Renal Disease In Children Research Articles

Risk factors for end stage renal disease in children with anorectal malformation and outcome comparison to children with isolated urological anomalies

End stage renal disease (ESRD) requiring kidney transplant (KT) remains an important cause of morbidity in anorectal malformations (ARM) patients. Current literature is scarce on defining the risk factors for ESRD and the outcomes of KT in ARM patients. This study aimed to identify predisposing factors to ESRD in ARM patients and verify if the long term outcome of KT in these patients differs from pure urological anomalies (UA). Databases of ARM and KT patients treated at our center between 2000 and 2016 were used for comparing characteristics of ARM cases which developed ESRD and those who did not, and the outcome features of MAR-KT vs UA-KT. Out of 117 ARM patients, 9 developed ESRD. All of them had a complex ARM. Association with UA were significantly higher in ARM-KT compared to other ARM patients (100% vs. 52%, p=0.001). The most common UA associated to KT in ARM patients was renal dysplasia. During the same period 23 patients underwent KT as a sequelae of pure urological anomalies (UA-KT group). The most represented UA were primary vesico-ureteral reflux (65.2%) and posterior urethral valves (14%) in UA-KT (table 2). ARM-KT patients required more often hemodialysis before KT (50% vs. 8.7%, p=0.05) and an aorto-caval anastomosis at the transplant (75% vs. 30%, p=0.04) compared to UA-KT. Moreover ARM-KT patients experienced more often graft failure and and the need for a second KT (50% vs. 8.6%, p=0.02). To our knowledge, this is the first study describing the differences in terms of risk factors and outcomes of KT in ARM patients. We observed a need for KT in 7% of ARM, which is at the higher end of the range reported in the literature. Bilateral dysplasia and cloaca malformation seem the leading cause to ESRD for ARM patients compared to vesico-ureteral reflux and posterior urethral valve in UA-KT. Our experience showed that KT has worst outcome in ARM vs pure UA patients. Patients with complex ARM are more frequently associated to renal dysplasia which lead to KT. Graft in ARM patients seems to be the more vulnerable and prone to failure.

Agonists of prostaglandin E2 receptors as potential first in class treatment for nephronophthisis and related ciliopathies

Nephronophthisis (NPH) is an autosomal recessive tubulointerstitial nephropathy belonging to the ciliopathy disorders and known as the most common cause of hereditary end-stage renal disease in children. Yet, no curative treatment is available. The major gene, NPHP1, encodes a protein playing key functions at the primary cilium and cellular junctions. Using a medium-throughput drug-screen in NPHP1 knockdown cells, we identified 51 Food and Drug Administration-approved compounds by their ability to alleviate the cellular phenotypes associated with the loss of NPHP1; 11 compounds were further selected for their physicochemical properties. Among those compounds, prostaglandin E1 (PGE1) rescued ciliogenesis defects in immortalized patient NPHP1 urine-derived renal tubular cells, and improved ciliary and kidney phenotypes in our NPH zebrafish and Nphp1 knockout mouse models. Furthermore, Taprenepag, a nonprostanoid prostaglandin E2 receptor agonist, alleviated the severe retinopathy observed in Nphp1−/− mice. Finally, comparative transcriptomics allowed identification of key signaling pathways downstream PGE1, including cell cycle progression, extracellular matrix, adhesion, or actin cytoskeleton organization. In conclusion, using in vitro and in vivo models, we showed that prostaglandin E2 receptor agonists can ameliorate several of the pleotropic phenotypes caused by the absence of NPHP1; this opens their potential as a first therapeutic option for juvenile NPH-associated ciliopathies.

STUDY ON RISK FACTORS FOR RELAPSE IN CHILDHOOD NEPHROTIC SYNDROME IN A TERTIARY CARE CENTRE OF EASTERN INDIA

Background: Nephrotic syndrome is a common renal disease in children characterised by massive proteinuria,hypoalbuminemia(serum albumin <2.5g/dl),hyperlipidemia(serum cholesterol>200mg/dl) and edema.It has high propensity for relapse.Approximately 80-90%of steroid sensitive nephrotic syndrome patients experience one or more relapses during their lifetime. So,the main problem in such disease is relapses and their association with complications of disease or side effects of drugs like steroid used in treatment.An understanding of risk factors that determine the course,is useful in taking decisions regarding therapy and counselling of parents.Ascarcity of reported data on risk factors for relapse from eastern India prompted to carry out this study in a tertiary care hospital. Aims And Objectives:To determine different risk factors for relapse in childhood nephrotic syndrome. Materials And Method: A retrospective analysis of medical records of children with steroid sensitive nephrotic syndrome of 1-12 years of age,with history of disease onset atleast 1 year back,attending inpatient and outpatient department of Pediatric medicine,IPGME&R,Kolkata was carried out from February 2016 –July 2017 after obtaining ethical clearance from Instituitional Ethics committee and written informed consent from parents. Results: Records of 60 children with SSNS were reviewed.The mean age of the study population was7.3±2.7 years. Boys constituted 63.3% & girls constituted 36.7% of total study population. 23 patients were included in FRNS/SDNS group,rest 37 patients were in IFRNS/No relapse group.Data were analyzed by using SPSS 20.0.1 programme and Graph Pad Prism version 5. Chi-square test & Two-sample t-tests were used as statistical test & p value <0.05 was taken as signicant.Compared to IFRNS/No relapse,patients with FRNS/SDNS had signicantly more infections during 1st episode,more association with massive edema, more number of patients with inadequate duration of treatment (<8weeks or irregular) and longer achievement of remission(14.3±2.7 days vs10±2.1),shorter steroid free time interval between completion of treatment of 1st attack & onset of 1st relapse.FRNS group had signicantly less serum albumin(1.68±0.202 vs 2.05±0.17g/dl) during disease onset than IFRNS/No relapse group. Conclusion: Presence of infection & massive edema during disease onset, inadequate initial treatment,prolonged achievement of remission,low serum albumin during disease onset ,short steroid free time interval between completion of treatment of 1st attack &onset of 1st relapse were observed as statistically signicant risk factors for frequently relapse.These observations need to be validated by multicenter prospective study with larger sample size.

POS-787 LONG-TERM OUTCOMES OF KIDNEY TRANSPLANTATION IN CHILDREN WITH CAKUT VERSUS NON-CAKUT CAUSES OF CHRONIC KIDNEY DISEASE

Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of end stage renal disease in children. Little is known about long-term outcomes after kidney transplantation in this group. The aim of this study is to evaluate the clinical characteristics of pediatric kidney transplantation (KTx) in CAKUT children and its outcomes. We conducted a retrospective study, from December 2007 to December 2020, including living donor kidney transplant recipients ≤17 years transplanted in our center. Patients were divided into those with CAKUT and those with non-CAKUT as the cause of chronic kidney disease (CKD). Our aim was to compare delayed graft function (DGF) rate, acute rejection, complication’s rates, and graft loss between groups. A total of 259 living donor kidney transplants were done till 2019. 38 (15%) were ≤17 years, The cause of CKD was CAKUT in 13 patients (34,2%) and non-CAKUT in 25 patients. Of the latter, 15 (60%) had glomerular disease. The most common CAKUT-related cause of CKD was primary vesicoureteral reflux (84,6%). There was no difference in age between the groups, with a mean age of 13,4 +/- 2,9 years in the CAKUT group and 12,7 +/- 3,4 years in the non-CAKUT group (p=0,542). Recipients with CAKUT showed female preponderance, and were more likely to be seropositive for both CMV and EBV (all p<0,05). A nephrectomy is most often performed in patients with CAKUT (53,8%) versus 4,3% in the non CAKUT patients (p=0,001). For both groups, there was no difference in cytotoxic PRA (15,4 % vs 16%, p=0,331) or mean number of compatibilities (3,53 vs 2,92, p=0,314). The post transplant hypertension was significantly higher in non CAKUT recipients than in those with CAKUT (p=0,049). . Compared to non CAKUT-group, CAKUT patients had more urinary tract infection (p=0,043). There was no difference in DGF (7,7% vs 8%, p=0,734), Acute rejection (7,7% vs 20%, p=0,141) or graft loss (7,7% vs 8%, p=0,784). Graft survival of the transplant in children with CAKUT is favourable. However, they have an increased risk of urinary tract infections.

End Stage Renal Disease in Children in Bahrain: Etiology and Outcome

Background: End-stage renal is an overwhelming illness associated with high morbidity and mortality worldwide. Identifying the risk factors in children and planning preventive strategies is of great significance. The aim of the present study is to assess the etiology and outcome of end-stage renal disease in children in Bahrain. Methods: As a part of the retrospective analysis, all children with end-stage renal disease were below 16 years and were on renal replacement therapies between 2008 and 2018. Data were collected from patients' chart and electronic medical records. Results: Out of the total 50 children (with end-stage renal disease) who enrolled for the study, the subjects were 37 (74%) and 13 (26%) were boys and girls, respectively. Among the subjects, 19 patients (38%) were diagnosed with congenital anomalies of the kidneys and urinary tract as the main cause of end-stage renal disease. Posterior uretheral valve was the main abnormality seen in 12 (24%) patients. Inherited renal diseases were the second leading cause of end-stage renal disease in children 15 (30%) patients. Glomerulopathies accounted for 12% of the total patients, focal segmental glomerulosclerosis was the most common glomerulopathy seen in 5 (10%) patients. 28 patients (56%) received hemodialysis; 18 patients (36%) received peritoneal dialysis. 24 (48%) children had renal transplantation, 4 children (8%) underwent preemptive kidney transplantation, while 3 (6%) children died. Conclusions: Congenital anomalies of the kidneys and urinary tract is the leading cause of end-stage renal disease in children followed by hereditary diseases. Thus, planning preventive strategies and counselling support for the children and their families are of great importance. Keywords: Bahrain, Chronic kidney disease, kidney transplantation, peritoneal dialysis, renal dialysis, urogenital abnormalities

Early Evidence on Genetic Polymorphisms in Conferring A "Two-Hit" Propensity to Renal Injury in Asian Indian Children.

Congenital anomalies of the kidney and urinary tract (CAKUT) are a common cause of end-stage renal disease in children. While certain nephrogenic genes have been incriminated in these malformations, data to identify the frequency of gene polymorphisms in Asian Indian children with CAKUT are scarce. This study was done to identify the effect of polymorphisms in paired-box gene 2 (PAX2), bone morphogenetic protein (BMP)-4, angiotensin-converting enzyme (ACE), and angiotensin II receptor Type 2 (AGTR2) nephrogenic genes on the development of CAKUT. In this prospective cohort study, 158 children <12 years old (86 cases with CAKUT and 72 age-matched controls) were analyzed. DNA from both sets was extracted from peripheral blood using the Keygen DNA extraction kit, and single-nucleotide gene polymorphisms (SNPs) in PAX2, BMP-4, ACE, and AGTR2 nephrogenic genes were detected by polymerase chain reaction (PCR) using previously published primers and PCR conditions. The presence of A allele SNP for AGTR2 gene at rs3736556 was found to be significantly correlated with the development of ureteropelvic junction obstruction and vesicoureteral reflux (VUR) with the TT allelic genotype having a lower incidence of pelviureteric junction obstruction (odds ratio [OR] 0.18 [95% confidence interval [CI], 0.06-0.55], P = 0.01) and VUR (OR 0.31 [95% CI, 0.11-0.91], P = 0.03). Furthermore, on substratification of the patients with the presence of the A allele of AGTR2, 24 out of 27 patients with scarring were found to harbor the D allele of the ACE gene, thus predisposing them to further renal damage. This study points to early evidence in the implication of nephrogenic genes in development as well as predisposition to renal injury in Asian Indian patients with CAKUT.

Pop-off mechanisms as protective factors against chronic renal disease in children with posterior urethral valves.

To identify whether pop-off mechanisms act as protective factors against chronic or end-stage renal disease in patients with posterior urethral valves. A retrospective cohort study of patients with posterior urethral valves treated at a tertiary care children's hospital was carried out. Demographic, clinical, analytical, and radiological variables were collected. Considered as pop-off mechanisms were: unilateral high-grade vesicoureteral reflux with ipsilateral renal dysplasia and without involvement of the contralateral kidney, urinoma, prenatal urinary ascites, large bladder diverticulum, and persistent urachus. Multiple logistic regression and multivariate Cox regression were used for statistical analysis. 70 patients undergoing posterior urethral valve surgery in our institution from 2010 to August 2020 were included. 14 (20%) had pop-off mechanisms and 56 (80%) did not. Pop-off mechanisms protected against developing chronic renal disease (0% vs. 27%; p=0.03) and could protect against the need for renal replacement therapy (0% vs. 9%; p=0.58). Nadir creatinine values (mg/dl) were predictors for the development of chronic renal disease (0.37 vs. 0.53; p<0.0001) and the need for renal replacement therapy (0.38 vs. 1.21; p<0.001). Pop-off mechanisms act as a protective factor against chronic renal disease in patients with posterior urethral valves. Nadir creatinine is a predictor of chronic renal disease and the need for renal replacement therapy. A larger sample size is needed to determine whether pop-off mechanisms protect against the need for renal replacement therapy.

Changing pattern of renal disease in children at pediatric nephrology clinic of a tertiary teaching hospital, Nepal: 10-year review

Introduction: Children present with different renal diseases with variations according to different geographic locations. This study aims to determine the trend of pediatric renal disease presenting. Method: This retrospective study from pediatric nephrology clinic register during 2008 to May 2018 at Patan Hospital, Patan Academy of Health Sciences, Nepal to analyze the changing pattern of renal disease. The prevalence and characteristic of renal diseases were compared between the 1st and 2nd 5-y period, the age at presentation and gender was analyzed. Mean age at presentation was analyzed by independent t-test, a p-value &lt;0.05 was considered significant. The study was approved by the ethical committee. Result: A total of 352 children visited the nephrology clinic, male:female ratio 1.42:1, mean age 6.25±4.5 y, the majority in 0-5 y. Congenital anomalies of the kidney and urinary tracts (CAKUT) were 39%, mostly vesicoureteral reflux. Acute glomerulonephritis and the nephrotic syndrome were seen in 32.7% and 23.6%. Children &lt;5 y of age presented with CAKUT while ≥5 y with acute glomerulonephritis. The mean age at presentation for CAKUT was 2.9±3 y and acquired diseases 8.46±3.91 y, p-value&lt;0.05; and for glomerulonephritis 9.8±2.91 y and nephrotic syndrome 6.91±4.08 y, p-value&lt;0.05. Conclusion: There was a decrease in the number of children visiting the nephrology clinic. Children &lt;5 y presented with CAKUT while ≥5 y had acquired conditions. Children with acute glomerulonephritis were of a higher age than children with nephrotic syndrome.

Immunoglobulin A nephropathy in paediatrics: An up‐to‐date

Immunoglobulin A nephropathy is the main cause of glomerulonephritis globally and an important aetiology of end-stage renal disease in children. It has been considered an autoimmune disease that can lead to the production of autoantibodies against abnormal IgA1 and formation of immune complexes. These autoantibodies and immune complexes deposit in the glomeruli, resulting in renal injury. At the beginning of IgA nephropathy course, most patients are asymptomatic and the first clinical manifestations in children are macroscopic hematuria and proteinuria. The diagnosis is defined by the detection of IgA mesangial deposits in kidney biopsy using immunofluorescence techniques. The Oxford MEST-C score is the most used classification to associate histological findings and clinical outcomes, being validated for application in children. Recommended treatment options are antihypertensive and antiproteinuric therapy, corticosteroids, immunosuppressive agents, and other non-pharmacological approaches. There is no ideal prognosis indicator but new perspectives are in science's scope to find possible biomarkers of the disease through OMICS's research. This review aims to summarize and to up-to-date the scientific literature on paediatric IgA nephropathy, focusing on pathophysiology, clinical findings, histopathology, current treatment, prognosis, and future perspectives.

Association of nephronophthisis 4 genetic variation with cardiorenal syndrome and cardiovascular events in Japanese general population: the Yamagata (Takahata) study

Abstract Background Nephronophthisis (NPHP) 4 gene encoding nephrocystin-4, which contributes to end-stage renal disease in children and young adults, is involved in the development of the heart and kidneys. Cardiorenal syndrome (CRS), which consists of bidirectional dysfunction of the heart and kidneys, is a risk factor for cardiovascular events. Single nucleotide polymorphisms (SNPs) within the NPHP4 gene are reportedly associated with kidney function, even in adults. However, the association of NPHP4 gene variability with CRS and cardiovascular events remains unknown. Purpose To examine whether NPHP4 gene variability is related to CRS and cardiovascular events in general population. Methods and results This prospective cohort study included 2,946 subjects who participated in a community-based health study with a 16-year follow-up period. We genotyped 11 SNPs within the NPHP4 gene whose minor allele frequency was greater than 0.1 in the Japanese population. The SNP rs12058375 was significantly associated with CRS and cardiovascular events. Multivariate logistic analysis demonstrated a significant association between the homozygous A-allele of rs12058375 with the presence of CRS. Haplotype analysis identified the haplotype with the A-allele of rs12058375 as an increased susceptibility factor for CRS. Kaplan-Meier analysis demonstrated that homozygous A-allele carriers of rs12058375 had the greatest risk of developing cardiovascular events among the NPHP4 variants. Multivariate Cox proportional hazard regression analysis revealed that the homozygous A-allele and heterozygous carriers of rs12058375 were associated with cardiovascular events after adjusting for confounding factors. The net reclassification index and integrated discrimination index were significantly improved by the addition of rs12058375 as a cardiovascular risk factor. Conclusion Genetic variations in the NPHP4 gene were associated with CRS and cardiovascular events in the general population, suggesting that it may facilitate the early identification of high-risk subjects with CRS and cardiovascular events. Funding Acknowledgement Type of funding sources: None.

Association of Nephronophthisis 4 genetic variation with cardiorenal syndrome and cardiovascular events in Japanese general population: the Yamagata (Takahata) study.

Nephronophthisis (NPHP) 4 gene encoding nephrocystin-4, which contributes to end-stage renal disease in children and young adults, is involved in the development of the heart and kidneys. Cardiorenal syndrome (CRS), which consists of bidirectional dysfunction of the heart and kidneys, is a risk factor for cardiovascular events. Single-nucleotide polymorphisms (SNPs) within the NPHP4 gene are reportedly associated with kidney function, even in adults. However, the association of NPHP4 gene variability with CRS and cardiovascular events remains unknown. This prospective cohort study included 2946 subjects who participated in a community-based health study with a 16-year follow-up period. We genotyped 11 SNPs within the NPHP4 gene whose minor allele frequency was greater than 0.1 in the Japanese population. The SNP rs12058375 was significantly associated with CRS and cardiovascular events. Multivariate logistic analysis demonstrated a significant association between the homozygous A-allele of rs12058375 with the presence of CRS. Haplotype analysis identified the haplotype with the A-allele of rs12058375 as an increased susceptibility factor for CRS. Kaplan-Meier analysis demonstrated that homozygous A-allele carriers of rs12058375 had the greatest risk of developing cardiovascular events among the NPHP4 variants. Multivariate Cox proportional hazard regression analysis revealed that the homozygous A-allele and heterozygous carriers of rs12058375 were associated with cardiovascular events after adjusting for confounding factors. The net reclassification index and integrated discrimination index were significantly improved by the addition of rs12058375 as a cardiovascular risk factor. Genetic variations in the NPHP4 gene were associated with CRS and cardiovascular events in the general population, suggesting that it may facilitate the early identification of high-risk subjects with CRS and cardiovascular events.

The pattern of Atopy in Childhood Nephrotic Syndrome-A Tertiary Hospital Study

Background: Idiopathic nephrotic syndrome is a common renal disease in children. Various atopic disorders are found in 30%-60% cases with childhood nephrotic syndrome.&#x0D; Objective: To evaluate the association of atopic disorders with childhood idiopathic nephrotic syndrome.&#x0D; Methods: This case-control study was conducted in the Department of Paediatrics, Sir Salimullah Medical College Hospital from January 2012 to December 2012. Fifty children of idiopathic nephrotic syndrome between 2 to 10 years of age were included and the diagnosis was based on history, clinical features and laboratory evidence. Age and sex-matched controls were taken from pediatrics outdoor who attended for problems other than nephrotic syndrome. Data regarding atopic disorders in both groups were collected and then analyzed.&#x0D; Results: Mean ages in this study were 5.32±2.88 years and 5.34±2.87 years in case and control respectively. The male-female ratio was 1.7: 1 in both groups. A positive history of atopy was present in 46.0% of cases and 20.0% in controls. Atopic disorders were asthma (42.0% vs. 20.0%), allergic rhinitis (30% vs. 10%), atopic dermatitis (0.0% vs. 2.0%) and allergic conjunctivitis (0.0% vs. 2.0%) found in cases and controls respectively. Bronchial asthma was frequently (37.5%) found in frequent relapse nephrotic syndrome compared to infrequent relapse and the first attack of nephrotic syndrome.&#x0D; Conclusion: Children with idiopathic nephrotic syndrome had a higher incidence of atopy. Asthma and allergic rhinitis was found as common atopic disorders associated with childhood idiopathic nephrotic syndrome.&#x0D; BANGLADESH J CHILD HEALTH 2021; VOL 45 (1) : 6-9

MO1018IS LOW NORMAL BLOOD PRESSURE LEVEL IN PATIENTS WITH X-LINKED ALPORT SYNDROME OUR GOAL?

Abstract Background and Aims The mean blood pressure &amp;lt;50th percentile for age, gender and height is recommended in children with chronic kidney disease, especially in case of proteinuria. The aim was to define the influence of low normal mean blood pressure level on the progression of renal disease in children with X-linked Alport syndrome (XLAS). Method mean day blood pressure normalized for sex, age, height (MBP), urine protein (mg/m2/day) and eGFR were assessed in retrospective single center study. Results The children with XLAS (n=69, 47M, age 9.49±4.18 years, eGFR=109±17.36 ml/min/1,73m2) were divided into 3 groups according the MBP level during follow up (4[3;5] years): (1) MBP&amp;lt;50‰ (n=27, 13М), (2) MBP 50-90‰ (n=33, 25M), (3) MBP≥90‰ (9М). The decline of eGFR (ml/min/1,73m2/year) was higher in male (-3[-0.8;-4.7] vs 0.2[-0.4;2]; χ2= 21.15587, p = 0.0067), in children with MBP ≥90‰ (0.65[-2.65;2] vs -2.3[-6;2.3] vs -3[-7.5;-1.8] in 1st, 2nd and 3 groups, respectively; р1,3=0.0091) and in patients with proteinuria (-2.5[-7;0.5] vs 0.2[-4;3]; p=0.0018). The risk of achieving eGFR&amp;lt;60 ml/min/1,73m2 was higher in pts of 3 group (OR=5.33, 95% CI 1.75;16.22) especially in the presence of proteinuria (OR=7.08, 95% CI 2.46;20.39). The multivariate analysis of predictive factors for eGFR reduction showed that the proteinuria (χ2=12.554, p=0.0019), the male gender (χ2=7.107, p=0.0077) and not MBP (χ2=5.4, p=0.07) were independent risk factors for eGFR decline. Conclusion The male gender and proteinuria are independent risk factors for renal disease progression in children with XLSA. We assumed that the goal of treatment, at least in XLAS’ patients with normal blood pressure, is to decrease proteinuria.

Long-term outcomes of living-donor kidney transplant children weighing less than 15 kg: Comparison of the surgical approach

Kidney transplantation (KTx) is the most effective treatment for end-stage renal disease in children. We aimed to compare the long-term outcomes and surgical complications of the intraperitoneal approach (IPA) and extraperitoneal approach (EPA) for KTx in children weighing <15kg. We performed a retrospective cohort study on pediatric kidney transplant recipients, weighing <15kg, who received their first living-related kidney transplant between January 1987 and December 2015. Patients were divided into two groups based on the surgical approach (IPA or EPA) during transplant, and clinical data were extracted from the medical records. The median follow-up duration was 14.1 years (interquartile range, 9.0-19.2). Comparing the two groups (IPA group, n=62; EPA group, n=38), the median age and body weight were significantly lower in the IPA group (4.2 vs. 4.8 years, P=0.03; 11.7 vs. 13.0kg, P<0.01). There were 26 surgical complications (26%) in 19 patients during the follow-up period. The surgical complication rate was higher in the IPA group (39% vs. 6%). We assessed the long-term outcomes of the surgical approaches used for pediatric patients weighing <15kg who underwent KTx and received a size-mismatched adult donor kidney. There was no significant difference in renal transplantation prognosis using the surgical approach, but IPA-related complications were more frequent in the long term. Therefore, our data suggest that in cases of donor-recipient size mismatch in pediatric KTx, the EPA, associated with fewer surgical complications, is preferable to the IPA if the patient's body size has sufficient space for allograft placement. The transplant approach did not influence the long-term outcomes in children weighing <15kg, but EPA had fewer surgical complications and was technically safe.

Renal Ciliopathies: Sorting Out Therapeutic Approaches for Nephronophthisis.

Nephronophthisis (NPH) is an autosomal recessive ciliopathy and a major cause of end-stage renal disease in children. The main forms, juvenile and adult NPH, are characterized by tubulointerstitial fibrosis whereas the infantile form is more severe and characterized by cysts. NPH is caused by mutations in over 20 different genes, most of which encode components of the primary cilium, an organelle in which important cellular signaling pathways converge. Ciliary signal transduction plays a critical role in kidney development and tissue homeostasis, and disruption of ciliary signaling has been associated with cyst formation, epithelial cell dedifferentiation and kidney function decline. Drugs have been identified that target specific signaling pathways (for example cAMP/PKA, Hedgehog, and mTOR pathways) and rescue NPH phenotypes in in vitro and/or in vivo models. Despite identification of numerous candidate drugs in rodent models, there has been a lack of clinical trials and there is currently no therapy that halts disease progression in NPH patients. This review covers the most important findings of therapeutic approaches in NPH model systems to date, including hypothesis-driven therapies and untargeted drug screens, approached from the pathophysiology of NPH. Importantly, most animal models used in these studies represent the cystic infantile form of NPH, which is less prevalent than the juvenile form. It appears therefore important to develop new models relevant for juvenile/adult NPH. Alternative non-orthologous animal models and developments in patient-based in vitro model systems are discussed, as well as future directions in personalized therapy for NPH.

Overexpression of Long Non-coding RNA 4933425B07Rik Causes Urinary Malformations in Mice.

Congenital anomalies of the kidney and urinary tract (CAKUT) is a common birth defect and is the leading cause of end-stage renal disease in children. The etiology of CAKUT is complex and includes mainly genetic and environmental factors. However, these factors cannot fully explain the etiological mechanism of CAKUT. Recently, participation of long non-coding RNAs (lncRNAs) in the development of the circulatory and nervous systems was demonstrated; however, the role of lncRNAs in the development of the kidney and urinary tract system is unclear. In this study, we used the piggyBac (PB) transposon-based mutagenesis to construct a mouse with lncRNA 4933425B07Rik (Rik) PB insertion (RikPB/PB) and detected overexpression of Rik and a variety of developmental abnormalities in the urinary system after PB insertion, mainly including renal hypo/dysplasia. The number of ureteric bud (UB) branches in the RikPB/PB embryonic kidney was significantly decreased in embryonic kidney culture. Only bone morphogenetic protein 4 (Bmp4), a key molecule regulating UB branching, is significantly downregulated in RikPB/PB embryonic kidney, while the expression levels of other molecules involved in the regulation of UB branching were not significantly different according to the RNA-sequencing (RNA-seq) data, and the results were verified by quantitative real-time polymerase chain reaction (RT-PCR) and immunofluorescence assays. Besides, the expression of pSmad1/5/8, a downstream molecule of BMP4 signaling, decreased by immunofluorescence. These findings suggest that abnormal expression of Rik may cause a reduction in the UB branches by reducing the expression levels of the UB branching-related molecule Bmp4, thus leading to the development of CAKUT.

Risk Factors Associated With Renal Involvement in Childhood Henoch-schonlein Purpura

Context: Henoch-Schonlein purpura (HSP) is a significant cause of chronic renal disease in children. This review determines some risk factors associated with renal involvement in childhood HSP. Evidence Acquisition: Electronic databases, including Google Scholar, PubMed, and Scopus were searched using the following keywords: “children”, “Henoch-Schonlein”, “risk factor”, “renal involvement”, and “IgA vasculitis”. This review was designed to identify the relevant electronic studies published in the English language from December 1998 to August 2018. Results: This review revealed that clinically older age at presentation, persistent rash, atypical rash, rash on unusual location, and gastrointestinal bleeding were significant risk factors for renal involvement. In contrast, joint involvement was not associated with renal involvement. Among biochemical markers, high red blood cell distribution width is a risk marker of renal involvement in HSP. In contrast, peripheral blood immunoglobulin A, antinuclear antibody, anti-streptolysin O titer, erythrocyte sedimentation rate, and C-reactive protein were not associated with renal involvement. In several studies, leukocytosis, thrombocytosis, or thrombocytopenia have been mentioned as predictors for renal involvement. Still, other studies showed the white blood cell count or platelet count are not risk factors. The effect of corticosteroids as a predictive factor of renal involvement in HSP is challenging and controversial. Furthermore, their impact was dose-dependent. Conclusions: Demographic factors, clinical features, and some abnormal laboratory findings are significant predictive factors for renal involvement in HSP.

Efficacy of tacrolimus in steroid dependent and steroid resistant childhood nephrotic syndrome - A retrospective study

Introduction: Nephrotic syndrome is a common renal disease in children. Majority of the children usually responds to steroids without any long term effects on kidney function. However about 10-20% of children are usually steroid dependent or steroid resistant and require multiple additional immunosuppressive medications such as cyclophosphamide, cyclosporine, tacrolimus, mycophenolate mofetil and Rituximab. All these drugs are associated with specific adverse effects and lack of response to the drug can result in slow decline in renal function and development of end stage renal disease. Material and Methods:A retrospective study was done to determine the efficacy of tacrolimus in steroid dependent and steroid resistant nephrotic syndrome (SDNS and SRNS). 40 children with SDNS and SRNS were included in the study. All patients were observed for complete remission, partial remission, decline in renal function and adverse effects of the drug. Results:Study included 40 patients of SDNS (n=19) and SRNS (n=21) with 18 boys and 22 girls with mesangioproliferative glomerulonephritis (MPGN) in 1. Complete remission was achieved in 14 children in SDNS group and 11 children in SRNS group. 3 children in SDNS group and 4 children in SRNS group did not achieve any remission despite treatment for 6 to 12 months. Adverse effects of the drugs included infections, tremors and hyperglycemia and were similar in both the groups.mean duration of follow up of 24 months. Renal biopsy of patients showed minimal change disease (MCD) in 23, focal segmental glomerulosclerosis (FSGS) in 13, IgM nephropathy in 3 and Conclusion: Tacrolimus is efficacious in inducing and maintaining remission in children with steroid dependent and steroid resistant nephrotic syndrome with minimal adverse effects. Keywords: Steroid resistant nephrotic syndrome, Calcineurin inhibitor, cyclosporine, tacrolimus, minimal change disease.

Henoch-Schönlein purpura in children: Use of corticosteroids for prevention and treatment of renal disease.

A few patients have previously presented to my clinic with palpable purpura, joint inflammation, and severe abdominal pain characteristic of Henoch-Schönlein purpura (HSP). Considering that renal injury is the primary long-term complication of HSP, are corticosteroids effective in preventing or treating renal disease in children with HSP? Henoch-Schönlein purpura is self-limiting in 94% of children, but permanent renal injury is reported in one-fifth of children with nephritic or nephrotic features. Corticosteroids have been considered as candidates for preventing and treating renal involvement in HSP. There is a moderate level of evidence to suggest corticosteroids are not effective in preventing renal involvement in HSP. However, based on low-level evidence and similarities with primary immunoglobulin A nephropathy, experts recommend corticosteroids in treating renal involvement in HSP to prevent long-term kidney injury. Dose and duration of therapy should be carefully considered in consultation with a pediatric nephrologist.

Blood pressure level and progression of renal disease in children with Х-linked Alport syndrome

AIM : The aim was to determine the significance of blood pressure level on progression of renal failure in children with X-linked Alport syndrome. PATIENTS AND METHODS . eGFR, urine proteine (mg/m 2 /day), mean day blood pressure – MBP (normalized for sex, age, height) were assessed in retrospective single center study. RESULTS . A 69 children (age 9.49±4.18 years, М/ F=47/22, eGFR=109±17.36 ml/min/1,73m 2 ) were followed for 4[3;5] years. The 27 pts (М/F=13/14) had MBP<50‰, the 33 children (М/F=25/8) – MBP 50-90‰ and pts (М/F=9/0) – MBP≥90‰. Rate of eGFR decline was higher in male (-3[-0.8;-4.7] vs 0.2[-0.4;2]; χ 2 = 21.15587, p = 0.0067), in pts with MBP ≥90‰ (0.65[-2.65;2] vs -2.3[-6;2.3] vs -3[-7.5;-1.8] in 1st, 2 nd and 3 groups, respectively; р 1,3 =0.0091) and proteinuria (-2.5[-7;0.5] vs 0.2[-4;3]; p=0.0018). Patients with blood hypertension had high risk of renal failure (OR=5.33, 95 % CI 1.75;16.22), especially in cases of proteinuria (OR=7.08, 95 % CI 2.46;20.39). MBP<50‰ associated with low risk of renal disease progression (OR=0.83, 95 % CI 0.31;2.2), especially in boys and proteinuric patients. The male gender and proteinuria are independent risk factors for eGFR decline. CONCLUSIONS . MBP≥90‰ is associated with renal disease progression, especially in case of proteinuria; the MBP<50‰ reduced the risk of eGFR decline in male and proteinuric patients with Alport syndrome; the male gender and proteinuria are independent risk factors for renal disease progression in children with Alport syndrome.