Digestion of Chromatin in Apoptotic Cell Microparticles Prevents Autoimmunity.

Antibodies to DNA and chromatin drive autoimmunity in systemic lupus erythematosus (SLE). Null mutations and hypomorphic variants of the secreted deoxyribonuclease DNASE1L3 are linked to familial and sporadic SLE, respectively. We report that DNASE1L3-deficient mice rapidly develop autoantibodies to DNA and chromatin, followed by an SLE-like disease. Circulating DNASE1L3 is produced by dendritic cells and macrophages, and its levels inversely correlate with anti-DNA antibody response. DNASE1L3 is uniquely capable of digesting chromatin in microparticles released from apoptotic cells. Accordingly, DNASE1L3-deficient mice and human patients have elevated DNA levels in plasma, particularly in circulating microparticles. Murine and human autoantibody clones and serum antibodies from human SLE patients bind to DNASE1L3-sensitive chromatin on the surface of microparticles. Thus, extracellular microparticle-associated chromatin is a potential self-antigen normally digested by circulating DNASE1L3. The loss of this tolerance mechanism can contribute to SLE, and its restoration may represent a therapeutic opportunity in the disease.

Management of antenatal hydronephrosis.

Antenatal hydronephrosis (AHN) is the most frequently detected abnormality by prenatal ultrasonography. Differential diagnosis of AHN includes a wide variety of congenital abnormalities of the kidney and urinary tract ranging from mild abnormalities such as transient or isolated AHN to more important ones as high-grade congenital vesicoureteral reflux or ureteropelvic junction obstruction. It is well known that the outcome depends on the underlying etiology. Various grading systems have been proposed for the classification of AHN on prenatal and postnatal ultrasonography. Mild isolated AHN represents up to 80% of cases, is considered to be benign, and majority of them resolve, stabilize, or improve during follow-up. Controversies exist regarding the diagnosis and management of some important and severe causes of AHN such as high-grade vesicoureteral reflux and ureteropelvic junction obstruction. Current approach is becoming increasingly conservative during diagnosis and follow-up of these patients with less imaging and close follow-up. However, there is still no consensus regarding the clinical significance, postnatal evaluation, and management of infants with AHN. The aim of this review is to discuss the controversies and provide an overview on the management of AHN.

Sacroiliitis in Children With Familial Mediterranean Fever.

BACKGROUND/OBJECTIVE: Familial Mediterranean fever (FMF) is an autosomal recessive disease, characterized by recurrent, self-limited attacks of fever with serositis. Various diseases were reported to be associated with FMF. The aim of this study was to investigate the frequency and characteristics of sacroiliitis in children with FMF. METHODS: Files of FMF patients who had been seen in 2 reference hospitals in Ankara were retrospectively evaluated. Patients with FMF and concomitant sacroiliitis were included to the study. All patients had magnetic resonance imaging evidence of sacroiliitis. RESULTS: Among 650 FMF patients, 17 (11 females, 6 males; mean age, 13.32 ± 4.24 years) (2.6%) of them were found to have sacroiliitis. Familial Mediterranean fever diagnosis was done prior to sacroiliitis diagnosis in 11 patients (65%) and concurrently or afterward in 6 patients (35%). Ten patients had isolated sacroiliitis, and 7 had associated diseases (5 enthesitis-related arthritis, 1 psoriatic arthritis, and 1 ulcerative colitis). Arthritis (59%), arthralgia (77%), leg pain (71%), heel pain (41%), and enthesitis (29%) were common complaints. Sacroiliac tenderness was detected in 77%, and M694V mutation in almost 90% of the patients. All patients received colchicine therapy. Additionally, 14 of them were treated with nonsteroidal anti-inflammatory drugs, 10 were on sulfasalazine treatment, and 7 of them were on biological agents. CONCLUSIONS: Sacroiliitis can be seen in patients with FMF during childhood, and M694V mutation seems to be a susceptibility factor for its development. Inflammatory low-back pain and leg and heel pain could suggest sacroiliitis.

Neonatal onset familial Mediterranean fever.

Objectives: Familial Mediterranean fever (FMF) is an autosomal recessive disease characterised by recurrent, self-limited attacks of fever with serositis. Recently, it was shown that FMF patients with early disease onset have more severe disease. The aim of this study was to describe the demographic, clinical and genetic features of FMF patients who had disease onset during the neonatal period. Methods: Medical records of all patients diagnosed as FMF and had been seen in the outpatient clinic of Paediatric Rheumatology department between January 2013 and January 2014 were retrospectively evaluated. Patients with disease onset during the first month of life were included to the study. Results: Among 317 patients; 19 (12 males) were included to the study. Approximately 60% of the patients had family history of FMF. Homozygous p.M694V mutation was detected in 42% of the cases. Thirteen patients present with attacks of fever and remaining had attacks in the form of restlessness, resembling infantile colic starting in the neonatal period. Majority of these patients developed classical abdominal attacks between the ages of 1 and 2.5 years. The diagnosis of FMF was significantly delayed; the median age at onset of therapy was 3.5 years (range 7 months-17 years). Conclusion: Patients with FMF could have complaints even in the neonatal period. Homozygous p.M694V mutation is a prominent mutation in this group of patients. In order to prevent diagnostic delay physicians dealing with these type of patients should be more vigilant.

Proteinuria in pediatric renal transplant recipients.

Proteinuria has been shown to be an important and potentially treatable risk factor for graft loss. The aim of this study was to evaluate prevalence, etiology, and outcome of proteinuria during the follow-up of children with renal transplantation. We retrospectively reviewed the files of renal transplanted children between 2006 and 2016 in our center. All patients were interpreted with respect to the demographic data and clinical and laboratory features including information about proteinuria. Chi-square test and Mann-Whitney U test were used for analysis. Fifty-two children were eligible for the study. Proteinuria was observed in 34 (65%) and nephrotic range proteinuria was detected in 5 (9.6%) patients. Etiology of proteinuria could be identified in 21 patients. Acute rejection and uncontrolled hypertension were the most frequent causes of proteinuria. Proteinuria had resolved during the follow-up in 59% of the patients. We found that children with and without proteinuria had similar glomerular filtration rate at the end of 50 months of follow-up period. Proteinuria seems to be a common complication in renal transplant recipients. Graft functions can be preserved by immediate evaluation of increasing proteinuria, and by fixing treatable causes rapidly and efficiently during the follow-up in majority of the patients.

Fatigue in pediatric patients with familial Mediterranean fever.

OBJECTIVES: Familial Mediterranean fever (FMF) is characterized by recurrent, self-limited attacks of fever with serositis involving the peritoneum, pleura and joints. Fatigue is a common problem in many pediatric rheumatic diseases; however, has not been evaluated systematically in FMF patients. Accordingly, the aim of this study was to evaluate fatigue and its possible allied factors in patients with FMF. METHODS: Patients with FMF, aged between 10 and 21 years, were assessed by completed validated fatigue questionnaire (Checklist Individual Strength-20). As a control group, patients with chronic rheumatic diseases and healthy children without any chronic disease were included. RESULTS: The study group comprised 111 patients with FMF, 54 with other chronic rheumatic diseases and 79 healthy subjects. While the CIS-20 total score and subscale scores (including subjective experience of fatigue) were similar between patients with FMF and those with other chronic rheumatic diseases (p > .05); both groups had significantly higher scores when compared with healthy subjects (p < .05). FMF patients with musculoskeletal complaints had significantly higher scores of subjective experiences of fatigue when compared to those without those complaints. CONCLUSIONS: Fatigue is a common but unrecognized complaint in patients with FMF. Familial Mediterranean fever seems to be a chronic disease with inter attack ongoing complaints.

Hypertension and improved left ventricular mass index in children after renal transplantation.

This study was conducted to evaluate the changes in BP and LVH after the transplantation and to evaluate the effect of BP changes in LVH. Forty-three pediatric renal transplant patients, with a mean age of 16.99 ± 3.88 years, were enrolled in this study. Twenty-three (53.5%) of the patients were male. Medical records for pretransplantation period (closest to the time of transplantation) and for post-transplantation period (9-12 months after transplantation) were reviewed. All the patients had BP measurements and echocardiographic evaluation in pre- and post-transplantation period. Hypertension was defined as an average systolic and/or diastolic BP that is ≥95th percentile for sex, age, and height. Although the number of patients with hypertension increased from 30 (69.76%) to 35 (81.4%), the number of patients with LVH decreased from 19 (44.1%) to 9 (20.9%) after the transplantation. Although the only significant difference in BP measurements was between the mean Z scores of 24 hour and nighttime mean DBP before and after the transplantation; the mean LVMI, and the prevalence of LVH was significantly lower after the transplantation. There was no significant correlation between the LVMI and the BP measurements. Even though hypertension may persist, there is significant improvement in LVH after renal transplantation.

Turkish pediatric atypical hemolytic uremic syndrome registry: initial analysis of 146 patients.

BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) is a devastating disease with significant morbidity and mortality. Its genetic heterogeneity impacts its clinical presentation, progress, and outcome, and there is no consensus on its clinical management. METHODS: To identify the characteristics of aHUS in Turkish children, an industry-independent registry was established for data collection that includes both retrospective and prospective patients. RESULTS: In total, 146 patients (62 boys, 84 girls) were enrolled; 53 patients (36.3%) were less than 2 years old at initial presentation. Among the 42 patients (37.1%) whose mutation screening was complete for CFH, CFI, MCP, CFB, C3, DGKE, and CHFR5 genes, underlying genetic abnormalities were uncovered in 34 patients (80.9%). Sixty-one patients (41.7%) had extrarenal involvement. During the acute stage, 33 patients (22.6%) received plasma therapy alone, among them 17 patients (51.5%) required dialysis, and 4 patients (12.1%) were still on dialysis at the time of discharge. In total, 103 patients (70.5%) received eculizumab therapy, 16 of whom (15.5%) received eculizumab as a first-line therapy. Plasma therapy was administered to 84.5% of the patients prior to eculizumab. In this group, renal replacement therapy was administered to 80 patients (77.7%) during the acute period. A total of 3 patients died during the acute stage. A total of 101 patients (77.7%) had a glomerular filtration rate >90 mL/min/1.73 m2 at the 2-year follow-up. CONCLUSIONS: The Turkish aHUS registry will increase our knowledge of patients with aHUS who have different genetic backgrounds and will enable evaluation of the different treatment options and outcomes.

Anti-VEGF-related thrombotic microangiopathy in a child presenting with nephrotic syndrome.

BACKGROUND: Targeting the vascular endothelial growth factor (VEGF) signaling pathway has become an important approach to current cancer therapy. Anti-VEGF therapy-related renal adverse effects may present as hypertension, non-nephrotic proteinuria, and rarely as nephrotic syndrome (NS) and acute kidney injury. CASE-DIAGNOSIS/TREATMENT: In this report, we present a 15-year-old boy who had developed nephrotic syndrome and thrombotic microangiopathy 26 months after administration of anti-VEGF therapy. Treatment was discontinued and nephrotic syndrome remitted spontaneously within 3 months. CONCLUSIONS: Nephrologists should be aware of the side effects of anti-VEGF therapy. Early diagnosis and prompt management with withdrawal of the agents will result in spontaneous remission.

Hypertension in children after renal transplantation.

BACKGROUND: Hypertension (HT) is a common and serious complication following renal transplantation in children, and an important risk factor for cardiovascular morbidity and mortality. This study evaluated the clinical characteristics of HT in children after renal transplantation. METHODS: Twenty-four children who were followed up at least 6 months after renal transplantation were enrolled in the study. From the clinical records, demographic and laboratory data, casual blood pressure (BP) measurement, ambulatory BP monitoring (ABPM), medication, and left ventricular mass index (LVMI) at echocardiogram were documented. RESULTS: Mean age at time of transplantation was 12.6 ± 3.0 years and mean follow-up period was 19.6 ± 15.8 months. HT was detected in 21 children (87.5%) after renal transplantation. Twelve patients (50%) had HT both before and after transplantation and nine (38%) had HT only after transplantation. HT developed in 67% within the first week and in 95% within the first month. All hypertensive children had night-time HT and no child had isolated daytime HT. The efficacy of HT control was 42%. Median LVMI in patients with HT after renal transplantation was 42.3 g/m(2.7). CONCLUSIONS: Severe HT, an important complication, was frequently seen in the early period after renal transplantation. Predominance of nocturnal HT and the lack of isolated daytime HT after transplantation underline the importance of ABPM. ABPM should be performed regularly in the first year after transplantation, not only for diagnosis but also for evaluation of HT control.

DNASE1L3 mutations in hypocomplementemic urticarial vasculitis syndrome.

OBJECTIVE: Hypocomplementemic urticarial vasculitis syndrome (HUVS) is characterized by recurrent urticaria along with dermal vasculitis, arthritis, and glomerulonephritis. Systemic lupus erythematosus (SLE) develops in >50% of patients with HUVS, although the pathogenesis is unknown. The aim of this study was to identify the causative DNA mutations in 2 families with autosomal-recessive HUVS, in order to reveal the pathogenesis and facilitate the laboratory diagnosis. METHODS: Autozygosity mapping was combined with whole-exome sequencing. RESULTS: In a family with 3 affected children, we identified a homozygous frameshift mutation, c.289_290delAC, in DNASE1L3. We subsequently identified another homozygous DNASE1L3 mutation leading to exon skipping, c.320+4delAGTA, in an unrelated family. The detected mutations led to loss of function, via either nonsense-mediated messenger RNA decay or abolished endonuclease activity, as demonstrated by a plasmid nicking assay. CONCLUSION: These results show that HUVS is caused by mutations in DNASE1L3, encoding an endonuclease that previously has been associated with SLE.

De novo amyloidosis in a renal transplant patient.

Systemic AA amyloidosis is a serious complication of many chronic inflammatory disorders and chronic infections. Renal involvement is seen in the majority of the patients and can lead to end-stage renal disease. Renal transplantation can be performed in these patients; however, amyloidosis can recur in the transplanted kidneys. On the other hand, de novo AA amyloidosis in renal transplant patients has been rarely reported. We report a 17-yr-old patient with end-stage renal disease due to genitourinary anomalies who developed recurrent pyelonephritis after transplantation. Three yr after transplantation, renal biopsy was performed for proteinuria and AA amyloidosis was identified in the renal allograft. Although rare, chronic infections might cause de novo amyloidosis in renal transplant patients. Therefore, amyloidosis should be kept in mind in those types of patients who present with proteinuria.

High frequency of kidney and urinary tract anomalies in asymptomatic first-degree relatives of patients with CAKUT.

BACKGROUND: Congenital anomalies of the kidney and urinary tract (CAKUT) commonly cause chronic kidney disease in children. While most CAKUT cases are sporadic, observed familial clustering suggests that the pathogenesis is influenced by genetic factors. METHODS: The purpose of the present study is to determine the frequency of the kidney and urinary tract anomalies in asymptomatic first-degree relatives of patients with CAKUT. A total of 218 index patients and their families followed at an academic hospital in Ankara, Turkey, were enrolled in the study. RESULTS: Family histories revealed at least one other member with a known kidney or urinary tract disease in 50% and CAKUT in 22.9% of the families. All asymptomatic first-degree relatives of 180 index patients were screened for kidney and urinary tract anomalies using ultrasound. New anomalies were diagnosed in 116 asymptomatic first-degree relatives (23%) in 87 families (48.3%). When family histories and ultrasound findings of 180 index patients were evaluated together, 129 first-degree relatives in 92 families (51.1%) had CAKUT. CONCLUSIONS: This study suggests that genetic mechanisms might be very important in the pathogenesis of apparently sporadic CAKUT. Identification of the underlying gene mutations will provide further insights into the knowledge of the kidney and urinary tract development and pathogenesis of CAKUT.

Hypocomplementemic urticarial vasculitis syndrome in three siblings.

Hypocomplementemic urticarial vasculitis syndrome (HUVS) is relatively uncommon and generally seen in the fourth decade of life. There are very few pediatric cases with the diagnosis of HUVS in the literature. In this report, we describe the first familial cases of HUVS in three siblings. The disease onset was during childhood period in all patients. One of them developed severe renal involvement and died. The other two had ongoing skin and eye manifestations and the elder one developed lupus. Presence of these three patients is a strong evidence for the role of genetic factors in the pathogenesis of this rare vasculitis.

The Clinical and Mutational Spectrum of 69 Turkish Children with Autosomal Recessive or Autosomal Dominant Polycystic Kidney Disease: A Multicenter Retrospective Cohort Study.

INTRODUCTION: Autosomal recessive polycystic kidney disease (ARPKD) is associated with pathogenic variants in the PKHD1 gene. Autosomal dominant polycystic kidney disease (ADPKD) is mainly associated with pathogenic variants in PKD1 or PKD2. The present study aimed to identify the clinical and genetic features of Turkish pediatric ARPKD and ADPKD patients. METHODS: This multicenter, retrospective cohort study included 21 genetically confirmed ARPKD and 48 genetically confirmed ADPKD patients from 7 pediatric nephrology centers. Demographic features, clinical, and laboratory findings at presentation and during 12-month intervals were recorded. RESULTS: The median age of the ARPKD patients at diagnosis was lower than the median age of ADPKD patients (10.5 months [range: 0-15 years] vs. 5.2 years [range: 0.1-16 years], respectively, [p = 0.014]). At the time of diagnosis, the median eGFR in the ARPKD patients was lower compared to that of ADPKD patients (81.6 [IQR: 28.7-110.5] mL/min/1.73 m2 and 118 [IQR: 91.2-139.8] mL/min/1.73 m2, respectively, [p = 0.0001]). In total, 11 (52.4%) ARPKD patients had malnutrition; 7 (33.3%) patients had growth retardation at presentation; and 4 (19%) patients had both malnutrition and growth retardation. At diagnosis, 8 (16.7%) of the ADPKD patients had malnutrition, and 5 (10.4%) patients had growth retardation. The malnutrition, growth retardation, and hypertension rates at diagnosis were higher in the ARPKD patients than the ADPKD patients (p = 0.002, p = 0.02, and p = 0.0001, respectively). ARPKD patients with malnutrition and growth retardation had worse renal survival compared to the patients without (p = 0.03 and p = 0.01). Similarly, ADPKD patients with malnutrition had worse renal survival compared to the patients without (p = 0.002). ARPKD patients with truncating variants had poorer 3- and 6-year renal outcome than those carrying non-truncating variants (p = 0.017). CONCLUSION: Based on renal survival analysis, type of genetic variant, growth retardation, and/or malnutrition at presentation were observed to be factors associated with progression to chronic kidney disease (CKD). Differentiation of ARPKD and ADPKD, and identification of the predictors of the development of CKD are vital for optimal management of patients with ARPKD or ADPKD.

The value of procalcitonin measurements in children with familial Mediterranean fever.

It is well known that the serum procalcitonin (PCT) levels increase in severe bacterial infections. However, there is little information about the levels of PCT in diverse diseases except mainly the infectious diseases. The aim of this study was to investigate the progress of serum levels of PCT together with traditional acute phase reactants in children with familial Mediterranean fever (FMF) during the attack and attack-free periods and to test whether PCT could help to diagnose the attack in FMF patients. The study group comprised 21 FMF patients (mean age 10 ± 4.6 years) and 19 healthy controls (mean age 10.6 ± 4.2 years). Serum levels of PCT and traditional acute phase reactants were measured during the attack and attack-free periods. Blood samples were obtained within the first 6-24 h of the attack period, 7 days later, and at least 2 months after the attack. Traditional acute phase reactants (hs-CRP, ESR, and fibrinogen) during the attack period were significantly higher than the attack-free levels and controls. PCT levels of the FMF patients during the attack period were also significantly higher than the attack-free and control group levels (median values, 0.044 ng/ml vs. 0.028 ng/ml and 0.031 ng/ml, P = 0.04, respectively). Although this difference was statistically significant (P = 0.04), median PCT values of the attack, attack-free period, and healthy subjects were lower than 0.05 ng/ml. As a result, these findings suggested that PCT levels were not conspicuously affected from inflammation and could not be used as a descriptive marker for attack in FMF patients.

Acute kidney injury in a paediatric intensive care unit: comparison of the pRIFLE and AKIN criteria.

AIM: The purpose of our study was to evaluate and analyse the prevalence and association of acute kidney injury (AKI) as defined by paediatric Risk, Injury, Failure, Loss of kidney function and End-stage kidney disease (pRIFLE) and Acute Kidney Injury Network (AKIN) classifications in a paediatric intensive care unit (PICU). METHODS: A prospective analysis of all patients that were admitted to our PICU between June 2009 and December 2010 was performed. Patients were classified according to AKIN and pRIFLE criteria. RESULTS: One hundred and eighty-nine patients (mean age 45.9 ± 54.7 months; 110 male, 79 female) were enrolled. Sixty-three (33.3%) patients developed AKI by AKIN criteria and 68 (35.9%) patients developed AKI by pRIFLE criteria. All patients that had AKI according to AKIN criteria also had this diagnosis with pRIFLE criteria. Five patients had developed AKI only according to pRIFLE classification, four of them owing to reduction in their estimated creatinine clearance and one of them owing to changes over 1-week period. The mean length of PICU stay was longer, need for mechanical ventilation and mortality rates were higher in patients with AKI when compared to patients without AKI. CONCLUSION: Although both pRIFLE and AKIN criteria were very helpful in the detection of patients with AKI even in the early stages of it, pRIFLE seems to be more sensitive in paediatric patients.

Evaluation and outcome of antenatal hydronephrosis: a prospective study.

Antenatal hydronephrosis (AHN), defined as dilatation of renal pelvis and/or calyces, is the most frequently detected antenatal abnormality. However, postnatal management of AHN is controversial. The purpose of this study was to describe the clinical outcomes of infants with AHN and to contribute to the definition of the postnatal evaluation of these patients. One hundred and thirty-six infants with AHN were prospectively followed up to 18 months. Patients were divided into two groups according to the degree of sonographic hydronephrosis (HN) on days 5-7: group I (n = 87, 64%) included patients who had grades 1 and 2 (64%) and group II (n = 49, 36%) included patients who had grade 3 and above HN. The grade of HN was found to be correlated with the increased risk of urologic pathologies. Frequency of vesicoureteral reflux was found to be significantly lower in patients with mild HN (6%) as compared to patients with severe AHN (29%) (p = 0.005). In addition, the risk of urinary tract infection increases with increasing grades of HN (10% vs. 29%, p = 0.006). The frequency of spontaneous resolution in patients with mild AHN (64%) was also significantly higher than in patients with severe HN (29%) (p < 0.001). The degree of AHN can be used for making decision about further diagnostic imaging and treatment. Our results strongly suggest that low-grade HN is a relatively self-limited condition and needs minimal investigation. In contrast, the outcome of more severe degrees of AHN needs clarification.

Familial Mediterranean fever in small children in Turkey.

OBJECTIVES: Familial Mediterranean fever (FMF) is an autosomal recessive disease, characterised by recurrent, self limited attacks of fever with serositis. The aim of our study was to describe the demographic, clinical and genetic features of FMF patients who had early disease onset and to compare them with late onset patients. Our second aim was to investigate the factors associated with delay in diagnosis. METHODS: The study group consisted of recently diagnosed FMF patients who came to routine follow-up visits between January and July 2009. Patients were divided into two groups according to age of disease onset (Group I: ≤ 3 years of age; Group II: >3 years of age). In the second part, patients were analysed according to the duration of delay in diagnosis. RESULTS: There were 83 patients in group I and 73 patients in Group II. Median delay in diagnosis was 4 years in Group I and 2 years in Group II (p<0.001). The presence of M694V mutation was more frequent in Group I (81%) as compared to Group II (65%), (p=0.034). Mean attack Hb was lower (p<0.01) and mean attack leukocyte count was higher (p=0.017) in Group I. Final colchicine dosages were higher in Group I as compared to Group II. There was a statistically significant negative correlation between the age at disease onset and period of delay in diagnosis (p<0.001). CONCLUSIONS: This study suggests that FMF patients with early disease onset have more severe disease. Moreover, the smaller the age of disease onset, the more likely their diagnoses are delayed.

Nutcracker syndrome manifesting with severe proteinuria: a challenging scenario in a single-kidney patient.

Nutcracker syndrome (NS) refers to compression of the left renal vein between the aorta and the superior mesenteric artery which results in left renal venous hypertension. The typical clinical presenting feature is hematuria. In this report we describe the case of patient with a single kidney who developed severe proteinuria due to NS. She was successfully treated with left renal vein transposition. This case clearly shows the relation between NS and severe proteinuria based on normal biopsy findings and the complete disappearance of proteinuria following surgery.