Kaan Gulleroglu

MICRONUCLEUS FREQUENCIES IN PERIPHERAL BLOOD LYMPHOCYTES OF CHILDREN WITH CHRONIC KIDNEY DISEASE

One of the crucial adverse effects of chronic kidney disease (CKD) and its treatment is an elevated cancer risk. There are no data on cytogenetic effects in children with CKD or children undergoing dialysis or those who have received a transplant. In this study, cytogenetic effects in children with CKD in pre-dialysis (PreD) stage, on regular haemodialysis (HD) and transplanted (Tx) compared with a control group of healthy children has been investigated using the cytokinesis-blocked micronucleus (CBMN) assay and fluorescence in situ hybridisation (FISH) combined with CBMN (CBMN-FISH) in peripheral blood lymphocytes. The results revealed a significant increase (P < 0.001) in micronucleus (MN) frequencies [mean ± SD (n)] in the PreD, HD and Tx groups versus the control group [CBMN assay; 9.19 ± 2.61 (16), 9.07 ± 4.86 (15), 6.12 ± 5.33 (17) versus 1.60 ± 0.99 (20), respectively]. Moreover, centromere negative micronucleus (C- MN) and centromere positive micronucleus (C+ MN) frequencies were significantly higher in each subgroup children (PreD, HD and Tx) than in the control group (P < 0.01) although children in Tx group had lower C- MN frequencies than PreD and lower C+ MN frequencies than PreD and HD groups (P < 0.05). Additionally, MN frequencies in mononuclear cells, nucleoplasmic bridges and nuclear buds in binucleated cells were increased in children with CKD (P < 0.001, P < 0.001, P > 0.05, respectively). The nuclear division index significantly decreased in Tx group relative to the control, PreD and HD groups (P < 0.001). Associations between cytogenetic parameters and creatinine or blood urea nitrogen were found (P < 0.05). To provide longer and better life expectancy of children with CKD and treatment modes, further research is needed to better understand and avoid these effects.

Basal damage and oxidative DNA damage in children with chronic kidney disease measured by use of the comet assay

One consequence of chronic kidney disease (CKD) is an elevated risk for cancer. There is sufficient evidence to conclude that there is an increased incidence of at least some cancers in kidney-dialysis patients. Cancer risk after kidney transplantation has mainly been attributed to immunosuppressive therapy. There are no data evaluating DNA damage in children with CKD, in dialysis patients, or following kidney transplantation. In this study, the comet assay and the enzyme-modified comet assay - with the use of endonuclease III (Endo III) and formamidopyrimidine glycosylase (FPG) enzymes - were conducted to investigate the basal damage and the oxidative DNA damage as a result of treatment in peripheral blood lymphocytes of children. Children at various stages of treatment for kidney disease, including pre-dialysis patients (PreD) (n=17), regular hemodialysis patients (HD) (n=15), and those that received kidney transplants (Tx) (n=17), comprised the study group. They were compared with age- and gender-matched healthy children (n=20) as a control group. Our results show that the %DNA intensity, a measure of basal damage, was significantly increased in children with CKD (mean ± SD) (5.22 ± 1.57) and also in each of the PreD, HD, and Tx groups [(4.92 ± 1.23), (4.91 ± 1.35), and (5.79 ± 1.94), respectively, vs the healthy children (2.74 ± 2.91) (p<0.001). Significant increases in oxidative DNA damage were only found in the FPG-sensitive sites for the PreD and Tx groups, compared with control and HD groups (p<0.05), suggesting that basal DNA damage was more evident for the PreD, HD, and Tx groups. The findings of the present study indicate a critical need for further research on genomic damage with different endpoints and also for preventive measures and improvements in treatment of pediatric patients, in order to improve their life expectancy.

Success of eculizumab in the treatment of atypical hemolytic uremic syndrome

BackgroundDisorders of complement regulation are the most important etiology of atypical hemolytic uremic syndrome (aHUS). Recent studies demonstrate that eculizumab is beneficial in long-term aHUS treatment. We present a series of children with aHUS resistant to/dependent on plasma exchange (PE) who were treated with eculizumab.MethodsThis was a retrospective study in which data were retrieved from the medical files of children who had received PE as treatment for aHUS. The data retrieved included age, sex, presenting symptoms, presence of diarrhea/vomiting, hospitalization duration, laboratory data on admission and follow-up, need for transfusion or dialysis, response to PE, response to eculizumab and outcome.ResultsOf the 15 children diagnosed with aHUS in 2011 and 2012 in our departments, ten were resistant to, or dependent on, plasma therapy and treated with eculizumab; these children were enrolled in the study. Three patients had relapses, and seven had a new diagnosis. Nine children had oliguria or anuria, and eight required dialysis. Hypertension was observed in six patients. Neurologic involvement developed in six patients, with the symptoms including seizures, loss of balance, vision loss and severe confusion. Five and five patients were resistant to and dependent on plasma therapy, respectively. Following the start of eculizumab treatment, all patients achieved full recovery of renal function and hematologic parameters.ConclusionsIn our ten pediatric patients with aHUS who did not respond to PE, eculizumab was a lifesaving therapy and improved their quality of life. Early eculizumab use was a rescue therapy for renal function. Our results show that eculizumab is an effective treatment for aHUS. However, more studies are needed on the long-term efficacy and safety of eculizumab in children with aHUS and to determine the optimal duration of treatment.

Abnormal circadian blood pressure regulation in liver transplanted children.

Bayrakci US, Baskin E, Ozcay F, Gulleroglu K, Ozbay F, Sevmis S, Karakayali H, Haberal M. Abnormal circadian blood pressure regulation in liver transplanted children. 
Pediatr Transplantation 2012: 16: 160–164.

Peritoneal dialysis requirements following open-heart surgery in children with congenital heart disease

This article reviews our experience with 111 pediatric patients following open-heart surgery over 1-year period. Peritoneal dialysis was required in 34 of 111 children (30.6%). We randomly selected 33 patients who did not require peritoneal dialysis as control group. The indications of dialysis were oligoanuria and/or elevated serum creatinine level (19/34, 55.8%), fluid overload and/or hemodynamic alterations (10/34, 29.5%), and hyperkalemia and/or acidosis (5/34, 14.7%). Among the 34 dialyzed patients, 19 (55.6%) had acute renal failure (ARF). Cyanotic congenital heart disease was significantly higher in patients who required dialysis than the patients who did not require dialysis (67.6% and 22.6%, respectively, p < 0.001). Cardiopulmonary bypass time was significantly longer in patients with ARF than those without ARF (p < 0.05). Overall mortality rate was significantly higher in patients who required dialysis than control group (42.1% and 18.2%, respectively, p < 0.05). However, in the dialyzed group the mortality for patients who developed ARF was 68.4% and 6.7% for those who did not develop ARF [odds ratio (OR): 30.3, confidence interval (CI) 95%: 3.2–28.7, p < 0.001]. In conclusion in children high mortality rate following open-heart surgery was associated with ARF. Patients with cyanotic congenital heart disease and prolonged cardiopulmonary bypass time are at risk for ARF. The presence of these factors can be predicted in the early institution of peritoneal dialysis after cardiac surgery.

Early Proteinuria After Renal Transplantation and Allograft Outcomes

BACKGROUND Proteinuria is among the major and nonspecific sign of the renal disease. It is well known that late-onset proteinuria after renal transplantation has been associated with poor allograft outcomes and with mortality. Knowledge about the impact of early proteinuria on the various outcomes is limited. We have evaluated the utility of measuring early proteinuria in the management of pediatric renal transplant recipients. METHODS We analyzed the effect of proteinuria at 3 months of posttransplantation on allograft rejection, graft loss, and estimated glomerular filtration rate (GFR) at 3 years. Proteinuria was assessed using 24-hour urine protein excretion. Renal biopsy was performed when elevated creatinine levels were elevated during routine follow-up and an acute rejection episode was proven with biopsy. RESULTS Sixty-seven pediatric renal transplant recipients were included to the study. Mean follow-up time after transplantation was 48.8 ± 12.1 months. Thirty-nine recipients (58%) have proteinuria >500 mg/d. The relationship could not be shown between proteinuria at posttransplant month 3 and other outcomes parameters, such as graft loss and lower estimated GFR. A significant positive correlation between acute rejection and the proteinuria at posttransplant month 3 was shown. CONCLUSION We demonstrated that early proteinuria is a common finding in children after transplantation. Posttransplant early proteinuria cannot be used as a long-term prognostic marker of poor renal outcome. However, early proteinuria is associated with an high risk of acute rejection episodes. This would permit an opportunity for early intervention.

Neurocognitive Functions in Pediatric Renal Transplant Patients

Neurocognitive dysfunction is one of the major complications of chronic renal failure (CRF). Uremic state during CRF encompasses a wide spectrum of neurobehavioral and neurological disturbances. Recent studies showed that the pathophysiology of neurocognitive dysfunction in CRF is related to plasma levels of uremic solutes. Successful renal transplantation improves renal, metabolic, and endocrine functions and the quality of life. The aim of our study was to determine the state of neurocognitive function in pediatric renal transplant recipients. We prospectively performed a neurological examination and neuropsychological test battery (Bender-Gestalt Test, Cancellation Test, and Visual and Auditory Number Assay Test) in 20 pediatric renal transplant recipients between 6 and 16 years of age. Twenty healthy children and 20 children with CRF were included in the study as the control groups. Mean age of the renal transplant recipients was 13.50 ± 3.40 years old. Mean evaluation time after transplantation was 2.0 ± 0.5 years. Bender-Gestalt Test result was abnormal in 40% of patients. The results of the Cancellation Test and the Visual and Auditory Number Assay Test showed significant decline in pediatric renal transplant patients when compared with the control. We found that neurocognitive dysfunction was frequent in pediatric renal transplantation patients. Awareness of this potential problem may be helpful for early recognition and treatment. Our findings suggest that periodic neurocognitive assessments may be indicated in transplant recipients.

The predictive value of resistive index obtained by Doppler ultrasonography early after renal transplantation on long‐term allograft function

DUSG is a useful diagnostic tool for the follow‐up of renal transplant recipients. The measurement of intrarenal arterial RI by DUSG has been proven to predict short‐term AF. The aim of the study was to evaluate the predictive value of DUSG performed during the early after RTx on long‐term AF. Seventy patients were enrolled into study. DUSG was performed at third and seventh days after RTx. Patients were divided into two groups according to rate of recovery of graft function as patients with normal graft function and abnormal graft function. Although the RI values were correlated with the AF early after transplantation, they were not correlated with long‐term AF. However, the rate of recovery of graft function at early period after RTx was correlated with creatinine level at first year and with glomerular filtration rate at first year and last visit. Although the RI has no predictive value for long‐term AF, the rate of recovery of graft function at early post‐transplantation period has predictive value for long‐term AF; patients with higher RI values early after RTx should be followed carefully for the development of chronic allograft injury.

Abnormal circadian blood pressure regulation in children with nocturnal enuresis

Abstract Introduction: To investigate autonomic nervous system function in enuretic children by performing ambulatory blood pressure monitor (ABPM) for 24 h. Methods: Twenty-eight children ranging in age from 6 to 15 years with primary nocturnal enuresis and 27 age-matched healthy controls were enrolled and they get 24 h ABPM. Hypertension was defined as standard deviation score (SDS) > 1.64 (i.e., >95th percentile) adjusted for gender and height. Urinalysis, urine electrolyte levels, urinary culture, and urinary system ultrasound were carried out in all children. They have also requested to have a diary about daily fluid intake and urine volume. Results: Although the mean 24-h and daytime diastolic blood pressure (BP) did not differ between the groups, systolic BP (SBP) was significantly higher in enuretic children (p < 0.05). The mean night-time SBP, DBP values, SDS and BP loads were found to be significantly higher than those in the controls (p < 0.01). A lack of nocturnal decrease was more prevalent in the enuretic children compared with the control subjects, the difference was statistically significant for DBP but not for SBP. Patients with elevated night-time BP load was found to have higher frequency of urinary incontinence per week as well as per night when compared with enuretic children with normal night-time BP load (r = 0.72, r = 0.69, p < 0.01, respectively). Conclusion: Subtle abnormalities of circadian BP regulation in enuretic children indicated by a selective elevation of nocturnal SBP, DBP, and MAP, and attenuated nocturnal dipping may reflect sympathetic hyper activation and its possible role in pathogenesis of enuresis.

Rituximab Therapy and Infection Risk in Pediatric Renal Transplant Patients.

OBJECTIVES Rituximab is a monoclonal antibody directed against the CD20 molecule on pre-B and mature B cells and is used in transplant recipients for the prevention and treatment of alloantibody-mediated rejection or for the treatment of disease recurrence after transplant. In most patients, rituximab has been safe and well-tolerated, but the long-term adverse effects of rituximab are currently unknown. MATERIALS AND METHODS We retrospectively evaluated 78 pediatric renal transplant recipients for the occurrence of infectious disease. Patients who received rituximab therapy were divided into 2 groups: those who developed an infection and those who did not. The 2 groups were compared for serious infections, hospitalization, graft loss, and death rates. RESULTS Eighteen transplant patients received rituximab therapy for various causes. The number of rituximab courses given varied according to the cause and ranged from 1 to 8 courses. The dose at each course was 375 mg/m(2). Median age of all recipients was 16.00 years (min-max:, 5.00-22.00 y), and median follow-up time was 2.00 years (min-max:, 1.00-3.00 y). Serious infections (bacterial sepsis, tuberculosis, Cytomegalovirus infection, varicella-zoster virus infection, Polyomavirus-associated nephropathy, and acute pyelonephritis) were observed in 8 patients who received rituximab therapy. We observed that patients with antibody-mediated rejection had significantly increased infection rate. Patients who had used rituximab combined with antithymocyte globulin and higher rituximab course number and higher pretreatment CD19 and CD20 levels had higher risk of infection (P < .05). CONCLUSIONS The combined use of rituximab with additional treatments such as antithymocyte globulin, intravenous immunoglobulin, and repeated plasma exchange may be associated with high risk of infectious disease. Especially for those patients who required intensive and repetitive treatment, such as antibody-mediated rejection, rituximab treatment should be used with caution. Infection risk should be closely monitored, although mainly in patients who receive T-cell-depleting agents.