Pre-transplant Type 2 Diabetes Mellitus Is Associated With Higher Graft Failure and Increased 5-Year Mortality After Heart Transplantation.

Aims: Cardiac transplant recipients often suffer from type 2 diabetes mellitus (T2DM) but its influence on graft failure and post-transplant mortality remains unknown. The aim of this study was to investigate the long-term effects of pre-transplant T2DM in patients after heart transplantation (HTX). Methods: This study included a total of 376 adult patients who received HTX at Heidelberg Heart Center between 01/01/2000 and 01/10/2016. HTX recipients were stratified by diagnosis of T2DM at the time of HTX. Patients with T2DM were further subdivided by hemoglobin A1c (HbA1c ≥ 7.0%). Analysis included donor and recipient data, immunosuppressive drugs, concomitant medications, post-transplant mortality, and causes of death. Five-year post-transplant mortality was further assessed by multivariate analysis (Cox regression) and Kaplan-Meier estimator. Results: About one-third of all HTX recipients had T2DM (121 of 376 [32.2%]). Patients with T2DM showed an increased 5-year post-transplant mortality (41.3% versus 29.8%; P = 0.027) and had a higher percentage of death due to graft failure (14.9% versus 7.8%; P = 0.035). Multivariate analysis showed T2DM (HR: 1.563; 95% CI: 1.053-2.319; P = 0.027) as an independent risk factor for 5-year mortality after HTX. Kaplan-Meier analysis showed a significantly better 5-year post-transplant survival of patients with T2DM and a HbA1c < 7.0% than patients with T2DM and a HbA1c ≥ 7.0% (68.7% versus 46.3%; P = 0.008) emphasizing the clinical relevance of a well-controlled T2DM in HTX recipients. Conclusion: Pre-transplant T2DM is associated with higher graft failure and increased 5-year mortality after HTX.

Validation of two severity scores as predictors for outcome in Coronavirus Disease 2019 (COVID-19).

BACKGROUND: An established objective and standardized reporting of clinical severity and disease progression in COVID-19 is still not established. We validated and compared the usefulness of two classification systems reported earlier-a severity grading proposed by Siddiqi and a system from the National Australian COVID-19 guideline. Both had not been validated externally and were now tested for their ability to predict complications. METHODS: In this retrospective, single-centre observational study, patients hospitalized with confirmed COVID-19 across all severity stages were enrolled. The clinical severity was graded at admission and during hospitalization. Multivariate Cox regression was used to identify independent risk factors for mortality, a composite primary (mortality, incident acute respiratory distress syndrome, incident mechanical ventilation), a secondary endpoint (mortality, incident acute myocardial injury, incident venous thrombosis, pulmonary embolism or stroke) and progression of severity grades. RESULTS: Of 109 patients 17 died, 31 and 48 developed the primary and secondary endpoint, respectively. Worsening of the severity grade by at least one stage occurred in 27 and 28 patients, respectively. Siddiqi and Australian classification were identified as independent predictors for the primary endpoint (adjusted hazard ratio (aHR) 2.30, p<0.001 and aHR 2.08, p<0.001), for the secondary endpoint (aHR 2.12, p<0.001 and aHR 1.79, p<0.001) and mortality (aHR 2.30, p = 0.071 and aHR 1.98, p = 0.017). Both classification systems showed very good agreement regarding initial grading and good agreement regarding progression of severity stages. CONCLUSIONS: Standardized and objective severity grading is useful to unequivocally stratify patients presenting with COVID-19 for their individual risk of complications.

Benefits of peritoneal ultrafiltration in HFpEF and HFrEF patients.

BACKGROUND: Peritoneal ultrafiltration (pUF) in refractory heart failure (HF) reduces the incidence of decompensation episodes, which is of particular significance as each episode incrementally adds to mortality. Nevertheless, there are insufficient data about which patient cohort benefits the most. The objective of this study was to compare pUF in HFrEF and HFpEF, focusing on functional status, hospitalizations, surrogate endpoints and mortality. METHODS: This study involves 143 patients, who could be classified as either HFpEF (n = 37, 25.9%) or HFrEF (n = 106, 74.1%) and who received pUF due to refractory HF. RESULTS: Baseline eGFR was similar in HFrEF (23.1 ± 10.6 mg/dl) and HFpEF (27.8 ± 13.2 mg/dl). Significant improvements in NYHA class were found in HFpEF (3.19 ± 0.61 to 2.72 ± 0.58, P <  0.001) and HFrEF (3.45 ± 0.52 to 2.71 ± 0.72, P <  0.001). CRP decreased in HFrEF (19.4 ± 17.6 mg/l to 13.7 ± 21.4 mg/l, P = 0.018) and HFpEF (33.7 ± 52.6 mg/l to 17.1 ± 26.3 mg/l, P = 0.004). Body weight was significantly reduced in HFrEF (81.1 ± 14.6 kg to 77.2 ± 15.6 kg, P = 0.003) and HFpEF (86.9 ± 15.8 kg to 83.1 ± 15.9 kg, P = 0.005). LVEF improved only in HFrEF (25.9 ± 6.82% to 30.4 ± 12.2%, P = 0.046). BCR decreased significantly in HFrEF and HFpEF (55.7 ± 21.9 to 34.3 ± 17.9 P > 0.001 and 50.5 ± 68.9 to 37.6 ± 21.9, P = 0.006). Number of hospitalization episodes as well as number of hospitalization days decreased significantly only in HFpEF (total number 2.88 ± 1.62 to 1.25 ± 1.45, P <  0.001, days 40.4 ± 31.7 to 18.3 ± 22.5 days, P = 0.005). CONCLUSIONS: pUF offers various benefits in HFpEF and HFrEF, but there are also substantial differences. In particular, hospitalization rates were found to be significantly reduced in HFpEF patients, indicating a greater medical and economical advantage. However, LVEF was only found to be improved in HFrEF patients. While pUF can now be regarded as an option to supplement classical HF therapy, further studies are desirable to obtain specifications about pUF in HFpEF, HFmEF and HFrEF patients.

Neuroimaging of hypothalamic mechanisms related to glucose metabolism in anorexia nervosa and obesity.

BACKGROUNDGiven the heightened tolerance to self-starvation in anorexia nervosa (AN), a hypothalamic dysregulation of energy and glucose homeostasis has been hypothesized. Therefore, we investigated whether hypothalamic reactivity to glucose metabolism is impaired in AN.METHODSTwenty-four participants with AN, 28 normal-weight participants, and 24 healthy participants with obesity underwent 2 MRI sessions in a single-blind, randomized, case-controlled crossover study. We used an intragastric infusion of glucose and water to bypass the cephalic phase of food intake. The responsivity of the hypothalamus and the crosstalk of the hypothalamus with reward-related brain regions were investigated using high-resolution MRI.RESULTSNormal-weight control participants displayed the expected glucose-induced deactivation of hypothalamic activation, whereas patients with AN and participants with obesity showed blunted hypothalamic reactivity. Furthermore, patients with AN displayed blunted reactivity in the nucleus accumbens and amygdala. Compared with the normal-weight participants and control participants with obesity, the patients with AN failed to show functional connectivity between the hypothalamus and the reward-related brain regions during water infusion relative to glucose infusion. Finally, the patients with AN displayed typical baseline levels of peripheral appetite hormones during a negative energy balance.CONCLUSIONThese results indicate that blunted hypothalamic glucose reactivity might be related to the pathophysiology of AN. This study provides insights for future research, as it is an extended perspective of the traditional primary nonhomeostatic understanding of the disease.FUNDINGThis study was supported by a grant from the DFG (SI 2087/2-1).

Peritoneal dialysis as therapeutic option in heart failure patients.

AIMS: Each episode of acute decompensated heart failure (HF) incrementally adds to mortality. Peritoneal dialysis (PD) offers an alternative therapeutic option in refractory HF and reduces the incidence of decompensation episodes. The objective of this study was to determine the efficacy of PD, in terms of functional status, surrogate endpoints, rate of hospitalizations, and mortality. METHODS AND RESULTS: This study is based on the registry of the German Society of Nephrology, involving 159 patients receiving PD treatment due to refractory HF between January 2010 and December 2014. Body weight was reduced by PD (82.2 ± 14.9 to 78.4 ± 14.8 kg, P < 0.001), and significant improvements in New York Heart Association functional class (3.38 ± 0.55 to 2.85 ± 0.49, P < 0.001) were found already after 3 months. Left ventricular ejection fraction did not change (31.5 ± 13.8 to 34.0 ± 15.7%, P = 0.175). C-reactive protein improved with PD treatment (33.7 ± 52.6 to 17.1 ± 26.3 mg/L, P = 0.004). Blood urea nitrogen/creatinine ratio decreased significantly (148.7 ± 68.3 to 106.7 ± 44.8 mg/dL, P < 0.001). Hospitalization rates decreased significantly (total number 2.86 ± 1.88 to 1.90 ± 1.78, P = 0.001, and 39.2 ± 30.7 to 27.1 ± 25.2 days, P = 0.004). One year mortality was 39.6% in end-stage HF patients treated with PD. CONCLUSIONS: Peritoneal dialysis offers an additional therapeutic option in end-stage HF and is associated with improved New York Heart Association classification and reduced hospitalization. Although PD treatment was associated with various benefits, further studies are necessary to identify which patients benefit the most from PD.

Overhydration Is a Strong Predictor of Mortality in Peritoneal Dialysis Patients - Independently of Cardiac Failure.

BACKGROUND: Overhydration is a common problem in peritoneal dialysis patients and has been shown to be associated with mortality. However, it still remains unclear whether overhydration per se is predictive of mortality or whether it is mainly a reflection of underlying comorbidities. The purpose of our study was to assess overhydration in peritoneal dialysis patients using bioimpedance spectroscopy and to investigate whether overhydration is an independent predictor of mortality. METHODS: We analyzed and followed 54 peritoneal dialysis patients between June 2008 and December 2014. All patients underwent bioimpedance spectroscopy measurement once and were allocated to normohydrated and overhydrated groups. Overhydration was defined as an absolute overhydration/extracellular volume ratio > 15%. Simultaneously, clinical, echocardiographic and laboratory data were assessed. Heart failure was defined either on echocardiography, as a reduced left ventricular ejection fraction, or clinically according to the New York Heart Association functional classification. Patient survival was documented up until December 31st 2014. Factors associated with mortality were identified and a multivariable Cox regression model was used to identify independent predictors of mortality. RESULTS: Apart from higher daily peritoneal ultrafiltration rate and cumulative diuretic dose in overhydrated patients, there were no significant differences between the 2 groups, in particular with respect to gender, body mass index, comorbidity and cardiac medication. Mortality was higher in overhydrated than in euvolemic patients. In the univariate analysis, increased age, overhydration, low diastolic blood pressure, raised troponin and NTproBNP, hypoalbuminemia, heart failure but not CRP were predictive of mortality. After adjustment, only overhydration, increased age and low diastolic blood pressure remained statistically significant in the multivariate analysis. CONCLUSIONS: Overhydration remains an independent predictor of mortality even after adjustment for heart failure in peritoneal dialysis patients and should therefore be actively sought and managed in order to improve survival in this population.

When is contrast-enhanced sonography preferable over conventional ultrasound combined with Doppler imaging in renal transplantation?

Conventional ultrasound in combination with colour Doppler imaging is still the standard diagnostic procedure for patients after renal transplantation. However, while conventional ultrasound in combination with Doppler imaging can diagnose renal artery stenosis and vein thrombosis, it is not possible to display subtle microvascular tissue perfusion, which is crucial for the evaluation of acute and chronic allograft dysfunctions. In contrast, real-time contrast-enhanced sonography (CES) uses gas-filled microbubbles not only to visualize but also to quantify renal blood flow and perfusion even in the small renal arterioles and capillaries. It is an easy to perform and non-invasive imaging technique that augments diagnostic capabilities in patients after renal transplantation. Specifically in the postoperative setting, CES has been shown to be superior to conventional ultrasound in combination with Doppler imaging in uncovering even subtle microvascular disturbances in the allograft perfusion. In addition, quantitative perfusion parameters derived from CES show predictive capability regarding long-term kidney function.

Increased peritoneal damage in glyoxalase 1 knock-down mice treated with peritoneal dialysis.

BACKGROUND: Peritoneal dialysis (PD) is limited by peritoneal fibrosis and ultrafiltration failure. This is in part caused by the high concentration of glucose degradation products (GDPs) present in PD fluids (PDF) as a consequence of heat sterilization. Existing research in long-term PD has mainly dealt with the toxicity induced by GDPs and the development of therapeutic strategies to reduce the cellular burden of GDPs. Currently, there are few data regarding the potential role of detoxification systems of GDP in PD. In this study, the role of glyoxalase 1 (Glo1), the major detoxification pathway for dicarbonyl-derived GD such as methylglyoxal (MG) and glyoxal (Gx), was investigated in vivo using heterozygous knock-down mice for Glo1 (Glo1(-/+)). METHODS: Wild-type (WT) and Glo1(-/+) mice were repeatedly treated with PDF containing low and high amounts of GDP, particularly with respect to the content of dicarbonyls. After 12 weeks of treatment with PDF, peritoneal damage and function were evaluated. RESULTS: Glo1(-/+) mice treated with PDF showed increased formation of advanced glycation endproduct (AGE) when compared with WT mice, particularly the Gx-derived AGE, carboxymethyl-lysine. This was associated with increased inflammation, neovascularization, increased peritoneal fibrosis and impaired peritoneal function. CONCLUSIONS: This study suggests a pivotal and underestimated role for Glo1 as a detoxifying enzyme in GDP-associated peritoneal toxicity in PD. The indirect and direct modulation of Glo1 may therefore offer a new therapeutic option in prevention of GDP-induced peritoneal damage in PD.

Cellular effects of everolimus and sirolimus on podocytes.

Everolimus (EVL) and Sirolimus (SRL) are potent immunosuppressant agents belonging to the group of mammalian target of rapamycin (mTOR) inhibitors used to prevent transplant rejection. However, some patients develop proteinuria following a switch from a calcineurin inhibitor regimen to mTOR inhibitors. Whether different mTOR inhibitors show similar effects on podocytes is still unknown. To analyze this, human podocytes were incubated with different doses of EVL and SRL. After incubation with EVL or SRL, podocytes revealed a reduced expression of total mTOR. Phosphorylation of p70S6K and Akt was diminished, whereas pAkt expression was more reduced in the SRL group. In both groups actin cytoskeletal reorganization was increased. Synaptopodin and podocin expression was reduced as well as nephrin protein, particularly in the SRL group. NFκB activation and IL-6 levels were lower in EVL and SRL, and even lower in SRL. Apoptosis was more increased in SRL than in the EVL group. Our data suggests that mTOR inhibitors affect podocyte integrity with respect to podocyte proteins, cytoskeleton, inflammation, and apoptosis. Our study is the first to analyze both mTOR inhibitors, EVL and SRL, in parallel in podocytes. Partially, the impact of EVL and SRL on podocytes differs. Nevertheless, it still remains unclear whether these differences are of relevance regarding to proteinuria in transplant patients.

Cellular infiltrates and NFκB subunit c-Rel signaling in kidney allografts of patients with clinical operational tolerance.

BACKGROUND: Nuclear factor kappa B (NFκB) plays a potential role in tolerance by orchestrating onset and resolution of inflammation and regulatory T cell differentiation through subunit c-Rel. We characterized cellular infiltrates and expression of NFκB1, c-Rel and its upstream regulators phosphatidylinositol 3-kinase/RAC-alpha serine/threonine kinase, in allograft biopsies from patients with spontaneous clinical operational tolerance (COT). METHODS: Paraffin-fixed kidney allograft biopsies from 40 patients with COT (n=4), interstitial rejection (IR; n=12), borderline changes (BC; n=12), and long-term allograft function without rejection (NR; n=12) were used in the study. Cellular infiltrates and immunohistochemical expression of key proteins of the NFκB pathway were evaluated in the cortical tubulointerstitium and in cellular infiltrates using digital image analysis software. Results were given as mean±SEM. RESULTS: Biopsies from patients with COT exhibited a comparable amount of cellular infiltrate to IR, BC, and NR (COT, 191±81; IR, 291±62; BC, 178±45; and NR, 210±42 cells/mm) but a significantly higher proportion of forkhead box P3-positive cells (COT, 11%±1.7%; IR, 3.5%±0.70%; BC, 3.4%±0.57%; and NR, 3.7%±0.78% of infiltrating cells; P=0.02). c-Rel expression in cellular infiltrates was significantly elevated in IR, BC, and NR when analyzing the number of positive cells per mm (P=0.02) and positive cells per infiltrating cells (P=0.04). In contrast, tubular PI3K and c-Rel expression were significantly higher in IR and BC but not in NR compared with COT (P=0.03 and P=0.006, respectively). With RAC-alpha serine-threonine kinase, similar tendencies were observed (P=0.2). CONCLUSIONS: Allografts from COT patients show significant cellular infiltrates but a distinct expression of proteins involved in the NFκB pathway and a higher proportion of forkhead box P3-positive cells.

Sustained low efficiency dialysis using a single-pass batch system in acute kidney injury - a randomized interventional trial: the REnal Replacement Therapy Study in Intensive Care Unit PatiEnts.

INTRODUCTION: Acute kidney injury (AKI) is associated with a high mortality of up to 60%. The mode of renal replacement therapy (intermittent versus continuous) has no impact on patient survival. Sustained low efficiency dialysis using a single-pass batch dialysis system (SLED-BD) has recently been introduced for the treatment of dialysis-dependent AKI. To date, however, only limited evidence is available in the comparison of SLED-BD versus continuous veno-venous hemofiltration (CVVH) in intensive care unit (ICU) patients with AKI. METHODS: Prospective, randomized, interventional, clinical study at a surgical intensive care unit of a university hospital. Between 1 April 2006 and 31 January 2009, 232 AKI patients who underwent renal replacement therapy (RRT) were randomized in the study. Follow-up was assessed until 30 August 2009. Patients were either assigned to 12-h SLED-BD or to 24-h predilutional CVVH. Both therapies were performed at a blood flow of 100 to 120 ml/min. RESULTS: 115 patients were treated with SLED-BD (total number of treatments n = 817) and 117 patients with CVVH (total number of treatments n = 877).The primary outcome measure, 90-day mortality, was similar between groups (SLED: 49.6% vs. CVVH: 55.6%, P = 0.43). Hemodynamic stability did not differ between SLED-BD and CVVH, whereas patients in the SLED-BD group had significantly fewer days of mechanical ventilation (17.7 ± 19.4 vs. 20.9 ± 19.8, P = 0.047) and fewer days in the ICU (19.6 ± 20.1 vs. 23.7 ± 21.9, P = 0.04). Patients treated with SLED needed fewer blood transfusions (1,375 ± 2,573 ml vs. 1,976 ± 3,316 ml, P = 0.02) and had a substantial reduction in nursing time spent for renal replacement therapy (P < 0.001) resulting in lower costs. CONCLUSIONS: SLED-BD was associated with reduced nursing time and lower costs compared to CVVH at similar outcomes. In the light of limited health care resources, SLED-BD offers an attractive alternative for the treatment of AKI in ICU patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT00322530.

Acute effects of calcineurin inhibitors on kidney allograft microperfusion visualized by contrast-enhanced sonography.

BACKGROUND: Calcineurin inhibitors induce detrimental vascular remodeling, which may be one cause of chronic allograft failure. Real-time contrast-enhanced sonography (CES) is a relatively new technique in providing quantitative information on microvascular tissue perfusion in kidney allografts in more detail. The purpose of the study was to explore whether acute changes of kidney allograft microperfusion due to the administration of cyclosporine A (CsA) and tacrolimus (Tac) can be evidenced using real-time CES. METHODS: In an explorative single-center clinical trial, renal parenchymal tissue perfusion of 32 stable kidney allograft recipients was evaluated with CES before and 2 hr after the intake of CsA or Tac. In addition to laboratory and clinical parameters, Doppler indices and estimated glomerular filtration rate were measured. RESULTS: Although systolic and diastolic blood pressure and color Doppler indices did not significantly differ, there was a significant decrease of renal blood flow 2 hr after the intake of CsA compared with baseline (4.78±2.31 dB/s, 49%, respectively). In contrast, kidney allograft microperfusion was neither significantly reduced in patients receiving CsA paralleled by calcium channel blockers nor significantly reduced in patients receiving Tac. Furthermore, there was a significant correlation between renal blood flow obtained before drug administration and kidney function. CONCLUSIONS: CES revealed a 49% reduction of kidney allograft microperfusion 2 hr after the intake of CsA, which might be abrogated by calcium channel blockers. In comparison to CsA, Tac did not result in a significant decrease of kidney blood flow.

Human RAGE antibody protects against AGE-mediated podocyte dysfunction.

BACKGROUND: Residual renal function (RRF) contributes to better patient survival in peritoneal dialysis (PD). It is known that glucose degradation products (GDP) and advanced glycation end-products (AGE) resorbed from the peritoneal cavity do not only cause local peritoneal toxicity but also systemic damage resulting in a loss of RRF. We hypothesize that GDP and AGE affect the structure and function of podocytes and investigate whether these effects can be rescued by human RAGE antibody (hRAGEab) to prevent AGE/RAGE interaction and podocyte damage. METHODS: Differentiated human podocytes were pre-incubated with ±hRAGEab to block the AGE/RAGE interaction and incubated afterwards either with control solution (control), PD fluid (PDF) or a GDP mixture (GDP) for 48 h. We analysed podocyte damage and rescue by hRAGEab using immunofluorescence, western blot, enzyme-linked immunosorbent assay and a functional migration assay. For quantitation, a semiquantitative score was used. RESULTS: When pre-incubating podocytes with hRAGEab, damage mediated by PDF and GDP was reduced. We observed lower expression of AGE in PDF and GDP as well as decreased levels of inflammation as shown by activation of nuclear factor kappa B and interleukin-6 release. The reorganization of the podocyte actin cytoskeleton was reduced in the presence of hRAGEab as well as ameliorated synaptopodin expression could be observed, both functionally associated with normal podocyte motility. Finally, podocytes underwent less apoptosis. CONCLUSIONS: It has been investigated that GDP-containing PDF causes a loss of RRF in PD. Our findings suggest that hRAGEab confers protection against PDF- and GDP-induced podocyte dysfunction. Blocking the AGE/RAGE interaction provides specific protective effects against PDF- and GDP-induced cytoskeletal reorganization, dynamics and stabilizes podocyte survival; this might be an implication for the preservation of RRF in PD.

Recompensation of heart and kidney function after treatment with peritoneal dialysis in a case of congestive heart failure.

We report the case of a 57-year-old woman suffering from congestive heart failure. Due to refractory congestions despite optimised medical treatment, the patient was listed for heart transplantation and peritoneal dialysis was initiated. Peritoneal dialysis led to a significant weight loss, reduction of hyperhydration and extracellular water obtained by bioimpedance measurement, and a significant improvement in clinical and echocardiographic examination. Furthermore, residual kidney function increased during the long-term followup, and subsequently peritoneal dialysis was ceased. Pulmonary artery pressure and left ventricular ejection fraction remained stable and the patient did well. This case demonstrates the possibility of treating hyperhydration due to congestive heart failure with peritoneal dialysis resulting in recompensation of both heart and kidney functions.

Emerging drugs for the treatment of transplant rejection.

INTRODUCTION: Kidney allograft rejection is an important cause of early and late allograft failure. The importance of antibody-mediated rejection especially in the context of late allograft failure has only recently been acknowledged. AREAS COVERED: This review summarizes new developments in the treatment of cellular and antibody-mediated kidney allograft rejection. Drugs presented here include monoclonal antibodies and novel innovative approaches such as proteasome and complement inhibition. In addition, other options for the treatment of allograft rejection such as the administration of intravenous immune globulins or the use of plasmapheresis and immunoadsorption are discussed. EXPERT OPINION: Especially the treatment of chronic antibody-mediated rejection represents a challenge and new therapeutic options are needed.

Benfotiamine protects against peritoneal and kidney damage in peritoneal dialysis.

Residual renal function and the integrity of the peritoneal membrane contribute to morbidity and mortality among patients treated with peritoneal dialysis. Glucose and its degradation products likely contribute to the deterioration of the remnant kidney and damage to the peritoneum. Benfotiamine decreases glucose-induced tissue damage, suggesting the potential for benefit in peritoneal dialysis. Here, in a model of peritoneal dialysis in uremic rats, treatment with benfotiamine decreased peritoneal fibrosis, markers of inflammation, and neovascularization, resulting in improved characteristics of peritoneal transport. Furthermore, rats treated with benfotiamine exhibited lower expression of advanced glycation endproducts and their receptor in the peritoneum and the kidney, reduced glomerular and tubulointerstitial damage, and less albuminuria. Increased activity of transketolase in tissue and blood contributed to the protective effects of benfotiamine. In primary human peritoneal mesothelial cells, the addition of benfotiamine led to enhanced transketolase activity and decreased expression of advanced glycation endproducts and their receptor. Taken together, these data suggest that benfotiamine protects the peritoneal membrane and remnant kidney in a rat model of peritoneal dialysis and uremia.

Uremia aggravates left ventricular remodeling after myocardial infarction.

BACKGROUND: Renal failure is a well-established cardiovascular risk factor. We hypothesized that uremia negatively affects post-myocardial infarction (MI) remodeling and left ventricular (LV) function and examined the pathohistological correlations. METHODS: Subtotally nephrectomized rats (SNX) and controls with MI only (MIC) were examined 1, 4 and 8 weeks after MI. MI size, ejection fraction (EF), cardiac fibrosis, vascular density and cardiomyocyte density were studied. RESULTS: The extension of MI was 0.08 +/- 0.02 in SNX versus 0.06 +/- 0.02 in MIC rats (p < 0.031). Prior to MI, EF was comparable in SNX and MIC (74 +/- 3 vs. 72 +/- 2%, n.s.). Despite a relatively small infarct size EF in SNX decreased to 58 +/- 4% 1 week after infarction and progressively worsened to 51 +/- 4% after 8 weeks. In MIC animals EF only slightly decreased 1 week after MI (70 +/- 3%) and remained unchanged at follow-up. In SNX animals LV end-diastolic diameter continuously increased following MI throughout the study period indicating accelerated remodeling. Furthermore, accelerated myocardial fibrosis was already notable 1 week after MI in SNX animals and the volume density of capillaries and cardiomyocytes was significantly lower in SNX rats. CONCLUSION: MI in experimental uremia is associated with progressive impairment of LV function, LV dilatation and accelerated myocardial fibrosis.

Glucose degradation products result in cardiovascular toxicity in a rat model of renal failure.

BACKGROUND: It has been shown that glucose degradation products (GDP) generated during heat sterilization of peritoneal dialysis (PD) fluids impair the peritoneal membrane locally, then enter the systemic circulation and cause damage to the remnant kidney. Here we examined in subtotally nephrectomized (SNX) rats whether GDP also affect the cardiovascular system. MATERIALS AND METHODS: Standard 5/6 nephrectomy was carried out in Sprague-Dawley rats; other rats were sham operated and left untreated for 3 weeks. Through an osmotic mini-pump, SNX+GDP group received GDP intravenously for 4 weeks; the SNX and the sham-operated groups remained without GDP. The experiment was terminated for all groups 7 weeks postoperatively. We analyzed cardiovascular damage by serum analyses and immunohistochemical investigation. RESULTS: In SNX+GDP animals, expression of the advanced glycation end product (AGE) marker carboxymethyllysine and receptor of AGE (RAGE) were significantly higher in the myocardium and the aorta compared to the SNX rats. We also found significantly higher levels of apoptosis measured by caspase 3 staining in the cardiovascular system in the SNX+GDP group. Moreover, we observed a more pronounced expression of oxidative stress in the SNX+GDP rats compared to the SNX rats. In serum analyses, advanced oxidation protein products and reactive oxygen species were increased, as was immunohistochemical endothelial nitric oxide synthase. CONCLUSIONS: In addition to local toxic effects, GDP cause systemic toxicity. Here we showed that, in SNX rats, administration of GDP increased cardiovascular damage. In particular, we found increased levels of AGE, RAGE, oxidative stress, and apoptosis. Whether these findings are of clinical relevance has to be further investigated.

Contrast enhanced sonography shows superior microvascular renal allograft perfusion in patients switched from cyclosporine A to everolimus.

BACKGROUND: Real-time contrast enhanced sonography (CES) provides quantitative information on microvascular tissue perfusion in renal allografts. In contrast to calcineurin inhibitors, mammalian target of rapamycin inhibitors may have beneficial effects on renal microvascular tissue perfusion. There is no information on the microperfusion of renal allografts in patients receiving either mammalian target of rapamycin inhibitor or calcineurin inhibitor. METHODS: In a prospective randomized, clinical trial, renal parenchymal tissue perfusion of 24 stable renal allograft recipients was evaluated with CES. Eleven patients were kept on cyclosporine A (CsA); 13 were converted to everolimus (EVR). Measurements were made at the time of the switch from CsA to EVR, 8.21+/-6.36 months posttransplantation, and 21.2+/-6.57 months posttransplantation. In addition to laboratory and clinical parameters, Doppler indices and estimated glomerular filtration rate (eGFR) were measured. RESULTS.: After the switch from CsA to EVR, microvascular perfusion in the EVR-treated patients (Axbeta value at baseline 9.23+/-7.44 dB/sec, Axbeta value at time of follow-up 19.6+/-13.0 dB/sec, P=0.03) and the estimated GFR (81.2+/-20.3 and 96.9+/-22.6 mL/min, P=0.001) improved significantly. Microvascular perfusion (Axbeta 7.04+/-5.32 dB/sec and Axbeta 8.66+/-9.01 dB/sec, P=0.34) and the eGFR of the group continuing CsA treatment remained stable (78.5+/-25.9 and 73.2+/-37.3 mL/min, P=0.1). CONCLUSION: The study demonstrates that renal microperfusion visualized by CES based on microbubble contrast agent and concomitantly kidney function, improved significantly after the switch from CsA to EVR.

RAGE expression in the human peritoneal membrane.

BACKGROUND: Experimental animal models have demonstrated that the interaction of advanced glycation end-products (AGE) with their receptor RAGE is, at least in part, responsible for peritoneal damage. This study investigates the in vivo expression of RAGE in the peritoneal membrane of uraemic human patients. METHODS: Peritoneal biopsies of 89 subjects (48 uraemic and 41 healthy age-matched patients) were examined. The expression of CD3, IL-6, activated NFkappaBp65, VEGF, transforming growth factor (TGF)-beta1, smooth-muscle actin (SMA), methylglyoxal (MGO) and RAGE was analysed immunohistochemically. Additionally, in 4 of the 48 uraemic patients, peritoneal biopsies were repeated after 15 months at the time of catheter removal to analyse the above parameters and the extent of NFkappaB-binding activity determined by electrophoretic mobility shift assay (EMSA) in the long-term follow-up. RESULTS: In comparison to the healthy controls, uraemic patients showed a significant increase in fibrosis, angiogenesis, submesothelial thickness, MGO-derived protein adducts, RAGE, IL-6, VEGF, TGF-beta1, SMA and NFkappaBp65 in their peritonea. Four patients, followed up longitudinally from peritoneal dialysis (PD) catheter insertion to removal, demonstrated further significant increase in the above parameters, particularly in RAGE expression and NFkappaB activation. CONCLUSIONS: Along with a higher expression of several indicators for inflammation, angiogenesis, fibrosis and AGE accumulation, the peritoneal membrane of the uraemic patients showed an increased submesothelial thickness and a marked induction of RAGE expression and NFkappaB-binding activity, which both further increased after PD treatment. These findings in human peritoneum support the concept of the AGE-RAGE interaction being crucial in peritoneal damage due to uraemia and PD.