Kidney disease profile and encountered problems during follow-up in Syrian refugee children: a multicenter retrospective study.

BACKGROUND: Children are one of the most vulnerable groups in conflict zones, especially those with chronic diseases. This study aimed to investigate kidney disease profiles and problems during follow-up in a population of Syrian refugee children residing in Turkey. METHODS: Syrian refugee children aged between 0 and 18 years were included in the study. Demographic data, diagnosis, particular interventions due to nephrological problems, and problems encountered during follow-up were obtained from all participating pediatric nephrology centers. RESULTS: Data from 633 children from 22 pediatric nephrology centers were included. Mean age of the children was 94.8 ± 61.7 months and 375 were male (59%). 57.7% had parental consanguinity and 23.3% had a close relative(s) with kidney disease. The most common kidney diseases were congenital anomalies of the kidney and urinary tract (CAKUT) (31.0%), glomerular disease (19.9%), chronic kidney disease (CKD) (14.8%), and urolithiasis (10.7%). Frequent reasons for CAKUT were nonobstructive hydronephrosis (23.0%), vesico-ureteral reflux (18.4%), and neurogenic bladder (15.8%). The most common etiology of glomerular diseases was nephrotic syndrome (69%). Ninety-four children had CKD, and 58 children were on chronic dialysis. Six children had kidney transplantation. Surgical intervention was performed on 111 patients. The language barrier, lack of medical records, and frequent disruptions in periodic follow-ups were the main problems noted. CONCLUSIONS: CAKUT, glomerular disease, and CKD were highly prevalent in Syrian refugee children. Knowing the frequency of chronic diseases and the problems encountered in refugees would facilitate better treatment options and preventive measures.

Gastric duplication cyst in an infant with Finnish-type congenital nephrotic syndrome: concurrence or coincidence?

Congenital nephrotic syndrome (CNS) is a rare disorder characterized by massive proteinuria and marked edema manifesting in utero or during the first 3 months of life. CNS can be caused by congenital infections, allo-immune maternal disease or due to the genetic defects of podocyte proteins most commonly NPHS1. Here we present a case of Finnish-type congenital nephrotic syndrome along with feeding problems and abdominal distention which was diagnosed during follow-up as a gastric-duplication cyst with a novel mutation in the nephrin gene. CNS feeding problems are attributed mainly to primary disease but in literature there are case reports of patients with CNS and hypertrophic pyloric stenosis. NPHS1 is also expressed in the stomach tissue. Physicians should be aware of this rare extra-renal manifestation or coincidence of this rare disease.

Clinical characteristics of childhood acute tubulointerstitial nephritis.

BACKGROUND: Acute tubulointerstitial nephritis (ATIN) is a rare cause of acute kidney injury in children that can lead to chronic kidney disease. The aim of this study was to describe the presenting features, etiology, and clinical characteristics of childhood ATIN, and to evaluate treatment modalities and renal outcomes. METHODS: The study included 38 patients who had been diagnosed with ATIN, were younger than 18 years old, and were admitted for at least 6 months of follow up. RESULTS: The median age at diagnosis was 13.1 years (range 1.2-16.6 years). The female / male ratio was 1.37. The most common symptoms were abdominal pain (65.7%) and nausea / vomiting (55.2%). Twenty-three of the patients had a history of drug intake (60.5%), and the most active drugs in the etiology were non-steroidal anti-inflammatory drugs (56.5%). Eleven patients were given steroid therapy due to severe kidney involvement and rapid increases in serum creatinine values, and ten of those patients were drug-related ATIN cases. Other patients were given symptomatic treatment. Four patients needed several sessions of dialysis due to the severity of their acute renal failure. The follow-up creatinine and estimated glomerular filtration rate levels were not statistically different between the symptomatic and corticosteroid treated groups (P > 0.05). CONCLUSIONS: Although our study was unable to show the beneficial effect of corticosteroid therapy on the extent of renal recovery, the use of steroids may be preferable in severe nephritis because of the rapid recovery of estimated glomerular filtration rate with corticosteroid therapy.

COL4A3 mutation is an independent risk factor for poor prognosis in children with Alport syndrome.

BACKGROUND: Alport syndrome (AS) is an inherited glomerular disease caused by mutations in COL4A3, COL4A4, or COL4A5. Associations between clinical manifestations and genotype are not yet well defined. Our study aimed to define clinical and genetic characteristics, establish genotype-phenotype correlations, and determine prognosis of AS in children. METHODS: A total of 87 children with AS from 10 pediatric nephrology centers, whom had genetic analyses performed at the Hacettepe University Nephrogenetics Laboratory between February 2017 and February 2019, were included. Data regarding demographics, family history, clinical and laboratory characteristics, histopathological and genetic test results, treatments, and yearly follow-up results were retrospectively analyzed. RESULTS: Of 87 patients, 16% presented with nephrotic syndrome. In patients with nephrotic syndrome, kidney biopsy findings showed focal segmental glomerulosclerosis (FSGS) in 79%, and COL4A3 mutations were the leading genetic abnormality (50%). Twenty-four percent of all patients progressed to chronic kidney disease (CKD). The rate of progression to CKD and the decline in the glomerular filtration rate of the patients with COL4A3 mutation were higher than other mutation groups (p < 0.001 and p = 0.04, respectively). In kidney survival analysis, nephrotic syndrome presentation, histopathology of FSGS, COL4A3 mutations, and autosomal recessive inheritance were found as independent risk factors for earlier progression to CKD. Cyclosporin A treatment did not improve kidney survival. CONCLUSIONS: We emphasize that genetic testing is important for patients suspected as having AS. Furthermore, COL4A mutations should be considered in patients with FSGS and steroid-resistant nephrotic syndrome. This approach will shed light on the prognosis of patients and help with definitive diagnosis, preventing unnecessary and potentially harmful medications. Graphical abstract.

A case of Type 1 Dent disease presenting with isolated persistent proteinuria.

Dent disease is a rare X-linked recessive tubular disorder, characterized by the triad of low molecular-weight proteinuria, hypercalciuria, nephrocalcinosis and/or nephrolithiasis. It is caused by mutations in the CLCN5 gene or OCRL gene. Thirty to 80% of affected males develop end-stage kidney disease between the ages of 30 and 50 years. Some children were reported to present with isolated persistent proteinuria and a part of these patients were diagnosed as having focal segmental glomerulosclerosis with kidney biopsy. Although there is no specific treatment, treatment of proteinuria and hypercalciuria is thought to delay the progression of the disease. For this reason, awareness of the disease findings and early diagnosis are important. In this case report, we present a boy followed-up with isolated persistent proteinuria and then diagnosed as having Dent disease with mutation analysis that showed c.328_330delT (p.Phe110Trpfs27*) in the CLCN5 gene. The importance of researching low-molecular- weight proteinuria and considering Dent disease in the differential diagnosis of children presenting with isolated persistent proteinuria has been emphasized.

CD80 expression and infiltrating regulatory T cells in idiopathic nephrotic syndrome of childhood.

BACKGROUND: CD80 (also known as B7-1) is a co-stimulatory molecule that is expressed in biopsies and also excreted in urine in patients with minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS). CD80 is inhibited by the cytotoxic T-lymphocyte-associated-antigen 4 (CTLA4), which is mainly expressed on regulatory T cells (Tregs). Ineffective circulating Treg response is involved in the pathogenesis of nephrotic syndrome. In this study, we evaluated CD80 expression and infiltrating Tregs in children with MCD and FSGS. METHODS: Evaluation of CD80 expression and semi-quantitative evaluation of Tregs (FOXP3-positive CD4 T cells) were carried out in 31 kidney biopsies (12 MCD, 19 FSGS) with immunofluorescence and immunohistochemistry staining. RESULTS: All MCD sections were stained negative; whereas six out of 19 FSGS sections (all from steroid-resistant (SR) patients), including one from a Wilms' tumor 1 (WT1) mutation-positive FSGS patient, stained positive for anti-CD80 goat antibody, and negative for anti-CD80 rabbit antibody. FSGS biopsy specimens had significantly higher FOXP3-positive cells/mm2 compared with MCD and control samples (P < 0.001). Biopsy samples from SR-FSGS patients (n = 12) with positive CD80 staining (n = 6) had significantly less Tregs (FOXP3-positive CD4 T cells) compared with CD80 (-) biopsies (n = 6; P = 0.004). CONCLUSION: CD80 expression was not detected in the majority of the archival biopsy sections and the results were not consistent across the different antibodies. In the SR-FSGS sections, however, CD80-positive biopsies had decreased FOXP3-positive CD4 T cells, suggesting that a decreased anti-inflammatory milieu may be the cause of increased CD80 expression.

A retrospective analysis of children with Henoch-Schonlein purpura and re-evaluation of renal pathologies using Oxford classification.

BACKGROUND: Henoch-Schönlein purpura (HSP) is the most common vasculitis in childhood. The long-term prognosis is variable and depends on renal involvement. The aims of this study were to investigate the clinical and laboratory characteristics of our HSP patients, to identify the risk factors for the development of Henoch-Schönlein purpura nephritis (HSPN) and to assess the efficacy of the Oxford Classification system for predicting renal outcomes. METHODS: We performed a retrospective review of HSP patients who admitted to our center between 2001 and 2016, and were < 18 years on admission. RESULTS: A total of 1120 children with HSP were analyzed. Their mean age was 7.4 ± 3.4 years. At onset, purpura was present in all cases, arthritis/arthralgia in 42.4%, abdominal involvement in 39% and renal involvement in 37%. Risk factors for the development of nephritis were age ≥ 8 years, atypical distribution of purpura, ESR > 20 mm/h and abdominal pain. Renal biopsy was performed on 75 patients before immunosuppressive treatment. The mesangial score was strongly associated with proteinuria. Segmental glomerulosclerosis, tubular atrophy/interstitial fibrosis, and crescent formation of ≥ 50% were associated with reduced eGFR at the time of biopsy. A Kaplan-Meier plot showed that segmental glomerulosclerosis and tubular atrophy/interstitial fibrosis significantly predict poor renal outcome. CONCLUSION: The long-term morbidity of HSP is predominantly attributed to renal involvement. Patients with HSP, who have a high risk to develop nephritis, could be followed for longer periods of time. The Oxford classification is useful in predicting long-term outcomes of HSPN.

MEFV gene mutations in children with Henoch-Schönlein purpura and their correlations-do mutations matter?

OBJECTIVE: To explore the frequency of MEFV gene mutations in children with Henoch-Schönlein purpura who had no prior familial Mediterranean fever diagnosis and to evaluate the association of MEFV mutations with the clinical and laboratory features of Henoch-Schönlein purpura. METHODS: Data of 1120 patients diagnosed with Henoch-Schönlein purpura were reviewed retrospectively. The spectrum and degree of organ involvement and acute phase reactant levels were documented for each patient. Blood for MEFV gene mutation analysis was obtained either at the time of the Henoch-Schönlein purpura diagnosis or during follow-up visits. Pathological specimens of patients who underwent biopsy (renal/skin) were evaluated with special consideration for immunofluorescent examinations. RESULTS: Two hundred and thirty-eight (21.3%) patients were found to have one of the MEFV mutations in which exon 10 mutations were the most common (16.7%). Abdominal pain, joint involvement, scrotal involvement, and relapse were more frequent, and acute-phase reactant levels were significantly high in patients with MEFV mutations. More severe characteristics were observed in the presence of homozygous exon 10 mutations. There was no significant association between exon 2 variants and clinical course of Henoch-Schönlein purpura. Patients carrying MEFV mutations did not have significantly higher levels of IgA deposits in the biopsy materials. CONCLUSION: Henoch-Schönlein purpura in patients with homozygous exon 10 MEFV mutations seems to be more severe than that in patients carrying other mutations. In patients with exon 10 MEFV mutations, Henoch-Schönlein purpura might be considered as an associated presentation of familial Mediterranean fever rather than a separate clinical entity. Key points • p.M694V mutation is more common in Henoch-Schönlein purpura than in the general population. • p.E148Q variants have no impact on clinical symptoms and laboratory findings in Henoch-Schönlein purpura patients. • The majority of Henoch-Schönlein purpura patients with familial Mediterranean fever have no IgA deposits. • Henoch-Schönlein purpura in familial Mediterranean fever patients may be considered as an integral clinical feature of familial Mediterranean fever.

Value of renal pelvic diameter and urinary tract dilation classification in the prediction of urinary tract anomaly.

BACKGROUND: The aim of this study was to identify the cut-offs of postnatal anteroposterior renal pelvic diameter (APRPD), according to the urinary tract dilation (UTD) classification system, to identify the predictors of final diagnosis of UTD and the need for surgery. METHODS: A total of 260 infants (336 renal units) with prenatally detected UTD were prospectively evaluated on serial ultrasonography by the same radiologist. Additional voiding cystourethrography and scintigraphy was done according to the clinical algorithm. RESULTS: Prenatal and postnatal APRPD in patients with transient dilation were significantly lower than in those with urinary tract anomalies (UTA). On follow up, the slope of decrease in APRPD was significantly higher in transient dilation compared with UTA. APRPD 10 mm at first-month ultrasonography, predicted UTA with a sensitivity of 83.1%, and specificity of 71.1%. On multivariate analysis the likelihood of surgical intervention and final diagnosis were predicted independently by the UTD system risk group. CONCLUSIONS: Careful ultrasonography evaluation can avoid unnecessary testing in patients with transient or clinically insignificant dilation. The UTD classification system is valid for evaluation of postnatal hydronephrosis and is reliable in predicting the need for surgical intervention.

Retrospective analysis of simple and stage II renal cysts: Pediatric nephrology point of view.

BACKGROUND: Increased ultrasonography (US) use has been correlated with an increased incidence of pediatric renal cysts. For simple and stage II cysts, the malignancy risk is low in adulthood, no follow up is recommended; but there is no consensus on childhood management. Given that pediatric renal cysts may be manifestations of hereditary cystic diseases, a different approach and follow up should be taken for these patients. Herein we present the clinical characteristics and follow-up data of pediatric patients with simple and stage II renal cysts. METHODS: This cross-sectional study involved 57 children (mean age, 12.44 ± 3.65 years) with simple (n = 35) and stage II cysts (n = 22) who were diagnosed and followed at the present institution for ≥2 years. RESULTS: The median follow-up period was 2.84 years for simple and 3.10 years for stage II cysts. None of the patients developed complications. No change in cyst diameter was detected in 65.7% of simple or in 45.5% of stage II cysts, whereas 13 simple cysts (37.1%) and eight stage II cysts (36.4%) increased in diameter. The diameter change per year was significantly higher in the stage II cysts than in the simple cysts (P = 0.017). Overall, 13 patients (22%) had an estimated glomerular filtration rate <90 mL/min/1.73 m2 , and two patients had hypertension. CONCLUSION: Although the malignancy risk of simple and stage II kidney cysts is low for this age group, potential complications such as renal dysfunction, hypertension and hereditary cystic disease should be closely monitored.

Canakinumab treatment in children with familial Mediterranean fever: report from a single center.

Familial Mediterranean fever (FMF), the most common hereditary autoinflammatory disorder is characterized by recurrent episodes of fever, serositis, arthritis. The major long-term result is amyloidosis. Colchicine remains the principle of the treatment; it not only prevents the acute attacks but also prevents the long-term complications such as amyloidosis; 5-10% of the patients are unresponsive to treatment. Recently new therapeutic options as anti-interleukin 1 agents are successfully used for the patients who do not respond to colchicine treatment. In this study, we retrospectively evaluated 11 pediatric colchicine-resistant FMF patients who were treated with canakinumab. Three of the patients had amyloidosis and two had uveitis. Based on our results, we suggest that canakinumab may be a safe and effective therapy in patients who are resistant to colchicine and even in the patients with amyloidosis. We also suggest that canakinumab might be a safe option for the patients with uveitis.

Evaluation of the level of dynamic thiol/disulphide homeostasis in adolescent patients with newly diagnosed primary hypertension.

BACKGROUND: Thiol/disulphide homeostasis plays a critical role in numerous intracellular enzymatic pathways including antioxidant defense and detoxification. This study was designed to investigate the impact of thiol/disulfide homeostasis in adolescent patients with recently diagnosed primary hypertension (HT) using a novel and automated method. METHODS: Native thiol/disulphide levels were measured by a novel spectrophotometric method (Cobasc 501, Roche Diagnostics, Mannheim, Germany) in 30 patients with primary HT together with 30 healthy controls. RESULTS: The levels of native thiol, total thiol, and native thiol/total thiol ratios were significantly lower, while the disulphide level, disulphide/native thiol, and disulphide/total thiol ratios were significantly higher in patients with primary HT compared with the control group. There were significant positive correlations between 24-h mean systolic and diastolic blood pressure and disulphide levels, disulphide/native thiol, and disulphide/total thiol ratios. A multiple linear regression model showed that a disulphide/native thiol ratio above 5 and family history of HT are independent predictors of HT. CONCLUSIONS: Our study showed that dynamic thiol/disulphide homeostasis shifted towards disulphide formation in adolescent patients with primary HT. Understanding the role of thiol/disulfide homeostasis in primary HT might provide new therapeutic intervention strategies for patients.

Publisher Correction: Evaluation of the level of dynamic thiol/disulphide homeostasis in adolescent patients with newly diagnosed primary hypertension.

Owing to an error in typesetting, the name of the author Atilla Halil Elhan was rendered wrongly. The original publication has now been corrected in this respect.

Type I IFN-related NETosis in ataxia telangiectasia and Artemis deficiency.

BACKGROUND: Pathological inflammatory syndromes of unknown etiology are commonly observed in ataxia telangiectasia (AT) and Artemis deficiency. Similar inflammatory manifestations also exist in patients with STING-associated vasculopathy in infancy (SAVI). OBJECTIVE: We sought to test the hypothesis that the inflammation-associated manifestations observed in patients with AT and Artemis deficiency stem from increased type I IFN signature leading to neutrophil-mediated pathological damage. METHODS: Cytokine/protein signatures were determined by ELISA, cytometric bead array, or quantitative PCR. Stat1 phosphorylation levels were determined by flow cytometry. DNA species accumulating in the cytosol of patients' cells were quantified microscopically and flow cytometrically. Propensity of isolated polymorhonuclear granulocytes to form neutrophil extracellular traps (NETs) was determined using fluorescence microscopy and picogreen assay. Neutrophil reactive oxygen species levels and mitochondrial stress were assayed using fluorogenic probes, microscopy, and flow cytometry. RESULTS: Type I and III IFN signatures were elevated in plasma and peripheral blood cells of patients with AT, Artemis deficiency, and SAVI. Chronic IFN production stemmed from the accumulation of DNA in the cytoplasm of AT and Artemis-deficient cells. Neutrophils isolated from patients spontaneously produced NETs and displayed indicators of oxidative and mitochondrial stress, supportive of their NETotic tendencies. A similar phenomenon was also observed in neutrophils from healthy controls exposed to patient plasma samples or exogeneous IFN-α. CONCLUSIONS: Type I IFN-mediated neutrophil activation and NET formation may contribute to inflammatory manifestations observed in patients with AT, Artemis deficiency, and SAVI. Thus, neutrophils represent a promising target to manage inflammatory syndromes in diseases with active type I IFN signature.

Molecular analysis of the AGXT gene in patients suspected with hyperoxaluria type 1 and three novel mutations from Turkey.

Primary hyperoxaluria type 1 (PH1) is a rare, autosomal recessive disease, caused by the defect of AGXT gene encoding hepatic peroxisomal alanine glyoxylateaminotransferase (AGT). This enzyme is responsible for the conversion of glyoxylate to glycine. The diagnosis of PH1 should be suspected in infants and children with nephrocalcinosis or nephrolithiasis. Early diagnosis and treatment is crucial in preventing disease progression to end stage kidney disease (ESKD). In this study, AGXT gene sequence analyses were performed in 82 patients who were clinically suspected (hyperoxaluria and nephrolithiasis or nephrocalcinosis with or without renal impairment) to have PH1. Disease causing mutations have been found in fifteen patients from thirteen families (18%). Novel mutations have been found (c.458T>A (p.L153X), c.733_734delAA (p.Lys245Valfs*11), c.52 C>T (p.L18F)) in three of 13 families. There were 3-year lag time between initial symptoms and the time of PH1 is suspected; additionally, 5.5-year lag time between initial symptoms and definitive diagnosis. Consanguinity was detected in 77% of the patients with mutation. After genetic diagnosis, one patient received combined kidney and liver transplantation. AGXT gene sequencing is now the choice of diagnosis of PH1 due to its non-invasive nature compared to liver enzyme assay. Early diagnosis and accurate treatment in PH1 is important for better patient outcomes.

Genetic and clinical features of cryopyrin-associated periodic syndromes in Turkish children.

OBJECTIVES: The aim of this study was to present the genetic and clinical data of the largest cohort of Turkish cryopyrin-associated periodic syndromes (CAPS) patients. METHODS: This is a two-centre descriptive study of Turkish children with clinical diagnosis of CAPS. NLRP3 analyses were performed by Sanger sequencing and by massively parallel sequencing. ASC dependent NF-κB activation and transfection-induced THP-1 cell death assays determined the functional consequences of the detected variants. Disease activity and response to anti interleukin 1 (anti-IL-1) treatment was also assessed. RESULTS: Heterozygous germline NLRP3 mutation was detected in 8 of 14 enrolled patients (57.1%). Two novel somatic mutations Y560H and G307D were found which induced both THP-1 cell death and ASC dependent NF-kB activation. With anti-IL-1 treatment the disease activity was improved in all patients except one. Except two patients with macrophage activation syndrome (MAS) attack, there were no serious adverse events requiring hospitalisation. CONCLUSIONS: CAPS should be considered in all patients with typical symptoms even if Sanger-based genetic analysis is negative, since a considerable number of patients have mosaicism. Treatment should be patient-tailored and MAS should be considered as a rare complication.

Failure to thrive, interstitial lung disease, and progressive digital necrosis with onset in infancy.

Key teaching points • SAVI is a recently described interferonopathy resulting from constitutive action of STING and up-regulation of IFN-ß signaling. • SAVI is characterized by facial erythema with telangiectasia, acral/cold-sensitive tissue ulceration and amputations, and interstitial lung disease. It has overlapping features with Aicardi-Goutières syndrome and familial chilblain lupus. • Traditional immunosuppressive medications and biologic therapies appear to be of limited benefit, but JAK inhibitors may impact disease progression.

Treatment of colchicine-resistant Familial Mediterranean fever in children and adolescents.

Familial Mediterranean fever (FMF) is the most common autoinflammatory disease worldwide. Approximately 5-10 % of patients are unresponsive to colchicine. Aim of this study was to determine the short- and long-term efficacy and safety of anti-interleukin 1 (anti-IL1) and anti-tumor necrosis factor agents in colchicine-resistant FMF cases in Turkish children and adolescents. This is a single-center retrospective case series of colchicine-resistant FMF patients. The included patients were treated with biologics for either colchicine resistance or because of one of the following: (1) amyloidosis, (2) recurrent prolonged febrile myalgia and frequent need of steroid and (3) persistent arthritis. Colchicine resistance was defined as at least one attack per month for three consecutive months and elevated erythrocyte sedimentation rate or C-reactive protein or serum amyloid A in-between attacks despite taking adequate dose of colchicine. Response to biologicals was evaluated by the Autoinflammatory Diseases Activity Index (AIDAI) score sheet, patients/parents'/physicians' global assessment of disease severity and laboratory parameters every 3-6 months. Fourteen patients were included in the study. Three patients were treated with etanercept for median 7 months (range 3-11 months), and all patients had to be switched to anti-IL1 treatment because of adverse effects and/or partial response. Eleven patients were treated with anakinra with a median duration of 8 months (4-60 months). Nine patients responded to treatment at the third month, but four of them switched to canakinumab because of noncompliance, local side effects and active arthritis. Nine patients were treated with canakinumab, all responded. At follow-up, in two patients the dose had to be increased, and on the other hand, in three patients the interval was increased to every 12-16 weeks. In three patients, anti-IL1 treatment could be stopped and they are fine with colchicine. This case series describes the largest cohort of colchicine-resistant FMF patients in childhood and adolescence. Anti-IL1 treatment is a safe and effective therapy to control inflammation. The treatment should be modified and decided for each patient on an individual basis.