Magnetic resonance imaging based kidney volume assessment for risk stratification in pediatric autosomal dominant polycystic kidney disease.

Introduction: In the pediatric context, most children with autosomal dominant polycystic kidney disease (ADPKD) maintain a normal glomerular filtration rate (GFR) despite underlying structural kidney damage, highlighting the critical need for early intervention and predictive markers. Due to the inverse relationship between kidney volume and kidney function, risk assessments have been presented on the basis of kidney volume. The aim of this study was to use magnetic resonance imaging (MRI)-based kidney volume assessment for risk stratification in pediatric ADPKD and to investigate clinical and genetic differences among risk groups. Methods: This multicenter, cross-sectional, and case-control study included 75 genetically confirmed pediatric ADPKD patients (5-18 years) and 27 controls. Kidney function was assessed by eGFR calculated from serum creatinine and cystatin C using the CKiD-U25 equation. Blood pressure was assessed by both office and 24-hour ambulatory measurements. Kidney volume was calculated from MRI using the stereological method. Total kidney volume was adjusted for the height (htTKV). Patients were stratified from A to E classes according to the Leuven Imaging Classification (LIC) using MRI-derived htTKV. Results: Median (Q1-Q3) age of the patients was 6.0 (2.0-10.0) years, 56% were male. There were no differences in sex, age, height-SDS, or GFR between the patient and control groups. Of the patients, 89% had PKD1 and 11% had PKD2 mutations. Non-missense mutations were 73% in PKD1 and 75% in PKD2. Twenty patients (27%) had hypertension based on ABPM. Median htTKV of the patients was significantly higher than controls (141 vs. 117 ml/m, p = 0.0003). LIC stratification revealed Classes A (38.7%), B (28%), C (24%), and D + E (9.3%). All children in class D + E and 94% in class C had PKD1 variants. Class D + E patients had significantly higher blood pressure values and hypertension compared to other classes (p > 0.05 for all). Discussion: This study distinguishes itself by using MRI-based measurements of kidney volume to stratify pediatric ADPKD patients into specific risk groups. It is important to note that PKD1 mutation and elevated blood pressure were higher in the high-risk groups stratified by age and kidney volume. Our results need to be confirmed in further studies.

Complement gene mutations in children with C3 glomerulopathy: do they affect the response to mycophenolate mofetil?

BACKGROUND: C3 glomerulopathy (C3G) is a complement-mediated disease. Although genetic studies are not required for diagnosis, they are valuable for treatment planning and prognosis prediction. The aim of this study is to investigate the clinical phenotypes, kidney survival, and response to mycophenolate mofetil (MMF) treatment in pediatric C3G patients with and without mutations in complement-related genes. METHODS: Sixty pediatric C3G patients were included, divided into two groups based on complement-related gene mutations. Demographic and clinical-pathological findings, treatment modalities, and outcome data were compared, and Kaplan-Meier analysis was performed for kidney survival. RESULTS: Out of the 60 patients, 17 had mutations. The most common mutation was in the CFH gene (47%). The mean age at diagnosis was higher in the group with mutation (12.9 ± 3.6 vs. 11.2 ± 4.1 years, p = 0.039). While the patients without mutation most frequently presented with nephritic syndrome (44.2%), the mutation group was most likely to have asymptomatic urinary abnormalities (47.1%, p = 0.043). Serum parameters and histopathological characteristics were similar, but hypoalbuminemia was more common in patients without mutation. During 45-month follow-up,10 patients progressed to chronic kidney disease stage 5 (CKD5), with 4 having genetic mutation. The time to develop CKD5 was longer in the mutation group but not significant. MMF treatment had no effect on progression in either group. CONCLUSIONS: This study is the largest pediatric C3G study examining the relationship between genotype and phenotype. We showed that the mutation group often presented with asymptomatic urinary abnormalities, was diagnosed relatively late but was not different from the without mutation group in terms of MMF treatment response and kidney survival.

Evaluation of the Claria sharesource system from the perspectives of patient/caregiver, physician, and nurse in children undergoing automated peritoneal dialysis.

BACKGROUND: Automated peritoneal dialysis (APD) is increasingly preferred worldwide. By using a software application (Homechoice with Claria sharesource system (CSS)) with a mod-M added to the APD device, details of the home dialysis treatment become visible for PD nurses and physicians, allowing for close supervision. We aimed to evaluate the perceptions of patients/caregivers, PD nurses, and physicians about the advantages and disadvantages of CSS. METHODS: Three different web-based questionnaires for patients/caregivers, nurses, and physicians were sent to 15 pediatric nephrology centers with more than 1 year of experience with CSS. RESULTS: Respective questionnaires were answered by 30 patients/caregivers, 22 pediatric nephrologists, and 15 PD nurses. Most of the nurses and physicians (87% and 73%) reported that CSS improved patient monitoring. A total of 73% of nurses suggested that CCS is not well known by physicians, while half of them reported reviewing CSS data for all patients every morning. Sixty-eight percent of physicians thought that CSS helps save time for both patients/caregivers and healthcare providers by reducing visits. However, only 20% of patients/caregivers reported reduced hospital visits. A total of 90% of patients/caregivers reported that being under constant monitoring made them feel safe, and 83% stated that the patient's sleep quality improved. CONCLUSIONS: A remote monitoring APD system, CSS, can be successfully applied with children for increased adherence to dialysis prescription by giving shared responsibility and may help increase the patient's quality of life. This platform is more commonly used by nurses than physicians. Its potential benefits should be evaluated in further well-designed clinical studies with larger patient groups. A higher resolution version of the Graphical abstract is available as Supplementary information.

Urinary HSP70 can predict the indication of surgery in unilateral ureteropelvic junction obstruction.

BACKGROUND: Distinguishing hydronephrosis that requires surgical intervention is a clinical challenge. The aim of this study is to determine the level of urinary heat shock protein 70 (HSP70) in children who required surgery for ureteropelvic junction obstruction and its potential use as a biomarker for prediction of surgery in children with isolated unilateral hydronephrosis. METHODS: The data of 43 children with ureteropelvic junction obstruction who underwent pyeloplasty, 25 patients with non-obstructive dilation (NOD) and 30 healthy children (control group) were collected prospectively for this study. Preoperative and postoperative urinary HSP70/Cr levels were also analyzed in 30 children in the pyeloplasty group who had available follow-up information. HSP70 levels were assessed using ELISA. RESULTS: The median age of the pyeloplasty group was 13 months (IQR 7-36 months), NOD group was 42.5 months (IQR 16-73) and it was 36 months (IQR 24-47.5) in the control group. The mean preoperative urinary HSP70/Cr was significantly higher in the pyeloplasty group when compared to controls as well as the NOD group (150.6 pg/mgCr vs. 65.0 pg/mgCr and vs. 64.7 pg/mgCr, p < 0.001 and p < 0.001, respectively). The urinary HSP70 levels significantly decreased in the postoperative period (151.5 vs 79.5, p < 0.001). Using the cutoff value of 94.7 pg/mgCr, the sensitivity and specificity of urinary HSP70 for predicting the risk of surgical intervention were 69.7% and 68%, respectively (AUC = 0.689). CONCLUSION: Urinary HSP70 may be used as an adjunct tool to clinical parameters to identify patients that would require surgery due to ureteropelvic junction obstruction.

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.

An adolescent girl with obstructive uropathy requiring nephro-ureterectomy was subsequently diagnosed with renal tuberculosis: case report.

A 15-year-old girl was followed up for 2 years in a district hospital for management of vesicoureteral reflux and, subsequently, hydronephrosis of both kidneys and required bilateral ureteroneocystostomy. Despite surgery, there was continuous progression of the left hydronephrosis. Referral to a tertiary hospital because of continued sterile pyuria prompted investigation for tuberculosis (TB): she was diagnosed with bilateral pulmonary TB and urine culture confirmed Mycobacterium tuberculosis. Despite tuberculous chemotherapy and dexamethasone, she required a left nephrectomy. Histology demonstrated necrotising granulomatous pyelonephritis. She remains well with normal function of the right kidney. Despite the rarity, chronic urinary tract disorders should always prompt investigation for tuberculosis.

Transplantation in pediatric aHUS within the era of eculizumab therapy.

aHUS is caused by the over-activation and dysregulation of the alternative complement pathway. Data regarding outcomes of pediatric aHUS patients after kidney transplantation are still very scarce. Accordingly, the aim of this study was to describe the clinical findings and outcomes of pediatric aHUS patients after renal transplantation. This is a retrospective, multicenter study including 12 patients from the national registry system. Among the 12 patients, eight had received prophylactic eculizumab and none of those patients (except one) had experienced aHUS recurrence during a median follow-up period of 58.5 (min-max, 4-94) months. Although eculizumab had been started on the day before transplantation in one of them, aHUS recurrence occurred during the transplantation procedure. Eculizumab had been stopped in only one patient who had no complement gene mutation after 35 months of therapy, and recurrence had not been observed during the 19 months of follow-up. In three patients, maintenance doses had been spaced out without any recurrence. One additional patient with anti-CFH antibody received only two doses of eculizumab for transplantation and had been followed for 46 months without aHUS recurrence. The remaining three patients had not received anti-C5 therapy and none of those patients experienced aHUS recurrence during a median follow-up period of 21 (min-max, 9-42) months. Prophylactic eculizumab is a safe and effective treatment for the prevention of aHUS recurrence. Eculizumab interval prolongation, discontinuation, and transplantation without eculizumab prophylaxis can be tried in selected patients with close follow-up.

Primary coenzyme Q10 Deficiency-6 (COQ10D6): Two siblings with variable expressivity of the renal phenotype.

Primary coenzyme Q10 deficiency-6 (COQ10D6) is a rare autosomal recessive disorder caused by COQ6 mutations. The main clinical manifestations are infantile progressive nephrotic syndrome (NS) leading to end-stage renal disease and sensorineural deafness. A 7-year-old girl was diagnosed with steroid-resistant NS (SRNS) and an audiological work-up revealed bilateral sensorineural deafness. A renal biopsy demonstrated focal segmental glomerulosclerosis. Despite immunosuppressive therapy, her serum levels of creatinine increased and haemodialysis was indicated within 1 year after the diagnosis. Living-donor kidney transplantation was performed in the eighth month of haemodialysis. A diagnostic custom-designed panel-gene test including 30 genes for NS revealed homozygous c.1058C > A [rs397514479] in exon nine of COQ6. Her older brother, who had sensorineural hearing loss with no renal or neurological involvement, had the same mutation in homozygous form. COQ6 mutations should be considered not only in patients with SRNS with sensorineural hearing loss but also in patients with isolated sensorineural hearing loss with a family history of NS. The reported p.His174 variant of COQ8B was suggested to be a risk factor for secondary CoQ deficiency, while p.Arg174 appeared to improve the condition in a yeast model. Family segregation and the co-occurrence of biallelic p.Arg174 of COQ8B in a brother with hearing loss implied that the interaction of the altered COQ8B with the mutant COQ6 alleviated the symptoms in this family. CoQ10 replacement therapy should be initiated for these patients, as primary CoQ10 deficiency is considered the only known treatable mitochondrial disease.

Urine Levels of Matrix Metalloproteinases and Tissue Inhibitor of Metalloproteinases in Children with Type 1 Diabetes Mellitus

Objective: Histopathological changes in the kidney in type 1 diabetes mellitus (T1DM) begin before detection of microalbuminuria. Therefore, there is interest in finding a better biomarker for the early detection of diabetic kidney injury. The aim of this present study was to determine whether urinary indicators of fibrosis are detectable early in the development of T1DM in children and if they may predict progressive renal injury. Methods: Urinary matrix metalloproteinase 2 and 9 (MMP2 and MMP9), tissue inhibitor of metalloproteinase 1 and 2 (TIMP1 and TIMP2) and transforming growth factor-ß1 (TGF-ß1) were assessed in 33 patients with T1DM with normal renal functions and in 24 healthy controls. Microalbuminuria was not present in the patient group with the exception of three patients. The results were adjusted to urine creatinine (Cr) and the differences between patients and controls were evaluated. These measurements were repeated after one year and the results were compared with the first year results. Results: Urine MMP2/Cr, MMP9/Cr, TIMP1/Cr, TIMP2/Cr, TGF-ß1/Cr were not different between the patient and control groups (p>0.05). There were also no significant differences between the first and second year results for these biomarkers (p>0.05). None of these parameters were correlated with hemoglobin A1c, body mass index and duration of T1DM. Interestingly, all parameters were negatively correlated to age of onset of T1DM (p<0.05). Conclusion: Our findings suggest that urinary biomarkers of fibrosis do not show an increase in diabetic children without microalbuminuria. The results also indicate that the risk of early fibrosis may increase as age of onset of T1DM decreases.

Higher urine heat shock protein 70/creatinine ratio in type 1 diabetes mellitus.

Insidious progressive renal damage caused by type 1 diabetes mellitus (T1DM) begins in childhood before it becomes manifest in adult ages. Heat shock proteins (HSPs) regulate the cell response to any hazardous factors to prevent cell structure. The aim of the study is to determine whether urine levels of HSPs increase in diabetic children with time and indicate a progressive renal injury in T1DM. Thirty-three patients with T1DM and 24 healthy children were enrolled in the study. Renal function was normal in all patients. Urine levels of HSP27, HSP40, HSP60, HSP70, and HSP90 were measured by enzyme-linked immunosorbent assay at two consecutive years (2012 and 2013). The results were evaluated as urine HSP/creatinine ratios (uHSP/Cr). Mean urine HSP27/Cr, HSP40/Cr, HSP60/Cr, HSP70/Cr, HSP90/Cr in patient group were significantly higher than in controls in 2012 (uHSP27/Cr 460.12 ± 217.64 versus 270.02 ± 136.83 pg/mgCr; uHSP40/Cr 180.89 ± 118.59 versus 99.44 ± 62.49 pg/mgCr; uHSP60/Cr 114.40 ± 64.91 versus 70.50 ± 43.70 pg/mgCr; uHSP70/Cr 41.17 ± 28.42 versus 16.47 ± 7.32 pg/mgCr; uHSP90/Cr 175.64 ± 102.22 versus 107.61 ± 75.85 pg/mgCr) (p < 0.05). In 2013, uHSP70/Cr level increased significantly (51.08 ± 27.72 pg/mgCr; p = 0.001), whereas uHSP60/Cr level decreased and uHSP27/Cr, uHSP40/Cr, uHSP90/Cr levels remained stable (p > 0.05). Area under the curve (AUC) for uHSP70/Cr (0.957) was significantly higher than the others. Using a cutoff 22.59 pg/mgCr for uHSP70/Cr to predict of diabetic damage, sensitivity and specificity were 85% and 96%, respectively. Our results suggest that uHSP70/Cr increases over time and may indicate early phases of progressive kidney damage in diabetic children.

Neutrophil Gelatinase-Associated Lipocalin as an Early Sign of Diabetic Kidney Injury in Children.

OBJECTIVE: There is some evidence indicating that histopathological changes in type 1 diabetes mellitus (T1DM) emerge before onset of microalbuminuria. The aim of our study was to determine whether urine neutrophil gelatinase-associated lipocalin (NGAL) levels can be considered as an early sign of diabetic kidney injury. METHODS: Urine NGAL (uNGAL) levels and urinary NGAL/creatinine ratio (uNGAL/Cr) were assessed in 76 patients with T1DM and compared with the findings of 35 healthy individuals. The relationship of uNGAL levels with diabetes duration, body mass index (BMI), serum lipids, HbA1c, and microalbuminuria was also evaluated. RESULTS: Mean uNGAL (100.16±108.28 ng/mL) and uNGAL/Cr (118.93-117.97 ng/mg) levels in both microalbuminuric and non-microalbuminuric diabetic patients were found to be higher than those in the control group (uNGAL: 21.46±18.59 ng/mL and uNGAL/Cr: 32.1±51.48 ng/mg) (p=0.0001). CONCLUSION: Urine NGAL level increases in the very early phase of T1DM before microalbuminuria develops. The patients with T1DM should be considered to have diabetic kidney injury from the time of diagnosis on and preventive interventions need to be initiated at an early stage to preclude the progression to end-stage renal disease.

Severe renal failure and hyperammonemia in a newborn with propionic acidemia: effects of treatment on the clinical course.

Neonatal-onset propionic acidemia (PA), the most common form, is characterized by poor feeding, vomiting, and somnolence in the first days of life in a previously healthy infant, followed by lethargy, seizures, and can progress to coma if not identified and treated appropriately. It is frequently accompanied by metabolic acidosis with anion gap, ketonuria, hypoglycemia, hyperammonemia, and cytopenias. PA is caused by deficiency of propionyl-CoA carboxylase (PCC), the enzyme that catalyzes the conversion of propionyl-CoA to methylmalonyl-CoA. Herein, we report a case of 3-day-old neonate with PA presented with acute renal failure and metabolic acidosis was effectively treated by peritoneal dialysis and conventional methods.