Variable phenotype and genotype of pediatric patients with HNF1B nephropathy.

AIMS: Hepatocyte nuclear factor 1ß (HNF1B) mutations are the most common monogenic cause of congenital anomalies of the kidney and urinary tract (CAKUT). We aimed to investigate clinical and genetic characteristics of patients with HNF1B nephropathy to expand its phenotypic and genetic spectrum. MATERIALS AND METHODS: This retrospective cohort study included 16 unrelated pediatric patients (6 females, 10 males) from 13 families with genetically confirmed HNF1B-related nephropathy. RESULTS: Abnormal prenatal kidney abnormalities were present in 13 patients (81.3%). The most common antenatal kidney abnormality was kidney cysts, which were observed in 8 patients (61.5%). Urinary system abnormalities (vesicoureteral reflux (VUR) and ureteropelvic junction obstruction (UPJO)) were present in 4 patients (25%). HNF1B analysis uncovered missense variants in 4 families (30.8%) as the most common genetic abnormality. In addition, 4 novel pathological variations have been defined. During follow-up, hypomagnesemia and hyperuricemia were observed in 7 (43.8%) and 5 patients (31.3%), respectively. None of the patients with a missense variant had hypomagnesemia. However, 7 out of 12 patients (58.3%) with a non-missense variant had hypomagnesemia (p = 0.09). None of the patients had an HNF1B score below 8, and the mean score was 15.3 ± 4.4. The mean follow-up period was 7.4 ± 5.0 years. While 100% of patients (n = 4) with missense variants were in various stages of CKD (CKD2: 2 patients, CKD3: 2 patients), 25% of those with non-missense variants had CKD (CKD2, 3, and 5; 1 patient, respectively) (p = 0.026). CONCLUSION: Patients with HNF1B-associated disease have concomitant urinary system abnormalities such as VUR or UPJO. Missense variants seem to be the most common pathological variations in HNF1B gene and have higher risk of CKD.

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.

Meningococcemia in a vaccinated child receiving eculizumab and review of the literature.

BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) is a rare and severe disease characterized by uncontrolled activation and dysregulation of the alternative complement pathway and development of thrombotic microangiopathy. Eculizumab, which is used as a first-line therapy in aHUS, blocks the formation of C5 convertase and inhibits the formation of the terminal membrane attack complex. It is known that treatment with eculizumab increases the risk of meningococcal disease by 1000-2000-fold. Meningococcal vaccines should be administered to all eculizumab recipients. CASE: We describe a girl with aHUS who was receiving eculizumab treatment and experienced meningococcemia with non-groupable meningococcal strains which rarely cause disease in healthy people. She recovered with antibiotic treatment and we discontinued eculizumab. CONCLUSIONS: In this case report and review, we discussed similar pediatric case reports in terms of meningococcal serotypes, vaccination history, antibiotic prophylaxis and prognosis of patients who experienced meningococcemia under eculizumab treatment. This case report highlights the importance of a high index of suspicion for invasive meningococcal disease.

Urinary HSP70 improves diagnostic accuracy for urinary tract infection in children: UTILISE study.

BACKGROUND: The accuracy of conventional urinalysis in diagnosing urinary tract infection (UTI) in children is limited, leading to unnecessary antibiotic exposure in a large fraction of patients. Urinary heat shock protein 70 (uHSP70) is a novel marker of acute urinary tract inflammation. We explored the added value of uHSP70 in discriminating UTI from other infections and conditions confused with UTI. METHODS: A total of 802 children from 37 pediatric centers in seven countries participated in the study. Patients diagnosed with UTI (n = 191), non-UTI infections (n = 178), contaminated urine samples (n = 50), asymptomatic bacteriuria (n = 26), and healthy controls (n = 75) were enrolled. Urine and serum levels of HSP70 were measured at presentation in all patients and after resolution of the infection in patients with confirmed UTI. RESULTS: Urinary (u)HSP70 was selectively elevated in children with UTI as compared to all other conditions (p < 0.0001). uHSP70 predicted UTI with 89% sensitivity and 82% specificity (AUC = 0.934). Among the 265 patients with suspected UTI, the uHSP70 > 48 ng/mL criterion identified the 172 children with subsequently confirmed UTI with 90% sensitivity and 82% specificity (AUC = 0.862), exceeding the individual diagnostic accuracy of leukocyturia, nitrite, and leukocyte esterase positivity. uHSP70 had completely normalized by the end of antibiotic therapy in the UTI patients. Serum HSP70 was not predictive. CONCLUSIONS: Urine HSP70 is a novel non-invasive marker of UTI that improves the diagnostic accuracy of conventional urinalysis. We estimate that rapid urine HSP70 screening could spare empiric antibiotic administration in up to 80% of children with suspected UTI. A higher resolution version of the Graphical abstract is available as Supplementary information.

Long-term Results in Children with Henoch-Schönlein Nephritis.

Objective: Henoch-Schönlein purpura (HSP) is a small vessel vasculitis and palpable purpura, with arthritis, gastrointestinal as abdominal pain, and renal involvement as typical clinical findings. The most important prognostic factor for HSP vasculitis is renal involvement. This study aimed to investigate the relationship between clinical, laboratory, and histopathologic findings of children with HSP nephritis with long-term renal prognosis. Methods: This retrospective study included children with HSP nephritis between January 2010 and December 2019. Initial clinical presentation, laboratory findings, and kidney biopsy results were obtained, and treatment modalities were recorded and classified using the Meadow classification and grouped into mild and severe cases. Additionally, data at the last follow-up were analyzed and classified. Results: A total of 90 children (59 male) with a mean age of 8.8±3.2 years were included. According to initial clinical findings, 18 children were in the Meadow's severe group. Fifteen (15/72) children in the mild group and all children in the severe group had undergone kidney biopsy. The severe group had higher histopathologic stages compared to the mild group (p=0.022). Immunosuppressive treatments were used in 44.4% of mild cases and 100% of severe cases (p<0.01). On follow-up, only four children (two in the mild group) had persistent proteinuria. Conclusions: Severe clinical findings in the initial presentation were related to more intensive immunosuppressive treatment. Additionally, renal histopathological stages were higher in the severe group. Long-term follow-up for proteinuria is mandatory for all children with HSP nephritis, even with mild initial clinical findings.

Anocutaneous Reflex Revisited: How Valuable Is Its Determination in Children with Spina Bifida? A Descriptive Study in A Cohort of 217 Patients.

AIM: To determine the clinical value of anocutaneous reflex (AR) in children with neurogenic bladder due to spina bifida (SB). MATERIAL AND METHODS: Patients who were diagnosed with SB were prospectively evaluated; moreover, AR and bulbocavernous reflex were examined. Patients were divided into those with and without AR. Age, gender, diagnosis, ventriculoperitoneal shunt presence, symptomatic urinary tract infections, leg movements, clean intermittent catheterization and anticholinergic therapy, lesion level, urodynamic detrusor, and sphincter activity were evaluated. Chi-square test and univariate regression analysis were done. The AR value was evaluated by two by two contingency table. RESULTS: This study evaluated 217 patients (109 boys and 108 girls). AR was present and absent in 53 and 164 patients, respectively. Anticholinergic therapy was necessary in 37.7% and 23.8% of patients with and without AR (p=0.015), respectively. Patients with AR had higher lesion level (p=0.005), more detrusor overactivity, and less detrusor underactivity (p=0.007). Less detrusor sphincter dyssynergia (DSD) was noted in patients with AR (p=0.029). AR specificity was 83%, and positive predictive value in predicting detrusor overactivity and DSD was 76% and 80, respectively. CONCLUSION: AR determination is a valuable and simple tool in neurogenic bladder. This report delineates the clinical significance of this reflex and is the largest cohort describing this significance. This simple examination should not be skipped in the initial evaluation and follow-up of these patients.

A broad clinical spectrum of PLCε1-related kidney disease and intrafamilial variability.

BACKGROUND: The phenotypic and genotypic spectrum and kidney outcome of PLCε1-related kidney disease are not well known. We attempted to study 25 genetically confirmed cases of PLCε1-related kidney disease from 11 centers to expand the clinical spectrum and to determine the relationship between phenotypic and genotypic features, kidney outcome, and the impact of treatment on outcome. METHODS: Data regarding demographics, clinical and laboratory characteristics, histopathological and genetic test results, and treatments were evaluated retrospectively. RESULTS: Of 25 patients, 36% presented with isolated proteinuria, 28% with nephrotic syndrome, and 36% with chronic kidney disease stage 5. Twenty patients underwent kidney biopsy, 13 (65%) showed focal segmental glomerulosclerosis (FSGS), and 7 (35%) showed diffuse mesangial sclerosis (DMS). Of the mutations identified, 80% had non-missense, and 20% had missense; ten were novel. No clear genotype-phenotype correlation was observed; however, significant intrafamilial variations were observed in three families. Patients with isolated proteinuria had significantly better kidney survival than patients with nephrotic syndrome at onset (p = 0.0004). Patients with FSGS had significantly better kidney survival than patients with DMS (p = 0.007). Patients who presented with nephrotic syndrome did not respond to any immunosuppressive therapy; however, 4/9 children who presented with isolated proteinuria showed a decrease in proteinuria with steroids and/or calcineurin inhibitors. CONCLUSION: PLCε1-related kidney disease may occur in a wide clinical spectrum, and genetic variations are not associated with clinical presentation or disease course. However, clinical presentation and histopathology appear to be important determinants for prognosis. Immunosuppressive medications in addition to angiotensin-converting enzyme inhibitors may be beneficial for selected patients. "A higher resolution version of the Graphical abstract is available as Supplementary information".

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.

COVID-19 in pediatric patients undergoing chronic dialysis and kidney transplantation.

The study aims to present the incidence of COVID-19 in pediatric patients undergoing renal replacement therapy (RRT) and to compare the severity and outcomes of the disease between the dialysis and kidney transplant (KTx) groups. This multicenter observational study was conducted between 1 April and 31 December 2020 in Istanbul. Members of the Istanbul branch of the Turkish Pediatric Nephrology Association were asked to report all confirmed cases of COVID-19 who were on RRT, as well as the number of prevalent RRT patients under the age of 20. A total of 46 confirmed cases of COVID-19 were reported from 12 centers, of which 17 were dialysis patients, and 29 were KTx recipients. Thus, the incidence rate of COVID-19 was 9.3% among dialysis patients and 9.2% among KTx recipients over a 9-month period in Istanbul. Twelve KTx recipients and three dialysis patients were asymptomatic (p = 0.12). Most of the symptomatic patients in both the dialysis and KTx groups had a mild respiratory illness. Only two patients, one in each group, experienced a severe disease course, and only one hemodialysis patient had a critical illness that required mechanical ventilation. In the entire cohort, one hemodialysis patient with multiple comorbidities died.Conclusion: While most cases are asymptomatic or have a mild disease course, pediatric patients undergoing dialysis and a kidney transplant are at increased risk for COVID-19. What is Known: • In adult population, both dialysis patients and kidney transplant recipients are at increased risk for severe illness of COVID-19 and have higher mortality rate. • Children with kidney transplantation are not at increased risk for COVID-19 and most have mild disease course. • Data on children on dialysis are scarce. What is New: • Pediatric patients undergoing dialysis and kidney transplantation have an increased risk for COVID-19. • Most patients undergoing renal replacement therapy either on dialysis or transplanted develop asymptomatic or mild COVID-19 disease with a favorable outcome.

Long-term obesity prevalence and linear growth in children with idiopathic nephrotic syndrome: is normal growth and weight control possible with steroid-sparing drugs and low-dose steroids for relapses?

BACKGROUND: Long-term steroid treatment in children is known to cause obesity and negatively affect growth. The objective of this study was to determine the prevalence of obesity and overweight and analyze linear growth in children with nephrotic syndrome. METHODS: The study involved 265 children treated with glucocorticoids for nephrotic syndrome for a mean duration of 43 months (range: 6-167, IQR: 17, 63.3). Height, weight, and BMI SDS were recorded at each visit. Rate of change between the final and initial height, weight, and BMI was calculated (Δ score). The cumulative steroid dose (mg/kg/day) during follow-up was calculated. Relapses without significant edema were treated with low-dose steroids and steroid-sparing drugs were used in children with steroid dependency/frequent relapses. RESULTS: Mean first BMI SDS was + 1.40 ± 1.30 and final + 0.79 ± 1.30. At initial assessment, 41.4% of the patients were obese (BMI ≥ 95th percentile) and 19.5% were overweight (BMI 85th-95th percentile). At the last clinical visit, 24% were obese and 17% overweight. The children had lower BMI SDS at last clinical visit compared to initial assessment. Mean first height SDS of the cohort was - 0.11 ± 1.22 and final score 0.078 ± 1.14 (p < 0.0001). Almost 85% of patients were treated with steroid-sparing drugs. CONCLUSIONS: Our results indicate that children with nephrotic syndrome, despite a need for steroid treatment for active disease, can improve their obesity and overweight and also improve their linear growth from their first to last visit with us.

Hepatocyte Nuclear Factor 1 Beta Mutation-associated Newborn Onset of Glomerulocystic Kidney Disease: A Case Presentation.

Mutations in hepatocyte nuclear factor-1 beta (HNF1B) are the most commonly identified genetic cause of renal malformations. Heterozygous mutations are associated with renal cysts and diabetes syndrome. Various renal developmental abnormalities and maturity-onset diabetes of the young could be the presenting factors of these mutations. A 10-year-old boy who was evaluated for bilateral cystic kidneys and chronic kidney disease from the newborn period was diagnosed with HNF1B-related glomerulocystic disease by DNA sequencing. The differential diagnosis of autosomal dominant polycystic kidney disease was a diagnostic pitfall. The genetic screening of the family revealed his mother, sister, and brother to have the same mutation. Therefore, genetic diagnosis and counseling are important for cystic kidney diseases not only for formulating the diagnosis and early management plan but also for the diagnosis of potential asymptomatic cases in the family.

PROGRESS STUDY: Progression of chronic kidney disease in children and heat shock proteins.

Various molecular and cellular processes are involved in renal fibrosis, such as oxidative stress, inflammation, endothelial cell injury, and apoptosis. Heat shock proteins (HSPs) are implicated in the progression of chronic kidney disease (CKD). Our aim was to evaluate changes in urine and serum HSP levels over time and their relationships with the clinical parameters of CKD in children. In total, 117 children with CKD and 56 healthy children were examined. The CKD group was followed up prospectively for 24 months. Serum and urine HSP27, HSP40, HSP47, HSP60, HSP70, HSP72, and HSP90 levels and serum anti-HSP60 and anti-HSP70 levels were measured by ELISA at baseline, 12 months, and 24 months. The urine levels of all HSPs and the serum levels of HSP40, HSP47, HSP60, HSP70, anti-HSP60, and anti-HSP70 were higher at baseline in the CKD group than in the control group. Over the months, serum HSP47 and HSP60 levels steadily decreased, whereas HSP90 and anti-HSP60 levels steadily increased. Urine HSP levels were elevated in children with CKD; however, with the exception of HSP90, they decreased over time. In conclusion, our study demonstrates that CKD progression is a complicated process that involves HSPs, but they do not predict CKD progression. The protective role of HSPs against CKD may weaken over time, and HSP90 may have a detrimental effect on the disease course.

The impact of Technetium-99m dimercapto-succinic acid scintigraphy on DNA damage and oxidative stress in children.

BACKGROUND: Technetium-99m-dimercapto succinic acid (Tc-99m DMSA) scintigraphy is a commonly used imaging modality in children with urological abnormalities. The radiopharmaceuticals, which have the effects of ionising radiation, are used in this method. This study aimed to investigate the impact of the Tc-99m DMSA scan on renal oxidative stress and mononuclear leukocyte (MNL) DNA damage. METHODS: Children, who were followed up by paediatric nephrology at Bezmialem Vakif University and underwent Tc-99m DMSA scintigraphy between April 2015 and January 2016 with the indication of detection of renal scars, were included in this study. The exclusion criteria were nephrolithiasis, history of premature birth and recent urinary tract infection 3 months prior to scintigraphy or antibiotic use in the last 1 month. 3 mL heparinised blood samples were obtained just before, immediately after and 1 week after the scintigraphy. MNL DNA damage, total antioxidant status (TAS) and total oxidant status (TOS) were measured in the blood samples. The oxidative stress index (OSI) was calculated. Spot urine samples were obtained from each patient before and within 3 days after performing the scintigraphy. TAS/Creatinine (TAS/Cr), TOS/Creatinine (TOS/Cr) and N-acetyl-glucosaminidase/creatinine (NAG/Cr) levels were measured in the urine samples. RESULTS: Twenty-seven children were evaluated. The values between TAS, TOS and OSI levels in serum samples at baseline, immediately after and 1 week after the scintigraphy (P = .105, P = .913, and P = .721, respectively) showed no statistically significant difference. The levels of TAS/Cr, TOS/Cr, NAG/Cr ratios and OSI, which were evaluated from urine samples before and within 3 days after the scintigraphy scan were also similar (P = .391, P = .543, P = .819 and P = .179, respectively). The levels of DNA damage only increased following scintigraphy scan and decreased a week later (P < .05). CONCLUSIONS: The effect of Tc-99m DMSA scintigraphy is insufficient to create oxidative damage, but it can cause DNA damage via the direct impact of ionising radiation which can be repaired again in a short time.

Rituximab treatment for difficult-to-treat nephrotic syndrome in children: a multicenter, retrospective study

Background/aim: This study aimed to evaluate the efficacy of rituximab in children with difficult-to-treat nephrotic syndrome, considering the type of disease (steroid-sensitive or ­resistant) and the dosing regimen. Materials and methods: This multicenter retrospective study enrolled children with difficult-to-treat nephrotic syndrome on rituximab treatment from 13 centers. The patients were classified based on low (single dose of 375 mg/m2) or high (2-4 doses of 375 mg/m2) initial dose of rituximab and the steroid response. Clinical outcomes were compared. Results: Data from 42 children [20 steroid-sensitive (frequent relapsing / steroid-dependent) and 22 steroid-resistant nephrotic syndrome, aged 1.9­17.3 years] were analyzed. Eleven patients with steroid-sensitive nephrotic syndrome (55%) had a relapse following initial rituximab therapy, with the mean time to first relapse of 8.4 ± 5.2 months. Complete remission was achieved in 41% and 36% of steroid-resistant patients, with the median remission time of 3.65 months. At Year 2, eight patients in steroid-sensitive group (40%) and four in steroid-resistant group (18%) were drug-free. Total cumulative doses of rituximab were higher in steroid-resistant group (p = 001). Relapse rates and time to first relapse in steroid-sensitive group or remission rates in steroid-resistant group did not differ between the low and high initial dose groups. Conclusion: The current study reveals that rituximab therapy may provide a lower relapse rate and prolonged relapse-free survival in the steroid-sensitive group, increased remission rates in the steroid-resistant group, and a significant number of drug-free patients in both groups. The optimal regimen for initial treatment and maintenance needs to be determined.

New guidelines for the diagnosis, evaluation, and treatment of pediatric hypertension.

Childhood hypertension has become a significant public health problem due to increased prevalence in recent decades. High blood pressure causes increased mortality and morbidity in childhood, precedes adult hypertension, and causes increased cardiovascular events in adulthood. These concerns have led to an update of guidelines about childhood hypertension by the European Society of Hypertension in 2016 and the American Academy of Hypertension in 2017. This review highlights the important developments in these guidelines and recent literature about childhood hypertension in terms of diagnosis, prevalence, risk factors, diagnostic tools, prevention and management.

An Extraordinary Complication in a Child With Combined Familial Mediterranean Fever and Inflammatory Bowel Disease: Multiple Ileal Perforations.

Familial Mediterranean fever (FMF) is a recurrent disease with autosomal recessive trait and fever that is generally self-limiting. Clinical manifestations are pain in the abdomen, chest, and joints as a result of inflammation in the serous surfaces. No case of multiple intestinal perforations has been reported in children with FMF, whereas cases with a single intestinal perforation have been encountered, although very rarely. In addition, co-occurrence of FMF and inflammatory bowel disease is a situation that is very rarely reported in the literature. Here, we report a case of a 5-year-old girl who was being followed up with the diagnosis of FMF and who also had inflammatory bowel disease, which was complicated with multiple ileal perforations. Our aim is to point out a rarely encountered co-occurrence and also the importance of evaluation of additional diseases with FMF that are unresponsive to treatment so as to prevent complications.