1-blockers, statins, ß-blockers and thiazide diuretics. Patients diagnosed with pre-diabetes were compared to subjects with normal test results. Fishers exact test and the Wilcoxon rank-sum test were applied to compare the two study populations, whereas multivariate logistic regression was used to seek potential risk factors as related to other covariates. Risk ratios (RRs) to develop pre-diabetes were calculated for significant variables. RESULTS: Ten patients had results indicative of post-transplant diabetes whereas data sets of three other patients were incomplete and were thus not included in the analysis. From the remaining 187 patients, 130 (69.5%) displayed normal test results whereas 57 (30.5%) had results indicative of pre-diabetes. On multivariate regression analysis, patients with pre-diabetes were significantly older {55.3 ± 12.1 versus 47.7 ± 12.6 years, P = 0.0007, RRs per 5 years increase 1.28 [95% confidence interval (95% CI) 1.11-1.47]}, had more rejection episodes [0.26 ± 0.48 versus 0.12 ± 0.37, P = 0.0024, RRs per rejection episode 3.99 (95% CI 1.63-9.77)] and showed lower diastolic blood pressure readings [77 ± 10 mmHg versus 81 ± 10 mmHg, P = 0.0362, RR per 5 mmHg decrease 1.14 (95% CI 1.04-1.49)]. CONCLUSIONS: There is a high incidence of latent pre-diabetes among renal transplant recipients. Increasing age, rejection episodes and lower diastolic blood pressure proved to be associated with pre-diabetes. In contrast to post-transplant diabetes, tacrolimus use and HbA1-c levels were not prognostic of pre-diabetes.

Regional citrate versus systemic heparin for anticoagulation in critically ill patients on continuous venovenous haemofiltration: a prospective randomized multicentre trial.

BACKGROUND: Continuous venovenous haemofiltration (CVVH) in the intensive care setting requires anticoagulation to prevent clotting of the extracorporeal circuit. Several protocols avoiding heparin and using regional citrate anticoagulation have been developed to diminish bleeding risks. However, data from randomized trials comparing citrate anticoagulation with systemic heparinization are very limited. METHODS: One hundred and seventy-four patients on mechanical ventilation, requiring renal replacement therapy for acute renal failure, were included in this prospective randomized multicentre trial comparing regional citrate with systemic heparin. The study was performed at nine different intensive care units at university or academic teaching hospitals. The participants were randomized to either CVVH using regional citrate anticoagulation or CVVH using systemic anticoagulation with unfractionated heparin. The primary outcome was to compare treatment efficacy represented by the patients' acid base status on Day 3 and on each consecutive day. Several parameters of safety and efficacy were analysed as secondary outcomes. RESULTS: Comparison of standard bicarbonate from Day 3 to Day 11 revealed no difference between both treatment modalities. Use of citrate resulted in less systemic anticoagulation, a lower risk of bleeding and a longer haemofilter patency. Episodes of hypercalcaemia, hypocalcaemia and the need for additional bicarbonate infusions occurred more often under citrate. The patients' high mortality was not influenced by the mode of anticoagulation. CONCLUSIONS: Citrate may be used as a regional anticoagulant and the only buffering agent in CVVH with adequate treatment efficacy and safety. However, neither citrate nor heparin anticoagulation should be regarded as a therapeutic standard, since there is no advantage of one of these substances with regard to patient mortality.

Are prothrombotic variants of platelet glycoprotein receptor polymorphisms involved in the pathogenesis of thrombotic microangiopathies?

Thrombotic microangiopathies are life-threatening disorders characterized by vascular microthromboses, schistocytic hemolytic anemia, and thrombocytopenia. Although recent research has partially explained the pathogenesis of these rare entities, the determinants contributing to the onset and modulating the severity of thrombotic microangiopathies are largely unknown. The present study assessed the putative role of prothrombotic platelet receptor polymorphisms in thrombotic microangiopathies that have been found to be associated with premature onset of myocardial infarction in predisposed individuals. Thirty-four consecutive patients admitted with the diagnosis of thrombotic microangiopathy and 759 healthy subjects were enrolled. Genotyping of the human platelet antigen (HPA) 2 an the Kozak sequence polymorphism of GP Ibalpha of the platelets' von Willebrand factor receptor glycoprotein (GP) Ib-V-IX, the HPA-1 and the HPA-3 polymorphism of the fibrinogen receptor GP IIb-IIIa (integrin alpha(IIb)beta( 3)) and the HPA-5 and GP Ia 807 C/T polymorphism of the collagen receptor GP Ia-IIa (integrin alpha(2)beta(1)) were determined according to standard procedures. As a result, no significant differences in the prevalence of prothrombotic variants of platelet-receptor polymorphisms between patients and healthy control subjects were observed. However, although not significant, the prothrombotic bb genotype of the HPA-1 polymorphism was more prevalent in the patients. The findings do not provide evidence that platelet receptor polymorphisms are determinants for the onset of thrombotic microangiopathies or predispose to a more severe course. Along with this observation, screening for respective platelet-receptor polymorphisms does not appear to contribute to risk stratification of affected patients.

The homozygous leu variant of the factor XIII Val34Leu polymorphism as a risk factor for the manifestation of thrombotic microangiopathies.

The 34 Leu (100T) variant of the factor XIII Val34Leu (G100T-) polymorphism slows down fibrinolysis and has been proposed as a thrombotic risk factor. In this pilot study, we enrolled 40 patients (mean age +/- SD = 38 +/- 11 years) and 728 controls to assess the role of this genetic variant for the manifestation of thrombotic microangiopathies. From the genotype prevalences, an increased manifestation risk for carriers of the TT genotype (homozygous Leu variant) of the factor XIII Val34Leu (G100T-) polymorphism was calculated (odds ratio [OR] = 2.44; 95% confidence interval [CI] = 0.8-7.6; P = .11). This association was statistically significant for patients with thrombotic thrombocytopenic purpura-hemolytic-uremic syndrome (TTP-HUS) (OR = 6.6; 95% CI = 1.7-25.9; P = .006). Our data suggest a role of the homozygous Leu variant of the factor XIII Val34Leu polymorphism in the manifestation of thrombotic microangiopathies. Decreased fibrinolysis in the presence of this genetic variant provides a plausible explanation for this association.

The TT genotype of the C677T polymorphism in the methylentetrahydrofolate reductase as a risk factor in thrombotic microangiopathies: results from a pilot study.

In this study, we assessed the potential role of the TT genotype of the gene of the methylenetetrahydrofolate reductase for the manifestation of thrombotic microangiopathies, enrolling 40 affected patients (mean age [+/- standard deviation] 35 +/- 11 years). As a result, the methylenetetrahydrofolate reductase 677TT genotype was more prevalent in patients with thrombotic microangiopathies compared with controls (adjusted odds ratio = 2.58, 95% confidence interval = 1.2-5.7, P = .018), particularly in those suffering from the hemolytic uremic syndrome. A hemolytic more severe clinical course of thrombotic microangiopathies in carriers of the methylenetetrahydrofolate reductase 677TT genotype was not observed. In summary, our findings suggest a significant influence of the methylenetetrahydrofolate reductase genotype on the manifestation of thrombotic microangiopathies. The 677 TT genotype of this polymorphism appears to be a risk factor for manifestation of these rare thrombotic disorders, possibly explained by endothelial activation and increased oxidative stress.

The G1691A mutation of the factor V gene (factor V Leiden) and the G20210A mutation of the prothrombin gene as risk factors in thrombotic microangiopathies.

Factor V Leiden (FVL) mutation and prothrombin G20210A mutation are common hereditary risk factors for venous thrombosis. In the current study, 40 patients (mean age +/- standard deviation, 35 +/- 11 years) and 764 healthy control subjects (mean age +/- standard deviation, 37 +/- 14 years) were enrolled to assess the potential role of these mutations in the manifestation of thrombotic microangiopathies. Compared with controls, neither the heterozygous FVL mutation (7.5% vs 8.5%; P = 1) nor the heterozygous prothrombin mutation (2.5% vs 2.8%; P = 1) was more prevalent in the patients. The findings do not support a significant role of FVL and prothrombin mutations as risk factors for the manifestation of thrombotic microangiopathies. Thus, screening for these mutations does not allow the identification of individuals at increased risk for these rare thrombotic disorders.

Plasma exchange in neuroimmunological disorders: part 2. Treatment of neuromuscular disorders.

Plasma exchange is a well-established therapeutic procedure commonly used in many neurological disorders of autoimmune etiology. In this second part of our review, we assess the role of plasma exchange in the treatment of neuromuscular disorders. In Guillain-Barré syndrome and other immune-mediated neuropathic disorders, randomized controlled trials have demonstrated the therapeutic efficacy of plasma exchange. Myasthenia gravis and Lambert-Eaton syndrome represent neuromuscular disorders where plasmapheresis might be of potential efficacy.

Plasma exchange in neuroimmunological disorders: Part 1: Rationale and treatment of inflammatory central nervous system disorders.

Plasma exchange is a well-established therapeutic procedure commonly used in many neurological disorders of autoimmune etiology. It is thought that the beneficial effects of plasma exchange occur through the elimination of pathognomonic inflammatory mediators, including autoantibodies, complement components, and cytokines. In various neurological disorders, randomized controlled studies have demonstrated the efficacy of plasma exchange (eg, in Guillain-Barré syndrome and other forms of immune neuropathies). Although widely used, the potential benefit of plasma exchange in the treatment of multiple sclerosis, myasthenia gravis, and Lambert-Eaton syndrome is less clear.

Citrate plasma levels in patients under regional anticoagulation in continuous venovenous hemofiltration.

BACKGROUND: Different methods of regional anticoagulation using citrate in continuous hemofiltration have been described. To date, only such surrogate parameters as pH, anion gap, total calcium concentration, or total calcium-ionized calcium ratio have been proposed to reflect increased plasma citrate levels and thus risk for side effects. However, none of these parameters has been correlated with plasma citrate levels in critically ill patients. METHODS: Sixteen patients were treated with continuous venovenous hemofiltration (CVVH) and citrate anticoagulation for a mean of 13 +/- 9 days. Citrate levels were measured every other day, and correlations were calculated with the mentioned parameters. RESULTS: Steady-state citrate levels on treatment day 3 were 16.39 +/- 15.77 mg/dL (range, 2.63 to 73.49 mg/dL [853 +/- 821 micromol/L; range, 137 to 3825 micromol/L]). The highest correlation was found between citrate plasma level and total calcium-ionized calcium ratio (R = 0.85; P < 0.001). pH (R = -0.15) and anion gap (R = 0.36) were not helpful in estimating citrate plasma levels in patients treated with citrate-CVVH. CONCLUSION: Calculating total calcium-ionized calcium ratio is a simple tool that correlates best with citrate plasma levels. We recommend close monitoring of this parameter in all patients administered high doses of citrate as part of regional anticoagulation protocols.

Vasculoprotective Effects of Dietary Cocoa Flavanols in Patients on Hemodialysis: A Double-Blind, Randomized, Placebo-Controlled Trial.

BACKGROUND AND OBJECTIVES: Hemodialysis (HD) per se entails vascular dysfunction in patients with ESRD. Endothelial dysfunction is a key step in atherosclerosis and is characterized by impaired flow-mediated dilation (FMD). Interventional studies have shown that cocoa flavanol (CF)-rich supplements improve vascular function. Aim of this study was to investigate the effect of flavanol-rich bioactive food ingredients on acute and chronic HD-induced vascular dysfunction in ESRD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted a randomized, double-blind, placebo-controlled trial from 2012 to 2013. Fifty-seven participants were enrolled, ingested CF-rich beverages (900 mg CF per study day), and were compared with those ingesting CF-free placebo. This included (1) a baseline cross-over acute study to determine safety and efficacy of CF and (2) a subsequent chronic parallel group study with a 30-day follow-up period to study effects of CF on HD-mediated vascular dysfunction entailing (3) an acute substudy during HD in flavanol-naive patients and (4) an acute on chronic study during HD. Primary and secondary outcome measures included changes in FMD and hemodynamics. RESULTS: CF ingestion was well tolerated. Acute ingestion improved FMD by 53% (3.2±0.6% to 4.8±0.9% versus placebo, 3.2±0.7% to 3.3±0.8%; P<0.001), with no effects on BP or heart rate. A 30-day ingestion of CF led to an increase in baseline FMD by 18% (3.4±0.9% to 3.9±0.8% versus placebo, 3.5±0.7% to 3.5±0.7%; P<0.001), with reduced diastolic BP (73±12 to 69±11 mmHg versus placebo, 70±11 to 73±13 mmHg; P=0.03) and increased heart rate (70±12 to 74±13 bpm versus placebo, 75±15 to 74±13 bpm; P=0.01). No effects were observed for placebo. Acute ingestion of CF during HD alleviated HD-induced vascular dysfunction (3.4±0.9% to 2.7±0.6% versus placebo, 3.5±0.7% to 2.0±0.6%; P<0.001). This effect was sustained throughout the study (acute on chronic, 3.9±0.9% to 3.0±0.7% versus placebo, 3.5±0.7% to 2.2±0.6; P=0.01). CONCLUSIONS: Dietary CF ingestion mitigates acute HD-induced and chronic endothelial dysfunction in patients with ESRD and thus, improves vascular function in this high-risk population. Larger clinical trials are warranted to test whether this translates into an improved cardiovascular prognosis in patients with ESRD.

Effects of candesartan on glomerular hemodynamics and permselectivity in patients with favorable renal allograft function.

BACKGROUND: Distinct effects of angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers on glomerular perfusion and permselectivity are important determinants of the substances nephroprotective quality. In renal allograft recipients, however, specific effects of angiotensin antagonism on glomerular function have not been evaluated so far. METHODS: Twenty patients with favorable allograft function were included into a prospective study within the first year after renal transplantation. Glomerular filtration rate, renal plasma flow, albuminuria, and the fractional clearances of neutral dextrans were determined at baseline and after 3 months of treatment with candesartan. Ten individuals after renal donation served as controls for the baseline evaluation. RESULTS: Compared with the control group, the allograft recipients had a higher renal-vascular resistance and a lower glomerular filtration rate. Albuminuria was significantly higher; however, the difference in the dextran sieving curve was not statistically significant. Apart from mild changes in biochemical parameters, the therapy with candesartan led to a rise in serum creatinine along with a nonsignificant drop in the glomerular filtration rate. There was a highly significant drop in filtration fraction and albuminuria. Glomerular permselectivity clearly improved for a range of dextran molecular diameters from 43 Angstrom up to 73 Angstrom. CONCLUSION: A therapy with candesartan has distinct effects on glomerular function in patients after renal transplantation. A drop in filtration fraction along with an improvement in glomerular permselectivity and albuminuria point to a nephroprotective quality that should lead to a systematic clinical evaluation of candesartan even in patients with favorable renal allograft function.

Filtration of Macrophage Migration Inhibitory Factor (MIF) in Patients with End Stage Renal Disease Undergoing Hemodialysis.

BACKGROUND: End stage renal disease (ESRD) patients are characterized by increased morbidity and mortality due to highest prevalence of cardiovascular disease. Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine that controls cellular signaling in human physiology, pathophysiology, and diseases. Increased MIF plasma levels promote vascular inflammation and development of atherosclerosis. We have shown that MIF is associated with vascular dysfunction in ESRD patients. Whether hemodialysis (HD) affects circulating MIF plasma levels is unknown. We here aimed to investigate whether HD influences the circulating MIF pool in ESRD patients. METHODS AND RESULTS: An observational single-center study was conducted. MIF plasma levels in ESRD patients were assessed before, during, and after a HD session (n = 29). Healthy age-matched volunteers served as controls to compare correlations of MIF plasma levels with inflammatory plasma components (n = 20). MIF removed from the circulating blood pool could be detected in the dialysate and allowed for calculation of totally removed MIF (MIF content in dialysate 219±4 µg/HD-session). MIF plasma levels were markedly decreased 2 hour after initiation of HD (MIF plasma level pre-HD 84.8±6 ng/ml to intra-HD 61.2±5 ng/ml p<0.001) and were replenished already 20 min after termination of HD to basal levels (intra-HD 61.2±5 ng/ml to post-HD 79.8±5 ng/ml, p<0.001). CONCLUSION: MIF is a dialyzable plasma component that is effectively filtrated during HD from the patient blood pool in large amounts. After removal of remarkable amounts of MIF during a single HD session, MIF plasma pool is early reconstituted after termination of HD from unknown sources.

Macrophage migration inhibitory factor is associated with vascular dysfunction in patients with end-stage renal disease.

BACKGROUND: Patients with end-stage renal disease (ESRD) show a high prevalence of cardiovascular disease with arterial stiffness, atherosclerosis and endothelial dysfunction, leading to increased morbidity and mortality. The cytokine macrophage migration inhibitory factor (MIF) exhibits proinflammatory and proatherogenic functions and has recently emerged as a major regulator of atherogenesis. Studies examining the relationship between circulating MIF levels and vascular dysfunction in this high-risk population do not exist. METHODS: In patients with ESRD (n = 39) and healthy controls (n = 16) we assessed endothelial function by flow-mediated dilation of the brachial artery and arterial stiffness (augmentation pressure, augmentation index and pulse pressure) using applanation tonometry. High-sensitive Troponin and subendocardial viability ratio were determined to assess myocardial injury. RESULTS: Patients with ESRD had impaired endothelial function and higher plasma MIF levels. MIF levels negatively correlated with endothelial function (r = -0.345, P = 0.031) and positively with arterial stiffness indices in patients with ESRD (pulse pressure r = -0.374, P = 0.019 and augmentation pressure r = -0.423, P = 0.025). In multivariate regression models besides age, gender, weight, and heart rate, MIF was an independent predictor for arterial stiffness. Impact on myocardial end-organ damage was reflected by correlation with high-sensitive Troponin I (r = 0.43, P = 0.009). CONCLUSION: Our findings show that high MIF plasma levels are associated with diminished endothelial function and arterial stiffness and are correlated with myocardial injury. Further studies are necessary to investigate whether modulation of MIF might have an impact on atherosclerotic disease in this high-risk population.

Indicators of acute and persistent renal damage in adult thrombotic microangiopathy.

BACKGROUND: Thrombotic microangiopathies (TMA) in adults such as thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) are life-threatening disorders if untreated. Clinical presentation is highly variable and prognostic factors for clinical course and outcome are not well established. METHODS: We performed a retrospective observational study of 62 patients with TMA, 22 males and 40 females aged 16 to 76 years, treated with plasma exchange at one center to identify clinical risk factors for the development of renal insufficiency. RESULTS: On admission, 39 of 62 patients (63%) had acute renal failure (ARF) with 32 patients (52%) requiring dialysis treatment. High systolic arterial pressure (SAP, p = 0.009) or mean arterial pressure (MAP, p = 0.027) on admission was associated with acute renal failure. Patients with SAP>140 mmHg on admission had a sevenfold increased risk of severe kidney disease (OR 7.464, CI 2.097-26.565). MAP>100 mmHg indicated a fourfold increased risk for acute renal failure (OR 4.261, CI 1.400-12.972). High SAP, diastolic arterial pressure (DAP), and MAP on admission were also independent risk factors for persistent renal insufficiency with the strongest correlation for high MAP. Moreover, a high C-reactive protein (CRP) level on admission correlated with renal failure in the course of the disease (p = 0.003). At discharge, renal function in 11 of 39 patients (28%) had fully recovered, 14 patients (23%) remained on dialysis, and 14 patients (23%) had non-dialysis-dependent chronic kidney disease. Seven patients (11%) died. We identified an older age as risk factor for death. CONCLUSIONS: High blood pressure as well as high CRP serum levels on admission are associated with renal insufficiency in TMA. High blood pressure on admission is also a strong predictor of sustained renal insufficiency. Thus, adult TMA patients with high blood pressure may require special attention to prevent persistent renal failure.

Monitoring oral anticoagulation may require determination of single coagulation factor activities in patients with antiphospholipid syndrome.

We describe a 32-year-old man with secondary antiphospholipid syndrome (APS) who received oral anticoagulation with phenprocoumon after deep vein thrombosis. Conventional monitoring of oral anticoagulation by INR measurement was impaired by coagulation factor inhibition in vitro due to a strong lupus anticoagulant. The case illustrates that monitoring of oral anticoagulation may require determination of single coagulation factor activities in selected patients with APS.