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.

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.

Evaluation of Renal Function in Obese Children and Adolescents Using Serum Cystatin C Levels, Estimated Glomerular Filtration Rate Formulae and Proteinuria: Which is most Useful?

Objective: There is a growing interest in the relationship between obesity and renal damage. The effect of obesity on renal function in children and adolescents has not been adequately investigated. In addition, there is no complete consensus on the reliability of various renal function parameters. The primary goal of this study was to evaluate renal function in obese children and adolescents using glomerular filtration rate (GFR), cystatin C, and creatinine (Cr)-derived formulas. We also compared classical GFR measurement methods with methods based on bioimpedance analysis-derived body cell mass (BCM). Methods: We enrolled 108 obese and 46 healthy subjects aged 6-18 years. Serum cystatin C, serum Cr, 24-hour proteinuria, Cr clearance, and GFR were evaluated in both groups. Estimated GFR was measured with Cr-based, cystatin C-based, combined (cystatin C and Cr) and BCM-based formulae. Both actual and fat-free mass body surface areas (BSA) were used when required. Metabolic parameters (blood glucose, insulin, and lipids) were analyzed in the obese subjects. International Diabetes Federation criteria were used to identify metabolic syndrome (MetS). Results: We did not detect statistically significant differences between the obese and control groups for mean Cr (p=0.658) and mean cystatin C (p=0.126). Mean cystatin C levels of MetS patients were significantly higher than those of non-MetS obese participants (p<0.001). Cr-based GFR measurements, BCM-based measurements and a combined Cr and cystatin C measurement showed a statistically significant increase in the GFR of obese subjects compared to controls (p=0.002 and p<0.001). This increase was negatively correlated with duration of obesity. Estimations based on actual or fat-free mass BSA did not differ either. Only the Filler equation showed a statistically significant decrease in eGFR in MetS patients. There were no statistically significant differences between the obese and control groups for proteinuria (p=0.994) and fat-free mass proteinuria (p=0.476). Conclusion: We conclude that cystatin C could be used as an earlier biomarker than Cr in the detection of impaired renal function in obese children, especially those with MetS. Cr-based formulae reveal hyperfiltration as the first change in renal function. Decreasing eGFR seen in MetS patients with cystatin C-based formulae, but not Cr-based formulae, may represent the early stages of renal damage. Using fat-free mass or BCM for eGFR formulae in obese children seems to provide no additional information.

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.

Response to Early Coenzyme Q10 Supplementation Is not Sustained in CoQ10 Deficiency Caused by CoQ2 Mutation.

BACKGROUND: COQ2 mutations cause a rare infantile multisystemic disease with heterogeneous clinical features. Promising results have been reported in response to Coenzyme Q10 treatment, especially for kidney involvement, but little is known about the long-term outcomes. METHODS: We report four new patients from two families with the c.437G→A (p.Ser146Asn) mutation in COQ2 and the outcomes of two patients after long-term coenzyme Q10 treatment. RESULTS: Index cases from two families presented with vomiting, nephrotic range proteinuria, and diabetes in early infancy. These patients were diagnosed with coenzyme Q10 deficiency and died shortly after diagnosis. Siblings of the index cases later presented with neonatal diabetes and proteinuria and were diagnosed at the first day of life. Coenzyme Q10 treatment was started immediately. The siblings responded dramatically to coenzyme Q10 treatment with normalized glucose and proteinuria levels, but they developed refractory focal clonic seizures beginning at three months of life that progressed to encephalopathy. CONCLUSIONS: In our cohort with CoQ10 deficiency, neurological involvement did not improve with oral coenzyme Q10 treatment despite the initial recovery from the diabetes and nephrotic syndrome.

Prevalence of Hypertension in Children with Early-Stage ADPKD.

BACKGROUND AND OBJECTIVES: Autosomal dominant polycystic kidney disease is the most common inheritable kidney disease, frequently thought to become symptomatic in adulthood. However, patients with autosomal dominant polycystic kidney disease may develop signs or symptoms during childhood, in particular hypertension. Although ambulatory BP monitoring is the preferred method to diagnose hypertension in pediatrics, data in children with autosomal dominant polycystic kidney disease are limited. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Our retrospective multicenter study was conducted to collect ambulatory BP monitoring recordings from patients with autosomal dominant polycystic kidney disease age <18 years old. Basic anthropometric parameters as well as data on kidney function, BP treatment, and kidney ultrasound were also collected. RESULTS: Data from 310 children with autosomal dominant polycystic kidney disease with a mean age of 11.5±4.1 years old were collected at 22 European centers. At the time when ambulatory BP monitoring was performed, 95% of children had normal kidney function. Reference data for ambulatory BP monitoring were available for 292 patients. The prevalence rates of children with hypertension and/or those who were treated with antihypertensive drugs were 31%, 42%, and 35% during daytime, nighttime, or the entire 24-hour cycle, respectively. In addition, 52% of participants lacked a physiologic nocturnal BP dipping, and 18% had isolated nocturnal hypertension. Logistic regression analysis showed a significant association between a categorical cyst score that was calculated on the basis of the number of cysts >1 cm per kidney and daytime hypertension (odds ratio, 1.70; 95% confidence interval, 1.21 to 2.4; P=0.002), nighttime hypertension (odds ratio, 1.31; 95% confidence interval, 1.05 to 1.63; P=0.02), or 24-hour hypertension (odds ratio, 1.39; 95% confidence interval, 1.08 to 1.81; P=0.01). Kidney length, expressed as SD score, was also significantly associated with nighttime hypertension (odds ratio, 1.23; 95% confidence interval, 1.06 to 1.42; P=0.10). CONCLUSIONS: These data indicate high prevalence of hypertension in children with autosomal dominant polycystic kidney disease starting at young ages.

Atypical Hemolytic Uremic Syndrome in Children Aged <2 Years.

BACKGROUND: There are limited data on infants with atypical hemolytic uremic syndrome (aHUS). The aim of this study was to determine the clinical and laboratory features, and to evaluate treatment modalities and outcomes in infants with aHUS. MATERIALS AND METHODS: Relevant data on patients with onset of aHUS at age <2 years were obtained from the Turkish Pediatric aHUS Registry. RESULTS: Among the 146 patients included in the Registry, 53 (36%) (23 male and 30 female) were enrolled for the study. Age at disease onset was ≤1 year in 29 of the patients. In all, 21 (40%) of the patients developed neurological symptoms. Disease-causing mutations were noted in 14 (36%) of the 39 patients in which genetic analysis was performed. Plasma therapy was performed in 42 (79%) patients; eculizumab therapy was administered to treat the first episode of aHUS in 33 (62%) patients and in 5 patients as the first- line therapy. In total, 38 (72%) patients received renal replacement therapy (RRT), 3 (6%) died due to acute illness, and 4 (8%) were discharged from hospital with RRT. Follow-up visit data were available for 46 patients and the median duration was 23 months (range 3-129 months). End-stage renal disease developed only in 1 patient. Proteinuria and hypertension persisted in 17 (37%) and 20 patients (44%) respectively. Eculizumab treatment was continued in 25 of the 39 patients during the follow-up period. CONCLUSION: One-third of the aHUS patients had disease onset during infancy. The prognosis of this life-threatening disease seems to get better with improved treatment modalities.

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.

Early Effects of Renal Replacement Therapy on Cardiovascular Comorbidity in Children With End-Stage Kidney Disease: Findings From the 4C-T Study.

BACKGROUND: The early impact of renal transplantation on subclinical cardiovascular measures in pediatric patients has not been widely investigated. This analysis is performed for pediatric patients participating in the prospective cardiovascular comorbidity in children with chronic kidney disease study and focuses on the early effects of renal replacement therapy (RRT) modality on cardiovascular comorbidity in patients receiving a preemptive transplant or started on dialysis. METHODS: We compared measures indicating subclinical cardiovascular organ damage (aortal pulse wave velocity, carotid intima media thickness, left ventricular mass index) and evaluated cardiovascular risk factors in 166 pediatric patients before and 6 to 18 months after start of RRT (n = 76 transplantation, n = 90 dialysis). RESULTS: RRT modality had a significant impact on the change in arterial structure and function: compared to dialysis treatment, transplantation was independently associated with decreases in pulse wave velocity (ß = -0.67; P < 0.001) and intima media thickness (ß = -0.40; P = 0.008). Independent of RRT modality, an increase in pulse wave velocity was associated with an increase in diastolic blood pressure (ß = 0.31; P < 0.001). Increasing intima media thickness was associated with a larger increase in body mass index (ß = 0.26; P = 0.003) and the use of antihypertensive agents after RRT (ß = 0.41; P = 0.007). Changes in left ventricular mass index were associated with changes in systolic blood pressure (ß = 1.47; P = 0.01). CONCLUSIONS: In comparison with initiating dialysis, preemptive transplantation prevented further deterioration of the subclinical vascular organ damage early after transplantation. Classic cardiovascular risk factors, such as hypertension and obesity are of major importance for the development of cardiovascular organ damage after renal transplantation.

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.

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.

Childhood polyarteritis nodosa: diagnosis with non-invasive imaging techniques.

There is limited number of publications about the use of non-invasive imaging modalities in the diagnosis of childhood polyarteritis nodosa (cPAN). The aim of this study was to present the clinical and imaging findings of the patients with cPAN who were diagnosed with non-invasive imaging techniques. Files of patients who had been diagnosed as cPAN in our department from 2005 to 2015 were reviewed, retrospectively. Demographic, clinical, laboratory, and imaging findings of the patients were evaluated. Nine patients (8M, 1F; age at disease onset: 12.5 years (7-16)) had been diagnosed as cPAN in our clinic with non-invasive imaging techniques within the last 10 years. Abdominal pain, fever, fatigue, and myalgia were the most frequent complaints. Doppler ultrasonography (US) was used in the diagnosis of seven patients and computed tomography (CT) angiography was done in four patients. Duration between admission to our center and diagnosis was median of 5 days (8 h-10 days), including four patients who were diagnosed within 24 h of admission. Approximately 80 % of our patients with cPAN had MEFV gene mutations and 90 % had elevated anti-streptolysin O levels. All of them had the involvement of the gastrointestinal tract. Hepatic and cystic arterial involvements were detected in seven and six patients, respectively. This report included the largest cPAN series that were diagnosed with non-invasive imaging modalities. We suggest that non-invasive modalities, especially Doppler US, should be considered in first line approach in the diagnosis of these patients, particularly in children.

Severe hyperphosphatemia after oral laxative administration in a 7-year-old patient.

Sodium phosphate based laxatives are commonly used for constipation and pre-procedural bowel cleansing. Phosphate intoxication related with these preparations is well recognized. Herein, we present a case of severe hyperphosphatemia and seizure in a 7-year-old male patient after administration of an oral sodium phosphate based laxative. At the time of admission, serum phosphorus level was 25.6 mg/dl. Aggressive fluid therapy was started. Although serum phosphorus level decreased to 20.9 mg/dl eight hours after admission, hemodialysis was performed because of the preexisting renal disease and declined glomerular filtration rate. Serum phosphorus level and blood gas analysis returned to normal after hemodialysis and the patient was discharged on hospital day two. In conclusion, sodium phosphate based laxatives should be used carefully in patients with preexisting renal diseases. Intravenous hydration and correction of hypocalcemia are important components of treatment. Hemodialysis is indicated in patients with renal failure.

First-Line, Early and Long-Term Eculizumab Therapy in Atypical Hemolytic Uremic Syndrome: A Case Series in Pediatric Patients.

INTRODUCTION: Studies relating to first-line, early, and long-term eculizumab treatment and outcomes in children with atypical hemolytic uremic syndrome (aHUS) are scarce and unclear. The aim of this case-series study was to evaluate the outcomes of first-line, early, and long-term eculizumab treatment in our aHUS patients. MATERIALS AND METHODS: We reviewed the data from four pediatric patients with aHUS who were treated with eculizumab. In three of them, eculizumab was used as a first-line therapy, and the follow-up period was ≥2 years in three patients. RESULTS: Plasma exchange could not be performed in any patient. Plasma infusions were used only in Patient 1 (a 14-month-old boy) for 8 days without any response. Therefore, eculizumab was started on day 11 after admission. Patient 2 (a 16-month-old boy), Patient 3 (an 11-year-old girl), and Patient 4 (a 32-month-old girl) were treated with eculizumab as a first-line therapy, which was started 2-4 days after admission. The dosage of eculizumab was adjusted according to body weight. The hematologic parameters (the time frames were 3-17 days) and C 3 (the time frames were 10-17 days) returned to normal in all patients after receipt of eculizumab. Although Patient 1 developed stage III chronic kidney disease, complete renal recovery occurred in Patients 2 and 4. Patient 3 also had reflux nephropathy with bilateral grade III vesicoureteral reflux and renal scars. Her creatinine clearance returned to the baseline value after receiving eculizumab. No complications related to eculizumab were observed in any patient during the follow-up period. CONCLUSION: Eculizumab can be successfully used as a first-line therapy in pediatric aHUS patients. We observed that the early initiation of eculizumab was associated with the complete recovery of renal function.

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.

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.

Late-onset disease is associated with a mild phenotype in children with familial Mediterranean fever.

Familial Mediterranean fever (FMF) is an autosomal recessive disease, characterised by recurrent, self-limited attacks of fever with serositis. Recently, it was shown that patients with early disease onset during childhood period had more severe disease. The aim of this study was to describe the demographic, clinical and genetic features of FMF patients who had late-onset disease during childhood period and to compare them to those with earlier onset patients. Files of patients who had been seen in our department between January 2013 and January 2014 were retrospectively evaluated. Patients were divided into two groups according to age of disease onset (group I, ≤8 years; group II, >8 years), and clinical findings were compared between the two groups. The study group comprised 317 FMF patients. There were 267 patients in group I and 50 patients in Group II. Median attack frequency was 24/year in group I and 12/year in group II (p < 0.05). Fever and M694V homozygosity were less frequently detected in group II (p = 0.003 and p = 0.022). Median delay in diagnosis was 24 months in group I and 12 months in group II (p = 0.002). Disease severity scores and final colchicine dosages were lower in group II (p < 0.001 and p = 0.003). Only a small number of FMF patients had disease onset at older ages in childhood period. It seems that FMF patients with late-onset disease have milder illness. However, more readily expression of their clinical findings in older ages yields earlier diagnosis in this group.