Kibriya Fidan

Unresponsiveness to Colchicine Therapy in Patients with Familial Mediterranean Fever Homozygous for the M694V Mutation

Objective. More than 50 disease-associated mutations of the Mediterranean fever gene (MEFV) have been identified in familial Mediterranean fever (FMF), some of which were shown to have different clinical, diagnostic, prognostic, and therapeutic implications. The aim of our study was to define the frequency of mutation type, genotype-phenotype correlation, and response to colchicine treatment in patients with FMF. Methods. This study included 222 pediatric FMF patients. All patients were investigated for 6 MEFV mutations. Then patients were divided into 3 groups according to the presence of M694V mutation on both of the alleles (homozygotes), on only 1 allele (heterozygotes), and on none of the alleles, and compared according to their phenotypic characteristics and response to treatment. M694V/M694V was denoted Group A, M694V/Other Group B, and Other/Other, Group C. Results. Complete colchicine response was significantly lower while the rate of unresponsiveness was significantly higher in Group A compared to Groups B and C (p = 0.031, p < 0.001 and p = 0.005, p = 0.029, respectively). No differences except proteinuria were found between the phenotypic features of 3 groups. Group C had the lowest rate of proteinuria development (p = 0.024). All the amyloidosis patients were in Group A. Conclusion. Our results indicate that the M694V/M694V mutation is associated with lower response to colchicine treatment. Therefore, patients homozygous for M694V/M694V may be carrying an increased risk for development of amyloidosis.

High serum adiponectin levels during steroid-responsive nephrotic syndrome relapse.

Adiponectin (ADPN), exclusively expressed and secreted from adipocytes, is a recently discovered protein hormone with anti-atherogenic and anti-inflammatory properties in contrast to other well-known adipocytokines. It has independent negative associations with obesity and hyperinsulinemia/insulin resistance. Apart from chronic renal failure, nephrotic syndrome was suggested as the only renal disease condition associated with raised plasma ADPN levels in adults. We aimed to evaluate the effect of nephrotic state on serum adiponectin (ADPN) levels in pediatric patients with steroid-responsive nephrotic syndrome (SRNS) by comparing the levels in relapse and remission as well as in control subjects and documenting possible relationships between ADPN and proteinuria as well as serum protein/lipid parameters. 34 patients with SRNS and 22 healthy age, sex and BMI-matched control subjects were enrolled into the study. 15 of the 34 SRNS patients had active diseases, and these were known as the SRNS-relapse group (ten relapsed and five newly-diagnosed patients), while the remaining 19 were in complete remission (the SRNS-remission group). Serum ADPN levels, blood chemistry (protein/albumin, triglyceride (TG), cholesterol (Cho) and lipoprotein levels) and 24-hour proteinuria were studied. ADPN levels were determined by ELISA. As expectedly, there were significant alterations in serum protein-lipid parameters and 24-hour proteinuria levels in SRNS patients consistent with their disease activity. SRNS-relapse patients had substantially higher ADPN levels (36.77±15.06 (5.61–59.41, median 39.84) μg/ml), compared to those in SRNS-remission and control groups (14.17±6.02 (3.28–29.40, median 12.80) μg/ml and 11.84±7.53 (2.81–31.46, median 10.85) μg/ml, respectively, p=0.001). There were strong positive correlations between serum ADPN levels and Cho (r=0.637, p=0.000), TG (r=0.516, p=0.002), low density lipoprotein (r=0.614, p=0.000) levels and 24-hour proteinuria (r=0.828, p=0.000) levels, whereas protein (r=−0.695, p=0.000) and albumin (r=0.732, p=0.000) levels were inversely correlated with ADPN levels. Regression analysis showed a significant correlation between ADPN and proteinuria (p=0.000). In conclusion, remarkably increased serum ADPN levels were detected in SRNS-relapse compared to those in SRNS-remission. This phenomenon might be the reflection of a compensatory response to nephrotic state characterized by massive proteinuria, hypoalbuminemia and hyperlipidemia.

Hypertension in Pediatric Patients With Renal Scarring in Association With Vesicoureteral Reflux

OBJECTIVE To examine the reflux nephropathy rate and severity as well as the hypertension rate in pediatric patients with vesicoureteral reflux (VUR). METHODS The study included 240 patients with VUR. Renal scarring (RS) was demonstrated by renal parenchymal examination using technetium-99m-labeled dimercaptosuccinic acid (99mTc-DMSA) scintigraphy. Office measurements of arterial blood pressure and ambulatory blood pressure monitoring (ABPM) of VUR patients were done during the follow-up period. RESULTS Follow-up was a mean duration of 24 months. Rates of RS and hypertension increased parallel to increases in the degree of VUR. A gradual elevation in hypertension rates was evident during the follow-up period. All patients with hypertension had RS. Severe RS in 56 patients was associated with increasing blood pressure readings by 24-hour ABPM or office measurements in 19 patients (33.9%). ABPM measurements enabled us to detect additional patients compared with office measurements alone. CONCLUSION Hypertension is a serious complication in children with reflux nephropathy and is associated with the severity of RS and VUR grade. ABPM seems to be superior over office measurements of blood pressure in identifying patients with hypertension.

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.

Osteoprotegerin and RANKL Serum Levels and Their Relationship with Serum Ghrelin in Children with Chronic Renal Failure and on Dialysis

Background: Osteoprotegerin (OPG) and receptor activator of the nuclear factor ĸB ligand (RANKL) constitute a complex system of mediators involved in the regulation of bone resorption process. Ghrelin, a growth hormone secretagogue, has been shown to modulate proliferation and differentiation of osteoblasts. The present study was carried out to evaluate the serum concentrations of OPG and sRANKL in children with chronic renal impairment (CRI) and on dialysis, and to establish a possible relationship between their serum levels and that of ghrelin. Methods: 33 patients including 10 patients with CRI, 12 peritoneal dialysis (PD) and 11 hemodialysis (HD) patients and 22 healthy controls were enrolled into the study. OPG, sRANKL and ghrelin levels were studied with radioimmunoassay. Results: Serum OPG levels in CRI, PD and HD groups were significantly higher than the healthy controls (p = 0.002, p < 0.001, p < 0.001, respectively) whereas sRANKL levels were significantly lower than the healthy controls (p = 0.03, p = 0.01, p = 0.001, respectively). Ghrelin levels were significantly higher in CRI, PD and HD groups compared to healthy controls (p = 0.001, p < 0.001, p < 0.001, respectively). We observed a negative correlation between the sRANKL and OPG levels (r = –0.27, p = 0.04) as well as between sRANKL and ghrelin levels (r = –0.31, p = 0.02). OPG levels showed a positive correlation with ghrelin levels (r = 0.63, p < 0.001). Conclusion: We found a lower RANKL bioactivity index in children with CRI and on dialysis. The mechanism and the role of elevated OPG and low sRANKL in uremia are unclear, but they might partly represent a compensatory mechanism to the negative balance of bone remodeling in renal bone disease in children. Additionally, we demonstrated for the first time that ghrelin and the RANKL/OPG system have a close relationship in CRF. Therefore, ghrelin may be of importance in mediating the effects of the RANKL/OPG system in renal bone disease.

Successful solid organ transplantation from septicemic cadaveric donors: case report.

Systemic donor infections especially with gram-negative organisms are regarded as an absolute contraindication to cadaveric organ donation for transplantation. This is largely due to fear of transmitting the pathogenic organisms to the immunosuppressed recipient. However, due to the current shortage of organs available for transplantation, clinicians are faced with the option to use organs from infected donors. Between 1996 to January 2006, we collected 44 solid organs. Two out of nine donors had microorganisms from blood cultured. Case 1 was of 23-year old woman whose cause of brain death was intracerebral bleeding due to a traffic accident. The donor had stayed 9 days in the intensive care unit prior to brain death. Two kidneys, two livers (split), and or heart were used. Klebsiella was the organism on blood culture. Case 2 was of 35-year-old man; cause of brain death was cerebral hematoma due to traffic accident. The donor had stayed 6 days prior to brain death onset. The liver and two kidneys were used. Acinetobacter baumannii was yielded upon blood culture. All donors were treated with appropriate antibiotics for at least 48 hours prior to organ procurement with consequent negative blood cultures, while the recipients received the same culture-specific antibiotics for 10 days following transplantation. One donor (case 1) heart and both donor corneas were not used due to infection. All patients are alive with excellent graft function at a median of 90 days following transplantation. In conclusion, our results suggested that bacteremic donors with severe sepsis under proper treatment can be considered for transplantation.

How often do we face side effects of sirolimus in pediatric renal transplantation

We analyzed 25 pediatric renal transplantation patients on sirolimus (SRL) therapy to assess changes in serum creatinine, glomerular filtration rate, electrolytes, triglycerides, cholesterol, and side effects. Mean time to initiate SRL therapy was 3.2 years. The serum creatinine levels of patients on SRL treatment at 1, 6, 12, and 24 months were 1.67 ± 1.15 mg/dL, 1.18 ± 0.52 mg/dL, 1.24 ± 0.32 mg/dL, 1.15 ± 0.31 mg/dL, and 1.17 ± 0.12 mg/dL, respectively. We observed proteinuria in 3, hyperlipidemia in 5, and anemia in 2 patients, but none had the treatment discontinued. We diagnosed interstitial pneumonia in (n = 1), nasal acneiform lesions (n = 1), and lower extremity edema (n = 1). Hypokalemia developed in 1 subject with high blood SRL levels. In the follow-up period there was no case of acute rejection episode during SRL therapy.

Post‐transplant glucose status in 61 pediatric renal transplant recipients: Preliminary results of five Turkish pediatric nephrology centers

Buyan N, Bilge I, Turkmen MA, Bayrakci U, Emre S, Fidan K, Baskin E, Gok F, Bas F, Bideci A. Post‐transplant glucose status in 61 pediatric renal transplant recipients: Preliminary results of five Turkish pediatric nephrology centers.
Pediatr Transplantation 2010:14:203–211

The association of cytokine gene polymorphism with reflux nephropathy

OBJECTIVE To identify genetic risk factors for the progression of vesicoureteral reflux (VUR) to reflux nephropathy, we examined polymorphisms of multiple cytokine genes among VUR patients with or without renal scarring. METHODS A total of 238 VUR patients aged between 1 and 18 years with (n = 113) or without renal scarring (n = 125) were included. The presence of renal scarring was demonstrated by renal parenchymal examination using Technetium-99m dimercaptosuccinate scintigraphy. Sera of the patients were examined for tumor necrosis factor-alpha (TNF-α, -308), transforming growth factor-beta1 (TGF-β1, +869, +915), interleukin-6 (IL-6, -174), interleukin-10 (IL-10, -1082, -819, -592) and interferon-gamma (IFN-γ, +874) gene polymorphisms using the polymerase chain reaction sequence-specific primer method. RESULTS Among patients with renal scarring, frequencies for the T/T G/C and C/C G/C genotypes of TGF-β1 gene (p = 0.003), GCC/GCC genotype of IL-10 gene (p = 0.015), GC phenotype of IL-6 gene (p = 0.001) and T/T genotype of IFN-γ gene (p = 0.001) were higher compared to patients without renal scarring. Regarding the TNF-α gene, among patients with low grade VUR only, the G/G genotype was associated with an increased risk. CONCLUSIONS Certain genotypes of cytokine gene polymorphisms seem to be associated with an increased or decreased susceptibility to reflux nephropathy, which may explain why only a proportion of VUR patients progress to reflux nephropathy. This information may aid in prediction of prognosis and implementing more aggressive management strategies at earlier stages. Further immunogenetic studies may identify novel targets for the management and prevention of the condition.