Z. Birsin Özçakar

Spectrum of Steroid-Resistant and Congenital Nephrotic Syndrome in Children: The PodoNet Registry Cohort

BACKGROUND AND OBJECTIVES Steroid-resistant nephrotic syndrome is a rare kidney disease involving either immune-mediated or genetic alterations of podocyte structure and function. The rare nature, heterogeneity, and slow evolution of the disorder are major obstacles to systematic genotype-phenotype, intervention, and outcome studies, hampering the development of evidence-based diagnostic and therapeutic concepts. To overcome these limitations, the PodoNet Consortium has created an international registry for congenital nephrotic syndrome and childhood-onset steroid-resistant nephrotic syndrome. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Since August of 2009, clinical, biochemical, genetic, and histopathologic information was collected both retrospectively and prospectively from 1655 patients with childhood-onset steroid-resistant nephrotic syndrome, congenital nephrotic syndrome, or persistent subnephrotic proteinuria of likely genetic origin at 67 centers in 21 countries through an online portal. RESULTS Steroid-resistant nephrotic syndrome manifested in the first 5 years of life in 64% of the patients. Congenital nephrotic syndrome accounted for 6% of all patients. Extrarenal abnormalities were reported in 17% of patients. The most common histopathologic diagnoses were FSGS (56%), minimal change nephropathy (21%), and mesangioproliferative GN (12%). Mutation screening was performed in 1174 patients, and a genetic disease cause was identified in 23.6% of the screened patients. Among 14 genes with reported mutations, abnormalities in NPHS2 (n=138), WT1 (n=48), and NPHS1 (n=41) were most commonly identified. The proportion of patients with a genetic disease cause decreased with increasing manifestation age: from 66% in congenital nephrotic syndrome to 15%-16% in schoolchildren and adolescents. Among various intensified immunosuppressive therapy protocols, calcineurin inhibitors and rituximab yielded consistently high response rates, with 40%-45% of patients achieving complete remission. Confirmation of a genetic diagnosis but not the histopathologic disease type was strongly predictive of intensified immunosuppressive therapy responsiveness. Post-transplant disease recurrence was noted in 25.8% of patients without compared with 4.5% (n=4) of patients with a genetic diagnosis. CONCLUSIONS The PodoNet cohort may serve as a source of reference for future clinical and genetic research in this rare but significant kidney disease.

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-IL-1 treatment in familial Mediterranean fever and related amyloidosis.

Colchicine is the standard treatment in familial Mediterranean fever (FMF) patients. New treatment strategies are needed in FMF patients who were unresponsive to colchicine therapy or who had developed amyloidosis. The aim of this study was to present clinical-laboratory features and treatment responses of pediatric FMF patients that were treated with anti-IL-1 therapies. Files of patients who had been followed in our department with diagnosis of FMF were retrospectively evaluated. Patients that have been receiving anti-IL-1 therapies (anakinra or canakinumab) were included to the study. All patients were interpreted with respect to the demographic data, clinical and laboratory features of the disease, genetic analysis of MEFV mutations and treatment responses. Among 330 currently registered FMF patients, 13 patients were included to the study. Seven of them received anti-IL-1 therapy due to colchicine resistance and 6 due to FMF-related amyloidosis (1 of them with nephrotic syndrome, 2 with chronic kidney disease, 3 with renal transplantation). In all treated patients, attacks completely disappeared or decreased in frequency; partial remission occured in nephrotic syndrome patient; and their life quality improved. Anti-IL-1 therapies can be successfully used in colchicine-resistant FMF patients and patients with amyloidosis during childhood and adolescent period without major side effects.

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.

Possible effect of subclinical inflammation on daily life in familial Mediterranean fever

This study was performed to investigate the attack-free complaints of patients with familial Mediterranean fever (FMF) and the impact of colchicine on these symptoms and on subclinical inflammation. A questionnaire that includes information about the disease course and symptoms during the attack-free period was administered to the parents of 50 FMF patients. For evaluation of the attack-free period, questions were asked about four items concerning daily activities of the children—weakness, lack of appetite, sleep problems, and decreased activity. The respondents rated the items and the total score was taken as the sum of all of the specific items. The laboratory values were noted from the patients’ files. During the attack-free period, patients with mild disease had higher total scores, higher weakness, and decreased activity scores than patients with moderate disease. When we compared the daily activity scores before and after colchicine therapy, a statistically significant increase was observed in the total scores and in all of the specific item scores. Also a significant decrease was seen in the erythrocyte sedimentation rate and white blood cell counts, and a significant increase was seen in the hemoglobin levels during the attack-free period after colchicine usage. Regression of inflammation together with improvement in daily activities were observed. FMF patients seem to have complaints during the attack-free period that may be related to subclinical inflammation. Moreover, colchicine besides preventing the FMF attacks and the dangerous complication ol amyloidosis also seems to hinder the symptoms of the attack-free period in children with FMF.

Hypertension induced reversible posterior leukoencephalopathy syndrome: a report of two cases.

Reversible posterior leukoencephalopathy syndrome (RPLS) is a recently described disorder with typical radiological findings of bilateral grey and white matter abnormalities in the posterior regions of the cerebral hemispheres. The majority of patients with RPLS are adults and it is rare in children. In this report, two patients with RPLS are presented. In the first patient the primary diagnosis was acute post-streptococcal glomerulonephritis, a known cause of RPLS both in adults and in children. The second patient had Henoch Schönlein purpura. Conclusion:These patients are presented to highlight the importance of reversible posterior leukoencephalopathy syndrome. As the spectrum of associated diseases is diverse, paediatricians must be aware of this syndrome in order to initiate appropriate management.

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).

Polyarteritis nodosa: successful diagnostic imaging utilizing pulsed and color Doppler ultrasonography and computed tomography angiography

The diagnosis of polyarteritis nodosa (PAN) is often delayed because patients present with diverse clinical symptoms, but with less disease-specific signs. However, early diagnosis and treatment of PAN is necessary to prevent serious organ damage. Herein, we present a boy in whom the diagnosis of classical PAN was established rapidly with ultrasound and computed tomography (CT) angiography. Moreover, complete disappearance of the aneurysms after one month of therapy was documented. This case is presented in order to underline the role of new imaging techniques in the diagnosis and follow-up of patients with PAN.

Infliximab therapy for familial Mediterranean fever-related amyloidosis: case series with long term follow-up

Familial Mediterranean fever (FMF) is an autosomal recessive disease characterized by recurrent self-limited attacks of fever and polyserositis. Reactive amyloid A amyloidosis is the most devastating complication of FMF, and amyloidosis continues to occur in the colchicine era in untreated and noncompliant patients. Unfortunately, there is no proven effective treatment for established amyloidosis. In this report, we present four FMF-related amyloidosis patients that were treated with long term infliximab therapy with the longest duration of follow-up, together with the literature review. Infliximab was very effective in controlling gastrointestinal system findings and protracted arthritis, and it also had a favorable impact on the clinical findings of nephrotic syndrome in these patients. In conclusion, by controlling debilitating complaints of amyloidosis with infliximab, quality of life increases in these patients, and they get rid of recurrent hospitalizations and return to school or work.

Global left-ventricular function by tissue Doppler imaging in pediatric dialysis patients

Cardiovascular abnormalities are observed in most children with end-stage renal disease (ESRD). The aim of this study was evaluation of left-ventricular (LV) myocardial performance using tissue-Doppler imaging (TDI) in patients with ESRD. Twenty-five patients with ESRD and 25 healthy gender- and age-matched control subjects were assessed with conventional M-mode echocardiography, pulsed-wave Doppler (PWD), and TDI. Myocardial Performance Index (MPI) and LV mass index (LVMI) were calculated. MPI and conventional echo-Doppler indices were compared in the ESRD and control groups. Significant differences were present in the mean systolic and diastolic blood pressure (BP) between children with ESRD and healthy children (p = 0.007 and p < 0.001, respectively). The mean LVMI was significantly greater in the patient group (p < 0.001). The tissue-Doppler MPI of patients was significantly higher than that in healthy children (p < 0.001). LVMI was significantly correlated with systolic and diastolic BP. MPI obtained by TDI was significantly correlated with LVMI. Our study confirms that LV dysfunction is present in patients with ESRD and hypertension is an important risk factor.