Effects of Rituximab on Atherosclerotic Biomarkers in Kidney Transplant Recipients.

INTRODUCTION: Cardiovascular disease is the leading cause of mortality in kidney transplant recipients. Rituximab is widely used in kidney transplantation for a variety of situations, and rituximab may inhibit some cytokines and antibodies that may play an active role in the atherosclerotic process. The aim of the study was to evaluate the efficacy of rituximab on atherosclerosis biomarkers in kidney transplant recipients. METHODS: All patients, 18 years of age and older, who underwent kidney transplantation and received at least 1 dose of 375 mg/m2 rituximab were considered for participation in this study. The primary study endpoint was the development of cardiovascular diseases after rituximab therapy. The secondary endpoint was the onset of cytomegalovirus (CMV) disease or biopsy-confirmed BK virus nephropathy. In addition, comparison of atherosclerosis biomarkers was performed between study and control groups. RESULTS: There were no cardiovascular events observed during follow up. Only 8 patients in the study group suffered from CMV disease during follow up. Serum interleukin 10 levels were significantly higher in the rituximab group compared with the control group, although anti-oxidized low-density lipoprotein levels were lower in the rituximab group compared with the control group, though this did not achieve statistical significance. DISCUSSION: Rituximab treatment may increase the risk of CMV reactivation and decrease lymphocyte counts and interleukin 10 levels; however, significant decreases in all atherosclerotic-related biomarkers have not been shown in our study.

Prevalence of Human Herpesvirus-8 and BK Polyoma Virus Infections in End-stage Renal Disease and the Influence of Renal Transplantation.

Viral infections lead to significant morbidity and mortality in kidney transplant recipients. We evaluated 49 kidney transplant recipients for human herpesvirus 8 (HHV-8) and BK polyomavirus infections in conjunction with data obtained from 43 donors. The seroprevalence of HHV-8 was 6.9% in donors and 12.2% in recipients. HHV-8 DNA was detected below the limit of quantification (<5000 copies/mL) in a recipient with HHV-8 seropositivity at the pretransplant period and was undetectable at month 3 after transplantation. Transient viruria with BK polyomavirus was recorded in 10.2% of recipients without viremia. Multiple factors contribute to viral reactivation, particularly immunosuppressive treatment. Reduction in maintenance immunosuppression seems beneficial in terms of viral reactivation. At our center, routine use of valganciclovir for antiviral prophylaxis may be effective for the prevention of HHV-8 reactivation.

Evaluation of TH17 and TH1 Immune Response Profile in Patients After Renal Transplant.

BACKGROUND: Renal transplantation (RT) is the best treatment option for patients with end-stage renal disease (ESRD) because it improves both quality of life and survival. However, allograft rejection remains the most important barrier to successful transplantation. Underlying immunologic mechanisms should be understood to develop appropriate treatment strategies. METHODS: In this prospective study, we followed renal transplant recipients for 6 months. The study population comprised 50 recipients of renal transplants, and these were divided into 2 groups: 44 patients with stable graft function (SGF) and 6 patients with rejection (RX). Peripheral blood samples were drawn from patients on the pre-RT day, at post-RT day 7, month 1, and month 6, and on the day of rejection for analysis of the percentages of cytokines interleukin (IL) 17 and interferon (IFN) γ with the use of flow cytometry and enzyme-linked immunosorbent assay. RESULTS: The percentages of intracellular IFN-γ were not significant in the group with RX compared with SGF. Levels of intracellular IL-17 obtained at the 6th month after RT were significantly higher in the RX group than in the SGF group. Plasma levels of pre-RT IL-17 were also higher in the RX group; therefore, it may be a predictive biomarker of acute rejection of renal transplants. CONCLUSIONS: The present study provides information about pre-RT and post-RT cytokine profiles of Turkish patients with ESRD. We consider cytokine analysis to be a valuable biomarker panel in the prevention of rejection and in assisting with new treatment strategies for patients undergoing renal transplant.

Eculizumab for Treatment of Refractory Antibody-Mediated Rejection in Kidney Transplant Patients: A Single-Center Experience.

Antibody-mediated rejection (AMR) is responsible for up to 20%-30% of acute rejection episodes after kidney transplantation. In several cases, conventional therapies including plasmapheresis, intravenous immunoglobulin, and anti-CD20 therapy can resolve AMR successfully. But in some cases the load of immunoglobulins that can activate complement cascade may submerge the routine desensitization therapy and result in the formation of membrane attack complexes. Eculizumab, a monoclonal antibody against C5, was reported to be an option in cases with severe AMR that are resistant to conventional therapy. Here, we present 8 cases that were resistant to conventional therapy and in which eculizumab was given as a salvage treatment. Given the bad prognosis for renal transplants displaying acute injury progressing rapidly to cortical necrosis on the biopsy, the prompt use of eculizumab could have the advantage of immediate effects by stopping cellular injury. This can provide a therapeutic window to allow conventional treatment modalities to be effective and prevent early graft loss.

Evaluation of oxidative stress using exhaled breath 8-isoprostane levels on chronic kidney disease.

BACKGROUND: There have been limited numbers of studies on patients with chronic kidney disease (CKD) to determine oxidative stress in exhaled breath condensate (EBC). Those two studies have been carried out on hemodialysis patients, and hydrogen peroxide and nitric oxide have been studied in order to show oxidative stress on EBC. AIMS: We investigated oxidative stress in EBC evaluating 8-isoprostane levels on different stages of CKD. MATERIALS AND METHODS: A total of 81 patients with 2-4 CKD stages have been evaluated prospectively. The patients have been categorized into three groups according to their CKD stages. For biochemical analysis, blood and breathing air samples were taken. 8-isoprostane has been measured using immunoassay method as the indicator of oxidative stress in EBC. RESULTS: 8-isoprostane values were 8.19 ± 4.56, 13.89 ± 8.70, and 14.20 ± 10.68 pg/min group 1, 2, and 3, respectively; and the EBC 8-isoprostane levels increased significantly as CKD stages advanced (P0 = 0.018). There was a statistically significant reverse correlation between 8-isoprostane and glomerular filtration rate (GFR; r = -0.275; P = 0.014), but not between 8-isoprostane and C-reactive protein (r = -0.183; P = 0.177). CONCLUSIONS: We determined the level of 8-isoprostane in EBC of patients with different stages of CKD and showed that the level of 8-isoprostane significantly increased through the progress of CKD. We consider that our study is important because there have been limited number of studies that evaluate oxidative stress in CKD using EBC which is a noninvasive method.

Eculizumab for salvage treatment of refractory antibody-mediated rejection in kidney transplant patients: case reports.

Antibody-mediated rejection (AMR) in a group of preoperatively desensitized patients may follow a dreadful course and result in loss of the transplanted kidney. In several cases, conventional therapies including plasmapheresis, intravenous immunoglobulin, and anti-CD 20 therapy can resolve AMR successfully. But in some cases the load of immunoglobulins that can activate complement cascade may submerge the routine desensitization therapy and result in the formation of membrane attack complexes. Eculizumab, monoclonal antibody against C5, was reported to be an option in cases with severe AMR that are resistant to conventional therapy. Here, we present two cases of acute-onset AMR in preoperatively desensitized patients. Eculizumab was used as a salvage agent in addition to conventional therapy. Given the bad prognosis for renal transplants displaying acute injury progressing rapidly to cortical necrosis on the biopsy, the prompt use of eculizumab could have the advantage of immediate effects by stopping cellular injury. This can provide a therapeutic window to allow conventional treatment modalities to be effective and prevent early graft loss.

Comparison of nutritional status in hemodialysis patients with and without failed renal allografts.

BACKGROUND: The survival of patients returning to hemodialysis (HD) following kidney transplant failure is unfavorable. However, the factors responsible for this poor outcome are largely unknown; chronic inflammation due to failed allograft and malnutrition may contribute to morbidity and mortality. We aimed to compare the nutritional status and its relation with inflammation in patients on HD with and without previous kidney transplantation. METHODS: Forty-three patients with failed renal allografts (27 males; mean age 36±9 yr) and 40 never transplanted HD patients (24 males; mean age 39±9 yr) were included in the study. Body weight, triceps (TSF), biceps (BSF), subscapular (SSSF), and suprailiac skinfold thicknesses (SISF); mid-arm, mid-arm muscle, hip and waist circumferences; as well as body mass indices (BMIs) were determined as anthropometric parameters. Moreover, biochemical markers of nutritional status, including serum cholesterol and albumin as well as high-sensitive C-reactive protein (hs-CRP), as a marker of inflammation, were measured. Associations among these variables were analyzed. RESULTS: There were no significant differences considering age, gender or duration of renal replacement therapy between the two groups. The TSF (p<0.0001), BSF (p=0.005), SSSF (p=0.001), SISF (p<0.0001) skinfold thicknesses; mid-arm (p=0.003) and mid-arm muscle circumferences (p=0.037) and BMIs (p=0.001) of the patients with failed renal allografts were significantly lower than those of the never transplanted HD patients. Waist circumference was significantly lower as well (p=0.028). Patients with failed transplants were characterized by lower serum albumin (p<0.0001) and higher hs-CRP levels (p=0.001) as compared with never transplanted HD patients. CONCLUSIONS: This study confirms the concept that retained failed allografts may induce chronic inflammation in chronic HD patients which may result in a worse nutritional status.

Endothelial dysfunction in peritoneal dialysis patients with and without failed renal transplants.

BACKGROUND: Endothelial dysfunction (ED) is a common, early abnormality that predisposes patients to develop atherosclerosis and cardiovascular events; inflammation is associated with atherosclerosis and malnutrition. Patients with failed transplants are usually complicated by inflammation; however, ED in this group of patients has not been well defined. In this cross-sectional study, we sought to investigate ED among naïve peritoneal dialysis (nPD) patients who were never transplanted as well as patients with failed renal transplants who were re-starting peritoneal dialysis (fTxPD). METHODS: Twenty-five nPD patients (15 female/10 males; mean age, 44 +/- 11 years), and 12 fTxPD patients (4 males; mean age, 37 +/- 10 years) were included in the study. Coronary flow reserve (CFR) measurements were used to evaluate ED. Serum creatinine, calcium, phosphorus, total cholesterol, albumin, hemoglobin, and intact parathyroid hormone (iPTH) were measured. Also, highly sensitive C-reactive protein (hs-CRP) levels and weekly Kt/V were determined as possible confounding factors. Results were compared between the 2 groups. RESULTS: There were no significant differences regarding age, gender, mean systolic and diastolic blood pressures, or smoking status. Mean duration on PD, peritoneal transport characteristics, PD modality and doses, frequency of peritonitis episodes, as well as serum creatinine, calcium, phosphorus, total cholesterol, albumin, hemoglobin and iPTH levels were similar between the 2 groups. Weekly Kt/V of both groups were similar as well. However, hs-CRP levels were significantly higher (34 +/- 52 vs 6.7 +/- 7.5 mg/L; P = .017) and CFR significantly lower among patients with fTxPD compared with nPD patients (1.52 +/- 0.20 vs 1.91 +/- 0.53; P = .022). CONCLUSION: ED was more prominent among patients with failed transplants than nPD cases, suggesting that the failed allograft may be responsible for this abnormality.

Association between chronic hepatitis C infection and coronary flow reserve in dialysis patients with failed renal allografts.

BACKGROUND: Hepatitis C infection occurs frequently among patients with end-stage renal disease and increases the risk of atherosclerotic cardiovascular diseases. Endothelial dysfunction (ED) is an early event in the pathogenesis of atherosclerosis. It has been reported among patients treated with hemodialysis (HD), peritoneal dialysis (PD), or renal transplantation. The aim of the present study was to evaluate effects of chronic hepatitis C infection on ED in patients with failed renal transplants. METHODS: Twenty-six nondiabetic, anti-hepatitis C virus (HCV)-positive (15 females, mean age: 38 +/- 8 years) and 26 anti-HCV-negative patients (15 females, mean age: 36 +/- 5 years), all of whom had returned to PD or HD after renal transplant failure were studied to assess coronary flow reserve (CFR) by transthoracic Doppler echocardiography. Serum high-sensitivity C-reactive protein (hs-CRP) levels were measured as markers of chronic inflammation. CFR recordings and intima-media thickness measurements were performed using the Vivid 7 echocardiography device. RESULTS: Demographic and clinical characteristics of patients were similar between the two groups. Serum hs-CRP levels were significantly higher among HCV-positive patients versus HCV-negative counterparts. HCV-positive patients showed lower CFR measurement than HCV-negative ones. Also, a negative correlation was observed between serum hs-CRP levels and CFR values. CONCLUSION: CFR values are worse among anti-HCV-positive patients with failed renal transplants compared with anti-HCV-negative subjects. Graft dysfunction per se may aggravate a proinflammatory states thereby inducing ED. Furthermore, the presence of HCV is a greater trigger of ED among patients with renal failed grafts.

Effects of dopexamine on rat cardiorenal functions during lipopolysaccharide-induced experimental sepsis.

We aimed to test the protective effect of dopexamine on renal function and systemic haemodynamics in rats with induced sepsis. Female Sprague-Dawley rats were randomized into three equal groups: group 1 (control, received 3% creatinine throughout the experiment); group 2 (sepsis, received 3% creatinine and Escherichia coli lipopolysaccharide [LPS] endotoxin [8 mg/kg per h]); and group 3 (sepsis plus dopexamine, received 3% creatinine, E. coli LPS and dopexamine [1 microgram/kg per min]). Time-adjusted heart rate, systolic, diastolic and mean arterial pressures, urine volume and glomerular filtration rate (from creatinine clearance) were recorded. After bacterial infusion heart rate increased and mean arterial pressure decreased; the fall in mean arterial pressure was less pronounced with dopexamine (group 3) than without (group 2). Dopexamine also induced significant and moderate increases in urine volume and heart rate, respectively. We concluded that dopexamine has some positive inotropic-chronotropic effects and induces favourable responses in renal function.

Effects of clonidine pre-treatment on bupivacaine and ropivacaine cardiotoxicity in rats.

BACKGROUND AND OBJECTIVE: Clonidine has cardiac and systemic effects that can modify the potentially lethal cardiovascular effects of local anaesthetics. We evaluated the effects of clonidine pre-treatment on cardiotoxicity induced by an infusion of bupivacaine or ropivacaine and the success rate of resuscitation in anaesthetized rats. METHODS: Thirty-two Sprague-Dawley rats (250-300 g) were anaesthetized with thiopental and ketamine. Lung ventilation was maintained mechanically, and the electrocardiograph and invasive blood pressure were recorded continuously. Two separate groups of rats were treated with intravenous clonidine 5 microg kg(-1) (n = 16) or saline (n = 16) in a randomized fashion. Fifteen minutes later, each group was randomly subdivided into two equal groups and an infusion of bupivacaine or ropivacaine, 3 mg kg(-1) min(-1), was given until cardiac arrest (asystole) occurred. The times when the cardiotoxic events (25%, 50% and 75% reduction of arterial pressure and heart rate, first dysrhythmia and asystole, respectively), induced by the local anaesthetic, occurred and the resuscitation outcome scores were recorded. RESULTS: Clonidine reduced heart rate and arterial pressure (P < 0.01). Clonidine did not alter cardiotoxicity or the success rate of resuscitation in bupivacaine-treated rats. In the ropivacaine group, clonidine increased the 25%, 50% and 75% reduction times of arterial pressure and the 50% and 75% reduction times of heart rate, times to first dysrhythmia and asystole (P < 0.05). Clonidine also increased the success rate of resuscitation in ropivacaine-treated rats (P < 0.05). CONCLUSIONS: Although pre-treatment with clonidine protects the effects of ropivacaine cardiotoxicity and increases the success rate of resuscitation, it does not affect bupivacaine toxicity.

The role of meatal disinfection in preventing catheter-related bacteriuria in an intensive care unit: a pilot study in Turkey.

The purpose of this study was to investigate the efficacy of antiseptics meatal care in preventing catheter-related urinary tract infections (UTIs) in patients with an indwelling urinary catheter in the intensive care unit of Osmangazi University Medical School. One hundred patients were divided into four groups (25 per group) and treated with once or twice daily application of chlorhexidine gluconate or povidone-iodine. A control group was also studied (N=30). Urine samples were taken weekly and cultures were evaluated quantitatively. Meatal swabs were obtained on the first, fifth, and 10th day and determinated semiquantitatively. UTI was defined as bacteriuria with 10(5)cfu/L. Cultures showing no growth or mixed growths were stated as negative for UTI. UTI developed in 16 patients on days two, three, four, five and seven (including control group). Dominant micro-organisms in the meatal area were found to be Candida species. In nine cases the causative agents of UTI were Candida species. It was therefore decided that the use of antiseptics to clean the periurethral area provides no benefit in decreasing the rate of bacteriuria.

The effect of intrathecal medetomidine on small bowel transit in the rat.

BACKGROUND AND OBJECTIVE: Gastrointestinal motility is influenced by abdominal trauma, laparotomy and particularly by intestinal ischaemia. The reflex inhibition of gastrointestinal motility is mediated mainly by the sympathetic nervous system. There are reports on the effects of systemically applied alpha2-adrenoceptor agonists on gastric emptying and recovery of bowel motility, but the effect of spinally applied alpha2-adrenoceptor agonists on intestinal motility has not been studied. The aim of this study was to investigate the effects of intrathecal medetomidine on gastrointestinal transit in rats after transient intestinal ischaemia. METHODS: Forty rats were randomly assigned to four groups of 10 each. Intrathecal catheter insertion and laparotomy were performed on each rat. Saline (10 microL) was injected intrathecally in Groups A and B. Medetomidine (10 microg in 10 microL) was injected intrathecally in Groups C and D. Intestinal ischaemia was induced in Groups B and D. Gastrointestinal transit was determined by measuring the length that a standardized marker meal of activated charcoal had travelled. Intrathecal medetomidine was compared to intrathecal saline in their effect on intestinal motility after 30 min period of bowel ischaemia. RESULTS: Laparotomy and intestinal ischaemia slowed gastrointestinal transit. Intrathecal medetomidine accelerated transit in both ischaemia and non-ischaemia groups. CONCLUSION: Intrathecal medetomidine markedly accelerated small intestinal transit and may also hasten the recovery from post-ischaemic paralytic ileus.

Sexuality in women with obsessive compulsive disorder.

This study assessed the effect of obsessive compulsive disorder (OCD) on sexual function. Twenty-three outpatients who met Diagnostic and Statistical Manual of Mental Disorders (DSM-IV; American Psychiatric Association, 1994) diagnostic criteria for OCD were obtained from consecutive cases recruited to Osmangazi University Department of Psychiatry and were compared to a group of 26 generalized anxiety disorder (GAD) female outpatients. Psychiatric, psychological, and sexual information was obtained with the Maudlsey Obsessional-Compulsive Inventory (Hodgson & Rachman, 1977), the State-Trait Anxiety Inventory (Spielberger, Gorsuch, & Lushere, 1970), and the Golombok Rust Inventory of Sexual Satisfaction (Rust & Golombok, 1986). We found that the women with OCD were more sexually nonsensual, avoidant, and anorgasmic than the women with GAD. These data suggest that OCD may be a risk factor for sexual problems in women.

Clonidine pretreatment inhibits stress-induced gastric ulcer in rats.

UNLABELLED: We studied the effects of clonidine (0.5 mg/kg) on hormonal stress response and antioxidant enzymes cold restraint-induced gastric lesions in rats. Rats in the study group were given 0.5 mg/kg intraperitoneal clonidine (n = 12), whereas the control group received 0.5 mL/kg intraperitoneal isotonic sodium chloride solution (n = 9). Animals were then subjected to immobilization at 4 degrees C in restraining devices for 4 h after a starvation period of 24 h. Gastric lesion index, gastric tissue malondialdehyde activity, and plasma cortisol concentrations were assayed. Histopathologic examination demonstrated a stress ulcer index of 3.17+/-0.92 mm in the clonidine group and 14.0+/-3.22 mm in the control group (P<0.05). The tissue malondialdehyde concentrations were slightly higher in the control group than in the clonidine group, but the differences were not statistically significant (P>0.05). Plasma cortisol levels were lower in the clonidine group (P<0.05). We concluded that clonidine attenuated the tissue damage and stress response in stress-induced gastric ulceration. IMPLICATIONS: Stressful circumstances can cause stomach ulcers, which can bleed, exposing patients to potentially life-threatening complications. In the present animal study, we showed that clonidine, a routinely available medication, may be useful in preventing stress-induced stomach ulcers.