Urine soluble TLR4 levels may contribute to predict urinary tract infection in children: the UTILISE Study.

BACKGROUND: One of the most common bacterial infections in childhood is urinary tract infection (UTI). Toll-like receptors (TLRs) contribute to immune response against UTI recognizing specific pathogenic agents. Our aim was to determine whether soluble TLR4 (sTLR4), soluble TLR5 (sTLR5) and interleukin 8 (IL-8) can be used as biomarkers to diagnose UTI. We also aimed to reveal the relationship between urine Heat Shock Protein 70 (uHSP70) and those biomarkers investigated in this study. METHODS: A total of 802 children from 37 centers participated in the study. The participants (n = 282) who did not meet the inclusion criteria were excluded from the study. The remaining 520 children, including 191 patients with UTI, 178 patients with non-UTI infections, 50 children with contaminated urine samples, 26 participants with asymptomatic bacteriuria and 75 healthy controls were included in the study. Urine and serum levels of sTLR4, sTLR5 and IL-8 were measured at presentation in all patients and after antibiotic treatment in patients with UTI. RESULTS: Urine sTLR4 was higher in the UTI group than in the other groups. UTI may be predicted using 1.28 ng/mL as cut-off for urine sTLR4 with 68% sensitivity and 65% specificity (AUC = 0.682). In the UTI group, urine sTLR4 levels were significantly higher in pyelonephritis than in cystitis (p < 0.0001). Post-treatment urine sTLR4 levels in the UTI group were significantly lower than pre-treatment values (p < 0.0001). CONCLUSIONS: Urine sTLR4 may be used as a useful biomarker in predicting UTI and subsequent pyelonephritis in children with UTI. A higher resolution version of the Graphical abstract is available as Supplementary information.

Characteristics and predictors of chronic kidney disease in children with myelomeningocele: a nationwide cohort study.

BACKGROUND: Myelomeningocele (MMC) is highly prevalent in developing countries, and MMC-related neurogenic bladder is an important cause of childhood chronic kidney disease (CKD). This nationwide study aimed to evaluate demographic and clinical features of pediatric patients with MMC in Turkey and risk factors associated with CKD stage 5. METHODS: Data from children aged 0-19 years old, living with MMC in 2022, were retrospectively collected from 27 pediatric nephrology centers. Patients > 1 year of age without pre-existing kidney abnormalities were divided into five groups according to eGFR; CKD stages 1-5. Patients on dialysis, kidney transplant recipients, and those with eGFR < 15 ml/min/1.73 m2 but not on kidney replacement therapy at time of study constituted the CKD stage 5 group. RESULTS: A total of 911 (57.8% female) patients were enrolled, most of whom were expectantly managed. Stages 1-4 CKD were found in 34.3%, 4.2%, 4.1%, and 2.4%, respectively. CKD stage 5 was observed in 5.3% of patients at median 13 years old (range 2-18 years). Current age, age at first abnormal DMSA scan, moderate-to-severe trabeculated bladder on US and/or VCUG, and VUR history were independent risk factors for development of CKD stage 5 (OR 0.752; 95%; CI 0.658-0.859; p < 0.001; OR 1.187; 95% CI 1.031-1.367; p = 0.017; OR 10.031; 95% CI 2.210-45.544; p = 0.003; OR 2.722; 95% CI 1.215-6.102; p = 0.015, respectively). Only eight CKD stage 5 patients underwent surgery related to a hostile bladder between 1 and 15 years old. CONCLUSION: MMC-related CKD is common in childhood in Turkey. A proactive approach to neurogenic bladder management and early protective surgery in selected cases where conservative treatment has failed should be implemented to prevent progressive kidney failure in the pediatric MMC population in our country.

Treatment of BK Polyomavirus-Associated Nephropathy in Paediatric Kidney Transplant Recipients: Leflunomide Versus Cidofovir.

OBJECTIVES: BK polyomavirus-associated nephropathy is a clinicopathological entity that negatively affects graft function in kidney transplant recipients. We compared the efficacy of leflunomide and cidofovir to treat BK polyomavirus-associated nephropathy in pediatric kidney transplant recipients. MATERIALS AND METHODS: Medical records of pediatric recipients with BK viremia for the period 2004 through 2019 were reviewed retrospectively, and patients diagnosed with BK polyomavirusassociated nephro-pathy were included in the study. A serum BK virus level above 104 copies/mL was accepted as BK viremia. We defined BK polyomavirusassociated nephropathy as detection of BK virus SV40 antigen on immunochemistry staining of renal graft tissue accompanied by signs of tubulointerstitial nephritis or elevated serum creatinine in addition to BK viremia. RESULTS: Of 304 kidney transplant recipients, 53 had persistent BK viremia; 36 of these patients (61.1% male) were included in the study with the diagnosis of BK polyomavirus-associated nephropathy. Twelve patients (33.3%) received cidofovir, and 14 (38.8%) received leflunomide. Results were similar between the cidofovir and leflunomide groups for serum creatinine level at last follow-up (0.91 ± 0.29 vs 0.94 ± 0.37 mg/dL, respectively; P = .843) and graft failure rate (8.3% vs 14.2%, respectively; P = .632). Graft failure was observed in 8.3% of patients with BK polyomavirus-associated nephropathy. CONCLUSIONS: Leflunomide and cidofovir showed similar efficacy for treatment of BK polyomavirus-associated nephropathy.

Comparison of EULAR/PRINTO/PReS Ankara 2008 and 2022 ACR/EULAR Classification Criteria for Granulomatosis with Polyangiitis in Children.

OBJECTIVE: Granulomatosis with polyangiitis (GPA) is an antineutrophil cytoplasmic antibody-associated vasculitis. The 2022 American College of Rheumatology/European Alliance of Associations for Rheumatology (ACR/EULAR)-endorsed classification criteria for GPA was derived using data only from adult patients. We aimed to assess the performance of the ACR/EULAR classification criteria for GPA in pediatric patients and compare it with the EULAR/Pediatric Rheumatology International Trials Organization (PRINTO)/Pediatric Rheumatology European Society (PReS)-endorsed Ankara 2008 criteria for GPA. METHODS: Retrospective data of pediatric patients with GPA in 20 centers from 9 countries were evaluated. The diagnosis of GPA was made according to the expert opinion. The sensitivity, specificity, positive predictive value, and negative predictive value of the criteria sets were evaluated. RESULTS: The study included 77 patients with GPA and 108 controls (immunoglobulin A vasculitis (n = 44), Takayasu's arteritis (n = 20), microscopic polyangiitis (n = 16), polyarteritis nodosa (n = 14), Behçet's disease (n = 12), eosinophilic granulomatosis with polyangiitis (n = 1), and Cogan's syndrome (n = 1)) with a median age of 17.8 and 15.2 years, respectively. Of patients with GPA, constitutional symptoms (85.7%) and ear-nose-throat involvement (79.2%) were the most common presentations. In the GPA group, 73 patients fulfilled the Ankara 2008 criteria and 69 the ACR/EULAR classification criteria. Sensitivities of the Ankara 2008 criteria and the ACR/EULAR classification criteria were 94.8% and 89.6%, while specificities were 95.3% and 96.3%, respectively. No significant difference was found between sensitivities and specificities of both classification criteria (p= 0.229 and p= 0.733, respectively). CONCLUSION: In children, both the ACR/EULAR and EULAR/PRINTO/PReS Ankara 2008 classification criteria for GPA perform well and similarly.

Clinical features of children with chronic non-bacterial osteomyelitis: A multicenter retrospective case series from Turkey.

OBJECTIVES: This study aims to evaluate demographic, clinical, and radiological characteristics of Turkish children with chronic non-bacterial osteomyelitis. PATIENTS AND METHODS: Between January 2008 and December 2018, a total of 28 patients (10 males, 18 females; median age: 12.5 years; range, 4.5 to 21 years) who were diagnosed with chronic non-bacterial osteomyelitis in three pediatric rheumatology centers were retrospectively analyzed. The demographic, clinical, and laboratory findings of the patients were recorded. RESULTS: The median age at the time of diagnosis was 10.2 years. The median time from symptom onset to diagnosis was 6.5 months. The median follow-up was 18.5 months. The most frequent symptom at onset was arthralgia (75.0%). The most frequently involved bone was the femur (67.9%). Eight (63.6%) of 12 patients had at least one Mediterranean fever gene (MEFV) mutation, indicating a significantly higher prevalence than the Turkish population (14.8%). Five of these patients fulfilled the diagnostic criteria for familial Mediterranean fever (FMF). All patients received non-steroidal anti-inflammatory drugs. Other drugs were methotrexate (46.4%), sulfasalazine (39%), corticosteroids (25%), anti-tumor necrosis factor (anti-TNF) agents (32%), pamidronate (25%), and colchicine (21.4%). Six of eight patients with MEFV mutations were administered with colchicine, and all of them responded to treatment. CONCLUSION: Clinical evolution and imaging investigations should be carefully performed to prevent any delay in the diagnosis of patients with chronic non-bacterial osteomyelitis. Based on our study results, FMF coexistence is worth investigating in patients with chronic non-bacterial osteomyelitis, particularly in the Turkish population.

Predictors of poor kidney outcome in children with C3 glomerulopathy.

BACKGROUND: C3 glomerulopathy (C3G) is characterized by heterogeneous clinical presentation, outcome, and predominant C3 accumulation in glomeruli without significant IgG. There is scarce outcome data regarding childhood C3G. We describe clinical and pathological features, treatment and outcomes, and risk factors for progression to chronic kidney disease stage 5 (CKD5) in the largest pediatric series with biopsy-proven C3G. METHODS: Sixty pediatric patients with C3G from 21 referral centers in Turkey were included in this retrospective study. Patients were categorized according to CKD stage at last visit as CKD5 or non-CKD5. Demographic data, clinicopathologic findings, treatment, and outcome data were compared and possible risk factors for CKD5 progression determined using Cox proportional hazards model. RESULTS: Mean age at diagnosis was 10.6 ± 3.0 years and follow-up time 48.3 ± 36.3 months. Almost half the patients had gross hematuria and hypertension at diagnosis. Nephritic-nephrotic syndrome was the commonest presenting feature (41.6%) and 1/5 of patients presented with nephrotic syndrome. Membranoproliferative glomerulonephritis was the leading injury pattern, while 40 patients had only C3 staining. Patients with DDD had significantly lower baseline serum albumin compared with C3GN. Eighteen patients received eculizumab. Clinical remission was achieved in 68.3%. At last follow-up, 10 patients (16.6%) developed CKD5: they had lower baseline eGFR and albumin and higher frequency of nephrotic syndrome and dialysis requirement than non-CKD5 patients. Lower serum albumin and eGFR at diagnosis were independent predictors for CKD5 development. CONCLUSIONS: Children with C3G who have impaired kidney function and hypoalbuminemia at diagnosis should be carefully monitored for risk of progression to CKD5. Graphical abstract.

Clinical and histopathological prognostic factors affecting the renal outcomes in childhood ANCA-associated vasculitis.

OBJECTIVE: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are very rare in childhood with an increased risk of morbidity and mortality. We aimed to evaluate renal prognostic factors in childhood AAV from the perspective of ANCA serotype, histopathological classification, and five-factor score (FFS). METHODS: Pediatric AAV patients from 11 referral centers in Turkey had been included to the study. The demographics, clinical findings, AAV subtypes, outcomes, and FFS were evaluated retrospectively. Kidney biopsies were classified histopathologically. RESULTS: Totally, 39 patients were enrolled in the study. Among all patients, 74.4% had renal involvement, 56.4% ear-throat-nose involvement, and 51.3% had musculoskeletal involvement. Proteinase 3 (PR3)-ANCA was positive in 48.7%, and myeloperoxidase (MPO)-ANCA was positive in 30.8%. 69.2% of patients had impaired renal function, and 28.2% had progressed to end-stage renal disease (ESRD) during the follow-up. At the time of diagnosis, FFS was ≥ 2 in 53.8%. The most common histopathologic classifications were as follows: crescentic type in 40.7% and sclerotic type in 25.9%. Gastrointestinal and renal involvement, MPO-ANCA positivity, serum creatinine levels, and impaired renal function during the follow-up were significantly higher in patients with FFS ≥ 2, compared to patients with FFS < 2. Patients with FFS ≥ 2 had more common crescentic, mixed and sclerotic histopathologic findings in biopsies. By logistic regression analysis forward method, the strongest single-risk factor among all the parameters was the initial level of creatinine in patients with ESRD, compared to the other patients (p = 0,007). CONCLUSIONS: Evaluation of the FFS, ANCA serology, and the creatinine levels may help to predict renal prognosis.

Delayed diagnosis of primary vesicoureteral reflux in children with recurrent urinary tract infections: Diagnostic approach and renal outcomes.

OBJECTIVE: In this study, we aimed to assess renal outcomes of delayed diagnosis of dilating primary vesicoureteral reflux (VUR) following recurrent febrile urinary tract infections (fUTIs) and its diagnostic imaging procedures. MATERIAL AND METHODS: The medical records of patients who underwent ultrasonography (US), non- acute dimercaptosuccinic acid (Tc-99mDMSA) scintigraphy and voiding cystourethrography (VCUG), and who were older than 2 years at the time of VUR diagnosis were retrospectively reviewed. RESULTS: A total of 32 children (female, n=27: 84.4%) with a mean age of 7.67±3.34 years at the time of diagnosis of VUR were included in the study. Grade III, IV, V VUR were found in 22%, 69%, and 9% of the patients, respectively. At the time of VUR diagnosis, abnormal US findings were detected in 75% of the cases. Tc-99mDMSA detected abnormalities in 83.9% (7 with a single scar, 7 with multiple lesions, 12 with reduced kidney function) of the patients. Estimated glomerular filtration rate of 3 patients with bilateral grade IV VUR was <75 mL/min/1.73 m2. In 5 patients (16%), VUR could not be predicted by US+DMSA scintigraphy (Grade IV VUR in 3 and Grade III in 2 cases ). The sensitivity in predicting VUR was 75.00% (95% CI: 56.60-88.54) and 83.87% (95% CI: 66.27-94.55), respectively, for US alone and combined US+DMSA. CONCLUSION: VCUG should be performed routinely in addition to US and non-acute DMSA in all children referred with recurrent fUTIs. Awareness of childhood UTI in public and healthcare personnels should be increased in order to refer these patients at a early stage to pediatric urology and nephrology units.

Eosinophilic tubulointerstitial nephritis on treatment with isotretinoin.

Drug-related acute tubulointerstitial nephritis is one of the most common causes of childhood acute renal failures which originate from kidneys. Sixteen-year old male patient with the history of isotretinoin use for the last 3 months was admitted with acute renal failure. Renal function parameters were measured as follows: blood urea nitrogen 21 mg/dL, serum creatinine 1.68 mg/dL, cystatin C 1.15 mg/L, and estimated glomerular filtration rate based on cystatin C 56.5 mL/min/1.73 m2. The patient whom pathological signs of renal biopsy sections revealed interstitial mononuclear cell and eosinophilic infiltration was diagnosed with acute tubulointerstitial nephritis. CONCLUSION: Isotretinoin is a vitamin A-derived agent which is commonly used in the treatment of acne and may cause drug-related acute tubulointerstitial nephritis. What is Known: •Drug-related acute tubulointerstitial nephritis (ATIN) is one of the most common causes of childhood acute renal failures. What is New: •Isotretinoin may cause drug-related acute tubulointerstitial nephritis.

Epstein-Barr virus infection in children with renal transplantation: 17 years experience at a single center.

OBJECTIVES: The aim of this study was to detect the frequency, time of occurrence, management and outcome of Epstein-Barr virus (EBV) infection and related complications in pediatric renal transplant recipients. METHODS: Pediatric renal allograft recipients transplanted between August 1994 and December 2011 at our hospital was evaluated retrospectively. The patients were divided into two groups; Groups 1 and 2 were composed of patients transplanted before and after November 2007, respectively, when plasma EBV DNA levels were periodically measured. RESULTS: The study included 166 children, 89 (53.6%) boys, with a mean age of 12.2 ± 3.8 years. Prior to transplantation, 144 patients (86.7%) were EBV seropositive. Within a median follow-up period of 36 months, 11 of 22 seronegative children (50%) developed primary EBV infection. EBV reactivation was observed in 23 of 144 children (15.9%). Two patients with primary infection developed post-transplant lymphoproliferative disorder, one of whom died. Elevated serum creatinine levels or graft loss were not observed in any patient with EBV reactivation. CONCLUSIONS: EBV DNA monitoring by PCR in high-risk pediatric renal transplant recipients will provide early diagnosis and treatment of EBV infections.

Hyperuricemia in pediatric renal transplant recipients.

OBJECTIVES: We sought to evaluate the prevalence and confounding clinical variables of hyperuricemia in pediatric kidney transplant patients. MATERIALS AND METHODS: We retrospectively evaluated the medical records of 151 pediatric renal transplant recipients who received their grafts at Akdeniz University Medical Faculty in Antalya, Turkey, with a follow-up longer than 6 months. This retrospective, single-center study included 117 pediatric renal transplant recipients, after we had excluded the patients with changes in immunosuppressive treatment and graft loss, who were receiving therapy with allopurinol and furosemide. Patient information and laboratory data were obtained from patient charts and an electronic hospital database. RESULTS: Mean uric acid levels of patients were 311 ± 74 µmol/L, and 24 of all of the patients (20%) had high uric acid levels. Fifteen patients taking tacrolimus (16%), and 9 of patients taking cyclosporine (39%) had hyperuricemia. The hyperuricemia rate of patients taking cyclosporine was significantly higher than it was for those patients taking tacrolimus (P = .014). Mean levels of uric acid in patients taking cyclosporine were higher than those of patients taking tacrolimus (344 ± 62 µmol/L and 303 ± 75 µmol/L; P = .006). There was a significant positive correlation between mean uric acid concentrations, and both serum creatinine (P = .000; r=0.487) and cystatin C (P = .000; r=0.433). There was negative correlation between mean uric acid concentration and estimated glomerular filtration rate (P = .000; r=-0.417). Mean uric acid levels of patients with intact graft function (estimated glomerular filtration rate ≥ 60 mL/min/1.73 m²) was lower than the patients with a low estimated glomerular filtration rate (291 ± 67 µmol/L and 353 ± 71 µmol/L; P = .000). Mean uric acid level of patients with normal body mass index was significantly lower than that of patients who were obese-overweight (301 ± 64 µmol/L vs 343 ± 94 µmol/L; P = .045). CONCLUSIONS: We found 20% of our patient group had high uric acid levels. We also found that lower glomerular filtration rate, higher serum creatinine, cystatin c, obesity, and being overweight were risk factors for hyperuricemia in pediatric renal transplant recipients.

Circulating endothelial cells in pediatric renal transplant recipients.

BACKGROUND: An increase in the number of circulating endothelial cells (CEC) indicates endothelial damage and the risk of cardiovascular disease. The aim of our study was to investigate the association of CEC with various clinical parameters in pediatric renal transplant recipients. METHODS: CEC, defined as CD45(-)CD146(+), were enumerated by flow cytometry from the peripheral blood of 50 pediatric renal transplant recipients and 20 healthy controls. Clinical parameters, including renal function tests, fasting blood glucose, serum cholesterol and triglyceride, cyclosporine A (CsA) (trough and 2nd-hour) and tacrolimus (tac) trough blood levels and their association with CEC numbers were analyzed. RESULTS: CEC numbers of patients were higher than those of controls (respectively, 128 ± 89 cells/ml (42-468 cells/ml), 82 ± 33 cells/ml (32-137 cells/ml), p = 0.024). There was a statistically significant negative correlation between CEC numbers and glomerular filtration rate (GFR) (r = -0.300, p = 0.012). There was also a statistically positive association between CEC numbers and transplant duration as well as cyclosporine trough level (respectively, r = 0.397, p = 0.004, r = 0.714, p = 0.004). CEC numbers in patients on tac and CsA were similar (p = 0.716). CONCLUSIONS: Our results demonstrate that renal transplant recipients with high CsA trough blood level, longer transplant duration, and lower GFR, are at greater risk of developing endothelial damage.

[BK virus infections in pediatric kidney transplant recipients]. / Pediatrik renal transplant alicilarinda BK virus enfeksiyonlari

Primary BK virus (BKV) infections acquired mainly during childhood are usually asymptomatic. Several studies revealed its seroprevalence in adult population as high as 90% worldwide. Following primary infection, virus persists as latent infection in the urogenital tract. In renal transplant recipients, primary infection and reactivations affect 10% of patients and without treatment, more than half of these patients lose their grafts. The only way of preventing graft loss due to BKV nephropathy (BKVN), seems to monitor BKV infection after transplantation and to diagnose patients developing BKVN during the early period and treat them accordingly. In this study, we analyzed BKV presence in plasma and urine samples with real-time PCR method and evaluated the renal biopsies of pediatric renal transplant recipients after transplantation, retrospectively. A total of 142 children (63 female, 79 male; mean age: 11.7 ± 3.9 years) who had renal transplantation in Akdeniz University Medical Faculty, Antalya, Turkey, between February 2006 and April 2011 were enrolled in the study. After transplantation, peripheral blood and urine samples were collected bi-weekly for the first three months, monthly till the sixth month and every three months thereafter. BKV DNA was additionally screened in patients with unexplained rise in serum creatinine or in patients receiving anti-rejection therapy. In any plasma positivity or during the BKVN therapy, BKV DNA analysis was done bi-weekly. After DNA extraction by automated system, an 83 base pair fragment in VP1 region was amplified. Signal detection for the target region was performed with a TaqMan probe dual-labelled at the 5' end with 6-carboxyfluorescein (FAM) and the 3' end with 6-carboxytetramethylrhodamine (TAMRA). Histopathological examinations of renal biopsies were done with routine histological stains and immunohistochemical staining with monoclonal antibodies directed to SV40 antigen. From 2171 plasma and 1995 urine samples without PCR inhibitors, 442 (20%) (range: 300-4.5 x 10(7) copies/ml; mean: 2.0 x 10(5) ± 2.2 x 10(6) copies/ml) and 800 (40.1%) (range: 300-3 x 10(12) copies/ml; mean: 5.9 x 10(9) ± 1.1 x 10(11) copies/ml) were found positive for BKV DNA, respectively. For 114 (80.3%) patients, at least one urine sample was positive and more than half of those patients (68/114, 59.6%) had viremia. Of the patients, 19.7% (28/142) had viral DNA above 10(4) copies/ml, which was choosen as a cut-off value for its high positive predictive value for BKVN. For all these 28 patients, prior to renal biopsy, immunosupressive treatment was decreased. Cidofovir and/or leflunomid were initiated to nine patients who did not respond to lowered immunosupressive therapy and eight of them had renal biopsy for the confirmation of BKVN. All renal biopsy results were compatible with BKVN. From these nine patients who were receiving cidofovir and/or leflunomid, two lost their grafts because of BKVN. Since viruria is frequently encountered and the viral load is usually in low quantities and transient, it is more appropriate to use blood samples for screening programmes after renal transplantation. The efficacy of antiviral treatment in BKVN could not be evaluated since it was only applied in patients non-responding to lowered immunosuppressive therapy and had decreased renal functions. Multicenter prospective studies are required to enlighten this important issue. Early diagnosis with close monitoring of renal function and viremia, seems to be the most effective way for controlling BKVN.