Does Age at Onset Affect the Clinical Presentation of Familial Mediterranean Fever in Children?

BACKGROUND/OBJECTIVE: The aim of this study was to compare the clinical and demographic features and evaluate the phenotypic and genotypic differences of pediatric familial Mediterranean fever (FMF) patients according to their age at disease onset. METHODS: Records of 854 patients who were diagnosed with FMF between 2006 and 2017 were evaluated. Patients were divided into 2 subgroups according to their age at disease onset. Group 1 comprised FMF patients who had experienced their first attack at 2 years or younger (younger onset), and group 2 comprised FMF patients who had experienced their first attack at older than 2 years. RESULTS: There were 155 patients in group 1 and 699 patients in group 2. Delay in diagnosis, attack frequency, duration of attacks, fever, chest pain, erysipelas-like erythema, incidence of family history, anti-interleukin 1 therapy use, and M694V homozygous and M680I homozygous mutations were significantly higher in group 1, whereas arthralgia and abdominal pain were significantly higher in group 2. There were no significant differences in arthritis, amyloidosis, and protracted febrile myalgia between the groups. The colchicine dose at last visit and Pras activity score were higher in group 1. CONCLUSIONS: It seems that FMF patients with a younger onset has a more severe disease course. They needed higher doses of colchicine to control the attacks. M694V and M680I homozygous mutations presented more frequently in younger-onset FMF patients. Increased awareness of physicians of the early presentation of FMF may prevent delays in FMF diagnosis.

Factors Affecting Bone Health in Kidney Transplant Recipients: Klotho Gene Single-Nucleotide Polymorphisms and Other Clinical Features.

OBJECTIVES: Posttransplant bone diseases are a major cause of morbidity in kidney transplant recipients. We investigated the relationship between klotho gene single-nucleotide polymorphisms and bone diseases after kidney transplant. We also aimed to identify possible risk factors for development of bone disease. MATERIALS AND METHODS: The study consisted of 251 kidney transplant recipients (164 men and 87 women) with minimum follow-up of 3 years after kidney transplant. Patients with prolonged immobilization, malignancy, parathyroidectomy, glomerular filtration rates less than 30 mL/min/1.73 m², hypo- or hyperthyroidism, and treatment with drugs that affect bone metabolism were excluded. We investigated the relationship between 6 single-nucleotide polymorphisms of the klotho gene (rs480780, rs211234, rs576404, rs211235, rs9536314, and rs1207568) and development of osteoporosis, avascular bone necrosis, and persistent hyperparathyroidism. RESULTS: Longer dialysis treatment (odds ratio, 1.13; P = .002) and rs211235 single-nucleotide polymorphism in the klotho gene (odds ratio, 9.87; P = .001 for GG genotype) were significantly associated with persistent hyperparathyroidism. A higher magnesium level was detected as a protective factor from development of persistent hyperparathyroidism (odds ratio, 0.19; P = .009). Persistent hyperparathyroidism was defined as a risk factor for development of osteopenia/osteoporosis (odds ratio, 2.76; P = .003) and avascular bone necrosis (odds ratio, 2.52; P = .03). Although the rs480780 (odds ratio, 8.73; P = .04) single-nucleotide polymorphism in the klotho gene was defined as a risk factor for development of osteopenia/osteoporosis, none of the klotho single-nucleotide polymorphisms was found to be associated with development of avascular bone necrosis. CONCLUSIONS: Persistent hyperparathyroidism could be an important indicator for development of bone disease in kidney transplant recipients. Also, some of the klotho gene single-nucleotide polymorphisms are associated with higher risk for bone disease after kidney transplant.

Serum fetuin-A is associated with the components of MIAC(malnutrition, inflammation, atherosclerosis, calcification) syndrome in different stages of chronic kidney disease

Background/aim: Fetuin-A, a circulating inhibitor of calcification, is a marker of inflammatory-nutritional state. We evaluated the association between serum fetuin-A levels and vascular calcification, intima-media thickness, and nutritional and inflammatory markers in different stages of chronic kidney disease (CKD). Materials and methods: CKD patients were sampled for calcium-phosphate parameters and nutritional and inflammatory markers [highly sensitive C-reactive protein (hs-CRP)], and serum fetuin-A levels. Intima-media thicknesses of the common carotid arteries (CIMT) were measured. Peripheral artery calcification scores were obtained. Results: A total of 238 patients were included in the study. Fetuin-A levels in patients with end-stage renal disease were significantly lower than those in patients with stage-3 and stage-4 CKD (stage-5 vs. stage-4, P < 0.001; stage-5 vs. stage-3, P < 0.001). Fetuin-A was negatively correlated with creatinine (P < 0.001), Ca × P product (P < 0.001), hs-CRP (P = 0.01), vascular calcification score (P < 0.001), and CIMT (P < 0.001), and positively correlated with BMI (P < 0.001, r = 0.30) and serum albumin (P < 0.001). Conclusion: Lower levels of fetuin-A were associated with higher vascular calcification scores, CIMT, hs-CRP levels, and lower BMI and albumin. Fetuin-A deficiency may be a key element for MIAC syndrome.

HLA Genotypes in Turkish Hematopoietic Cell Recipients and Likelihood of Finding a Matched Donor Through Family Searches.

OBJECTIVES: Allogeneic hematopoietic stem cell transplant is a life-saving treatment, but donor numbers in Turkey do not meet the increasing demand for this procedure. Here, our objectives were (1) to assess the frequency of HLA-matched related donors in the Turkish population and (2) to identify the HLA antigens and haplotypes that are most frequent in Turkey. MATERIALS AND METHODS: The HLA genotypes of 841 consecutive recipients and 3071 family members were retrospectively reviewed. RESULTS: Matched related donors were identified for 368/841 recipients (44%). Extended family donor searches were performed for 111/181 pediatric recipients (61%), with nonsibling matched related donors found for 23 patients (21%). Matched related donors were found for a significantly higher proportion of pediatric patients (52%) than adult patients (41%) (odds ratio of 2.5; 95% confidence interval, 1.9-4.1; P = .02). The percentage of pediatric versus adult patients with 3 or more siblings was 13% versus 46% (odds ratio of 5.6; 95% confidence interval, 3.6-8.5; P = .001). The most frequent HLA class I antigens at each locus were HLA-A*02 (20.2%), HLA-B*35 (19.5%), and HLA-C*07 (19.8%). The most frequent HLA class II antigens at each locus were HLA-DRB1*11 (21.6%) and HLA-DQB1*03 (40.2%). The most common 3-locus haplotypes were HLA-A*24 B*35 DRB1*11 (F:0.020) and HLA-A*01 B*08 DRB1*03 (F:0.015). When adult and pediatric groups were combined, the most common locus haplotypes were found in 43/345 sibling donors (12%) and in 7/23 nonsibling pediatric donors (30%) (odds ratio of 2.7; 95% confidence interval, 1.2-6.4; P = .02). CONCLUSIONS: The results indicate that, in Turkey, it can be beneficial to revise donor search algorithms to include an extended family donor search before an unrelated donor search. This type of search can be effective because of the HLA haplotype diversity in Turkey, the frequency of consanguinity, and the country's limited donor pool.

Avaliação de antígeno leucocitário humano classe I e II em pacientes pediátricos com gastrite e úlcera duodenal ativas e Helicobacter pylori positivo / Evaluation of human leukocyte antigen class i and ii antigens in helicobacter pylori-positive pediatric patients with active gastritis and duodenal ulcer

ABSTRACT BACKGROUND: As being the first bacteria determined to be carcinogenic, Helicobacter pylori (H. pylori) is a pathogen localized in the stomach in more than half of the world population. Some earlier studies have found a relation between tissue histocompatibility antigens and gastric cancers depending on the regions. OBJECTIVE: The present study aimed to determine the distribution of human leukocyte antigen (HLA) class I and class II antigens in H. pylori-positive pediatric patients with active gastritis and duodenal ulcer, excluding cancer cases, in our center. METHODS: The study included 40 patients diagnosed with H. pylori-positive active gastritis and duodenal ulcer and 100 controls consisting of healthy donor candidates. The HLA class I and class II antigens were studied in the isolated DNA samples using the polymerase chain reaction sequence-specific oligonucleotide probes. RESULTS: The frequency of HLA-B*51 antigen was significantly higher in the patient group than in the control group (40% vs 17%; P=0.003). There was no difference between the two groups in terms of the frequencies of HLA-A, HLA-C, HLA-DR, and HLA-DQ antigens. CONCLUSION: It was determined that HLA-B*51 plays a critical role in H. pylori infection.

RESUMO CONTEXTO: Determinada como sendo a primeira bactéria cancerígena, o Helicobacter pylori (H. pylori) é um patógeno localizado no estômago em mais da metade da população mundial. Alguns estudos anteriores têm encontrado uma relação entre câncer gástrico e antígenos de histocompatibilidade de tecido dependendo das regiões. OBJETIVO: O presente estudo teve como objetivo determinar a distribuição em nosso centro do antígeno leucocitário humano (HLA) de classe I e antígenos classe II em pacientes pediátricos H. pylori-positivos com gastrite e úlcera duodenal ativas, excluindo casos de câncer. MÉTODOS: O estudo incluiu 40 pacientes H. pylori-positivos diagnosticados com gastrite e úlcera duodenal ativas e 100 controles consistindo de candidatos doadores saudáveis. Foram estudadas nas amostras de DNA isoladas o antígeno leucocitário humano classe I e antígenos classe II, utilizando-se as cadeias de sequência específica de polimerase do oligonucleotideo. RESULTADOS: A frequência do antígeno HLA - B * 51 foi significativamente maior no grupo de pacientes do que no grupo controle (40% vs 17%; P=0,003). Não houve diferença entre os dois grupos em termos das frequências dos antígenos HLA-A, HLA-DR, HLA-DQ e HLA-C. CONCLUSÃO: Determinou-se que o HLA - B * 51 desempenha um papel crítico na infecção pelo H. pylori.

EVALUATION OF HUMAN LEUKOCYTE ANTIGEN CLASS I AND II ANTIGENS IN HELICOBACTER PYLORI-POSITIVE PEDIATRIC PATIENTS WITH ACTIVE GASTRITIS AND DUODENAL ULCER.

BACKGROUND: As being the first bacteria determined to be carcinogenic, Helicobacter pylori (H. pylori) is a pathogen localized in the stomach in more than half of the world population. Some earlier studies have found a relation between tissue histocompatibility antigens and gastric cancers depending on the regions. OBJECTIVE: The present study aimed to determine the distribution of human leukocyte antigen (HLA) class I and class II antigens in H. pylori-positive pediatric patients with active gastritis and duodenal ulcer, excluding cancer cases, in our center. METHODS: The study included 40 patients diagnosed with H. pylori-positive active gastritis and duodenal ulcer and 100 controls consisting of healthy donor candidates. The HLA class I and class II antigens were studied in the isolated DNA samples using the polymerase chain reaction sequence-specific oligonucleotide probes. RESULTS: The frequency of HLA-B*51 antigen was significantly higher in the patient group than in the control group (40% vs 17%; P=0.003). There was no difference between the two groups in terms of the frequencies of HLA-A, HLA-C, HLA-DR, and HLA-DQ antigens. CONCLUSION: It was determined that HLA-B*51 plays a critical role in H. pylori infection.

Evaluation of urinary KIM-1, NGAL, and IL-18 levels in determining early renal injury in pediatric cases with hypercalciuria and/or renal calculi.

AIM: One has to measure urinary enzymes and proteins to determine renal dysfunction and tubular injury in earlier stage during the course of disease. The aim of this study was to investigate the role of urinary NGAL (neutrophil gelatinase-associated lipocalin), IL-18 (Interleukin 18), and KIM-1 (kidney injury molecule-1) levels in determining early renal injury in pediatric patients with hypercalciuria (HC) and/or nephrolithiasis (NL) and to compare the levels of these markers between the sick and healthy subjects. MATERIAL AND METHODS: Urinary NGAL, KIM- 1, and IL- 18 levels were measured in 40 pediatric patients diagnosed with NL, 23 patients with HC, and 20 healthy controls. RESULTS: A significant difference was found between patient groups (NL and HC) and healthy children with respect to urinary NGAL/cr ratio (p < 0.001). There were no significant differences between patient and control groups with respect to urinary IL18/cr and KIM1/cr ratios. CONCLUSIONS: We found that urinary NGAL is a useful marker for determining renal tubular damage in NL and HC. To our knowledge, this is the first study to report significantly increased urinary NGAL levels in NL and HC.

Neutrophil gelatinase-associated lipocalin as a follow-up marker in critically ill pediatric patients with established acute kidney injury.

AIM: To assess the utility of neutrophil gelatinase-associated lipocalin (NGAL) in both urine and serum as a follow-up marker for the discrimination of prerenal acute kidney injury (AKI) from intrinsic AKI in critically ill pediatric patients with established AKI at the time of patient presentation. PATIENTS AND METHODS: This was a prospective cohort study of a heterogeneous group of critically ill children in the pediatric intensive care unit (PICU). Serum creatinine (SCr) values were obtained daily as part of routine patient care. AKI was defined as a 50% or greater increase in SCr from baseline and classified as prerenal and intrinsic AKI. RESULTS: A total of 32 critically ill children (mean age: 105 ± 71.7 months, 56% female) with established AKI were included to the study. Area under curve (AUC) for urine and serum NGAL to distinguish prerenal AKI from intrinsic AKI was 0.94, 95% confidence interval (CI): 0.869-1.02 (p < 0.001) and 0.86, 95% CI: 0.71-1.02 (p = 0.002), respectively. CONCLUSION: In a heterogeneous group of critically ill children with established AKI, we found that NGAL in both urine and serum at the time of patient presentation discriminated intrinsic AKI from prerenal AKI.

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-ß1, +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-ß1 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.

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.

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 kappaB 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.

Leptin and resistin levels and their relationships with glucose metabolism in children with chronic renal insufficiency and undergoing dialysis.

AIM: The aim of the present study is: (i) to evaluate the serum concentrations of leptin and resistin in the paediatric patients with chronic renal impairment (CRI), on haemodialysis (HD) and on peritoneal dialysis (PD) treatment; (ii) to examine the relationship between these hormones; and (iii) to investigate the possible influence of these hormones on the insulin resistance and sensitivity indexes as well as on serum insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) levels. METHODS: In total, 52 patients (15 patients with CRI, 24 PD patients and 13 HD patients) and 23 healthy age- and sex-matched control subjects were included in the present study. RESULTS: Homeostasis model assessment of insulin resistance (HOMA-IR) was higher than 2.5 in 47.1% of the patients. IGF-1 levels of patients with CRI, PD and HD patients were significantly lower than those in the controls (P < 0.001, P < 0.001, P < 0.001, respectively). The leptin levels of patients with CRI and on PD and HD treatment were significantly higher than the control group (P = 0.038, P = 0.002, P = 0.006, respectively). Similarly, serum resistin levels of patients with CRI and those of PD and HD patients were higher when compared with healthy controls (P = 0.037, P < 0.001, P = 0.005, respectively). CONCLUSION: Leptin and resistin levels were increased in the children with CRF; however, this elevation was not found to be associated with hyperinsulinism. Further studies to explain the mechanisms and consequences of the accumulation of these hormones in CRF may provide the therapeutical approach aiming to normalize their circulating levels.

Renin-angiotensin system gene polymorphisms: association with susceptibility to Henoch-Schonlein purpura and renal involvement.

The clinical course of Henoch-Schönlein Purpura (HSP) in children is variable, with some patients having a much more rapidly progressing course than others. We investigated whether polymorphisms of the renin-angiotensin system (RAS) genes are involved in HSP. Three RAS genotypes were examined in 114 children with HSP and in 164 healthy children: the angiotensin I converting enzyme (ACE) insertion/deletion polymorphism, the M235T mutation in the angiotensinogen gene (Agt), and the A1166C in the angiotensin II type I receptor (AT1R) gene. Significant differences were observed between HSP patients and control group in the frequency of ACE and Agt genotypes (p=0.004 and p=0.003, respectively). The TT genotype of Agt gene was associated with a 3.5-fold increased risk for Henoch-Schönlein nephritis (HSN) compared with the MM/MT genotype (odds ratio, 3.5; 95% confidence interval, 1.2-10.4). There was a trend to a higher prevalence of the TT genotype of the Agt gene among patients with nephrotic range proteinuria when compared to the patients with mild proteinuria, although the difference did not reach a statistical significance. The results of this study suggest that polymorphisms of ACE gene and Agt gene likely influence the risk of developing HSP. However, among the three genes of the RAS studies, only Agt gene was associated with the susceptibility to HSN. RAS gene polymorphisms studied are not associated with the presence of nephrotic range proteinuria. Additional studies are warranted to verify the correlation between RAS gene polymorphisms and susceptibility to HSP.