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".

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.

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.

Is there any relation between connective tissue growth factor and scar tissue in vesicoureteral reflux?

Gültekin ND, Benzer M, Tekin-Neijmann S. Is there any relation between connective tissue growth factor and scar tissue in vesicoureteral reflux. Turk J Pediatr 2019; 61: 71-78. Vesicoureteral reflux (VUR) is the most common uropathy in childhood which leads to increased frequency of urinary tract infection (UTI) and renal scarring. Connective tissue growth factor (CTGF) plays an important role in the development of glomerular and tubulointerstitial fibrosis in progressive kidney diseases. The aim of this study was to investigate the relation between urinary CTGF and renal damage resulted from VUR. This cross sectional study included 70 patients with VUR and 62 healthy sex and age matched children. Urinary creatinine and CTGF (uCTGF) concentrations were analysed in all cases and CTGF to creatinine ratio were calculated. The records of radiologic evaluations of the patients including ultrasound, voiding cystouretrography and 99m-technetium dimercaptosuccinic acid (DMSA) scintigraphy were obtained retrospectively. The patient group was further divided into two groups according to the existence of renal cortical scarring in the DMSA scan. The study consisted of three groups; Group 1 (control group) 62 children, Group 2 (VUR positive, scar negative) 24 patient, Group 3 (VUR positive, scar positive) 46 patient (VUR+scar). The medians of uCTGF and uCTGF to creatinine ratio of the three groups were significantly different (p < 0.001). Pairwise group comparisons revealed that Group 1 had significantly lower uCTGF level and uCTGF/creatinine ratio, as compared to Groups 2 and 3 (p < 0.001 and p=0.002, respectively). There was no statistically significant difference between Groups 2 and 3 (p=0.052). uCTGF is significantly increased in children with VUR, independent on the presence of renal scarring. Increased uCTGF, even in the absence of the renal scarring, could be interpreted as development and a progression of glomerular and tubulointerstitial fibrosis in vesicoureteral reflux. Further experimental and clinical investigations are required to fully elucidate the mechanism of CTGF in vesicoureteral reflux.

Outbreak of Shiga toxin-producing Escherichia-coli-associated hemolytic uremic syndrome in Istanbul in 2015: outcome and experience with eculizumab.

BACKGROUND: This study aims to identify epidemiological and clinical characteristics of patients and report our experience with eculizumab treatment during an outbreak of hemolytic uremic syndrome (HUS) caused by Shiga toxin-producing Escherichia coli (STEC) in Istanbul in 2015. METHODS: Thirty-two children (21 females, median age 3.25 years) were included in this study. Demographic, clinical and laboratory data, and treatment details were retrospectively collected. Renal outcomes were assessed at last follow-up visit. To assess the effect of eculizumab on prognosis of STEC-HUS, subgroup analysis was performed on patients who required dialysis. RESULTS: A high number of cases occurred within a certain region of Istanbul. Stool samples were cultured from 21 patients (65%), and enteroaggregative E. coli (EAEC; n = 7) and enterohemorrhagic E. coli (EHEC; n = 3) strains were detected. Rates of dialysis treatment, neurological manifestations, and death were 59%, 25%, and 3%, respectively. Mean follow-up duration was 8.6 ± 2.6 months (range 3-12 months). None of the patients (n = 25) was on dialysis at the final visit. The complete renal recovery rate was 54%. Nine patients were treated with eculizumab. At final follow-up visit, no differences in estimated glomerular filtration rate, proteinuria level, or hypertension incidence were observed between patients treated with eculizumab and those not treated with eculizumab. CONCLUSIONS: An outbreak of EAEC occurred in a specific region of Istanbul. Livestock markets were suspected as the source. Evidence for beneficial effects of eculizumab on renal outcome was not clear in this cohort.

Hemolytic uremic syndrome with multiple organ involvement secondary to complement factor H p.Arg1215X mutation.

Complement mediated hemolytic uremic syndrome which is caused by excessive activation of the alternative complement system is a thrombotic microangiopathy. The disease frequently occurs as a result of mutations in the genes that regulates complement proteins. Complement factor H gene has the most common mutations. A nine-month-old male patient was transferred to pediatric intensive care unit with the diagnosis of hemolytic uremic syndrome. Nonsense heterozygous p.Arg1215X mutation in the complement factor H gene was detected. The patient who had pulmonary, intestinal and hepatic involvement accompanying acute renal failure was successfully treated with therapeutic plasma exchange and eculizumab. Nonsense heterozygous p.Arg1215X mutation is extremely rare and can cause severe hemolytic uremic syndrome. As far as we know, our patient is the third case with this mutation in the literature.

Urinary L-FABP as a marker of vesicoureteral reflux in children: could it also have a protective effect on the kidney?

PURPOSE: Liver-type fatty acid-binding protein is a small cytoplasmic protein which is expressed in the human renal proximal tubular epithelium and synthesized in response to renal tubular injury. The aim of the present study was to investigate the importance of urinary liver-type fatty acid-binding protein levels in children who diagnosed with vesicoureteral reflux. METHODS: Fifty-six patients with vesicoureteral reflux and 51 healthy controls were enrolled to the study. The cases were divided into three groups as follows: group A-the controls, group B-the patients who had renal parenchymal scarring and group C-the patients who had no scarring. Urinary liver-type fatty acid-binding protein was measured by enzyme-linked immunosorbent assay method. Creatinine was measured by modified Jaffe method, protein was measured by turbidimetric method, and urine density was determined by using the "falling drop" procedure. RESULTS: Urinary liver-type fatty acid-binding protein and urinary liver-type fatty acid-binding protein/creatinine levels were significantly higher in the whole patient group than in the controls (p = 0.016, 0.006). Significant differences were also determined by comparing the three groups (p = 0.015, 0.014), and those levels were found as significantly higher in group C. CONCLUSION: Urinary liver-type fatty acid-binding protein was considered to be helpful for the diagnosis of vesicoureteral reflux, and also it might contribute to understand the mechanisms causing scar tissue formation especially for the patients who had vesicoureteral reflux. Further clinical and experimental investigations are required to elucidate in detail the physiology of liver-type fatty acid-binding protein.

Serum NGAL, cystatin C and urinary NAG measurements for early diagnosis of contrast-induced nephropathy in children.

AIM: The study investigated a number of biomarkers for the early diagnosis of contrast-induced nephropathy (CIN), which is an important cause of acute kidney injury (AKI). MATERIAL AND METHODS: The study included 91 children scheduled for elective cardiac angiography and 50 healthy controls. Biomarkers including serum (s) and urinary (u) sodium, serum and u-creatinine, s-cystatin-C, serum neutrophil gelatinase-associated lipocalin (NGAL) and urinary N-acetyl beta glucosaminidase (u-NAG)/creatinine ratio were measured 4 times sequentially in the patients and once in the controls. RESULTS: The patient group comprised 40 males (44%) and 51 females (56%) while the control group comprised 16 males (32%) and 34 females (68%). Age, gender, s-creatinine, estimated-glomerular filtration rate (eGFR), s-cystatin-C and fractional-excretion of sodium did not differ significantly between the groups. Serum sodium and s-NGAL were found to be lower in the patients than those of in the controls, while their u-NAG/creatinine ratio was found to be higher. Sequential data analysis revealed that s-NGAL and u-NAG/creatinine ratio increased in the first 6 h after radiocontrast media (RCM) administration and decreased at 12 and 24 h. Serum BUN and s-cystatin-C levels also showed a significant difference during the 24-h follow-up. eGFR, s-sodium and s-creatinine levels did not change in the following period. Serum cystatin-C levels revealed a significant negative correlation with eGFR. Administered RCM doses showed a positive correlation only with u-NAG/creatinine ratios. CONCLUSION: In the first 24 h, s-cystatin-C, s-NGAL and especially u-NAG/creatinine ratio showed promise as biomarkers, but eGFR is not adequate for early diagnosis of CIN. Sequential measurement of biomarkers may contribute to more accurate diagnosis of AKI.

Is microalbuminuria a risk factor for hypertension in children with solitary kidney?

BACKGROUND: The correlations between ambulatory blood pressure measurements (ABPM) and serum cystatin C (Cys C), serum creatinine (Cr), microalbumin (MA), and ß2-microglobulin (ß2-MG) levels in 24 h (24-h) urine were analyzed in children with solitary kidney (SK) and compared to healthy children. METHODS: Fifty children with normal functioning SK and 25 controls were studied. The ABPM, serum Cys C, serum Cr, MA, and ß2-MG levels in 24-h urine were measured in all children. Clinical symptoms and signs, laboratory results, urinary ultrasonography, voiding cystourethrography, and Dimercaptosuccinic acid (DMSA) scintigraphy results were recorded in the SK group. Four patients with Wilms' tumor and two with renal scarring were excluded from the study. RESULTS: The mean ages of the SK group and controls were 9.6 ± 3.6 and 9.3 ± 3.3 years, respectively. The serum Cys C and Cr levels, 24-h urinary ß2-MG and MA levels were similar in both groups (p > 0.05). However, 24-h urinary MA excretion was higher in patients living with SK more than 5 years (p = 0.01). Standard deviation scores of ABPM parameters showed no significant correlation with serum Cr, serum Cys C, MA, and ß2-MG in 24-h urine of both groups. CONCLUSIONS: Children with SK have increased 24-h urinary MA excretion in the long term, and need prolonged follow-up to detect early deterioration of renal function and to prevent end-organ damage later in life.

Can peritoneal dialysis be used in preterm infants with congenital diaphragmatic hernia?

Peritoneal dialysis (PD) is considered as the most common form of renal replacement therapy for newborns including preterms with acute kidney injury (AKI). Although there are several reports describing successful PD performed for AKI in preterm infants, there is no data describing the use of PD to treat AKI in preterm newborns with congenital diaphragmatic hernia (CDH), which is one of the contraindications for PD. We present a preterm newborn with CDH, truncus arteriosus and AKI treated with PD and emphasize that PD may be successfully performed with caution even in cases of contraindications when other renal replacement therapies cannot be used.