Kidney Disease In Childhood Research Articles

Kidney transplantation in pediatric patients with rheumatologic disorders.

Providers caring for children with end-stage kidney disease from rheumatologic conditions face questions such as when to proceed with kidney transplantation, how common is disease recurrence posttransplant, how does recurrent disease impact patient and allograft outcomes, and what approaches are available to prevent and treat recurrent disease. We discuss recent developments and relevant literature that address these questions for the most common rheumatologic disorders that lead to end-stage kidney disease in childhood namely, systemic lupus erythematosus, IgA nephropathy, IgA Vasculitis/Henoch Schoenlein Purpura, and Anti-Neutrophil Cytoplasmic Antibody (ANCA)-associated vasculitis. Recent data suggest that children with IgA nephropathy, IgA vasculitis, and ANCA-associated vasculitis have similar patient and allograft survival to other conditions despite the risk of recurrent disease, yet those with lupus have worse posttransplant patient and allograft outcomes. A period of disease quiescence may be prudent prior to transplantation to decrease the risk of recurrence, which is associated with decreased allograft survival. Data on preventive strategies and treatment options are limited. It is recommended that patients with systemic rheumatologic conditions not be excluded from kidney transplantation but that patients be counseled on the risk of potential recurrent disease with its impact on transplant outcomes.

Chronic intracellular hypoxia as a clustering and stratifying factor for clinical severity grade in nephrotic syndrome in children

Abstract. Nephrotic syndrome is the most common glomerular kidney disease in childhood. It is known that chronic hypoxia is a severe disorder and potent factor of kidney damage. The limited success of existing therapeutic strategies in slowing the progression of chronic kidney disease requires the study of new ways to assess and interpret the levels of chronic intracellular hypoxia concerning basic clinical data, grades of NS activity in children, type of therapeutic response.
 The study aimed to investigate the state of transcription factor and marker of intracellular hypoxia HIF-1alfa in children with different degrees of change in basic clinical and laboratory parameters; to evaluate HIF-1alfa as a possible factor of stratification of activity grade of nephrotic syndrome.
 Methods. This case-control study was carried out in the duration from June 2018 to August 2020. The study was conducted on 35 selected patients with NS collected from the nephrology department, Pediatric Clinical Hospital №7 (Kyiv, Ukraine). Plasma samples were used to measure marker intracellular hypoxia HIF-1alfa. ANOVA followed by the post hoc Kruskal-Wallis test for multiple comparisons was used to test the significance of differences. GraphPad Prism 9.0 Software for Windows and Statistica 10.0 software used. P values <0,05 considered statistically significant.
 Results. Three groups of children with different activity grades were stratified on basis of indicators of proteinuria levels, total blood protein, blood alpha2-globulin levels, serum cholesterol levels, and edema. 1st-grade group found to have a mild increase of HIF-1alfa up to 185-195 a.u. proteinuria 3,5-5,5 g/24 h, total blood protein 47-53 g/L, alfa2-globulins level in blood 20-23 g/L, serum cholesterol level 6-8,5 mMol/L, edema - 1-1.6 points. 2nd grade group found to have moderate increase of HIF-1alfa up to 195,1-205 a.u., proteinuria 5,51-8,5 g/24 h, total blood protein 46,9-40 g/L, alfa2-globulins level in blood 23,1-27 g/L, serum cholesterol level 8.51-10,5 mMol/L, edema 1.61-2.2 points. 3rd-grade group found to have pronounced increase of HIF-1alfa up to 205,1-220 a.u., proteinuria 8,51-14 g/24 h, total blood protein 39,9-32 g/L, alfa2-globulins level in blood 27,1-30 g/L, serum cholesterol level 10.51-13.5 mMol/L, edema 2.21-3 points. Higher HIF-1alfa level appears in children with NS and frequent relapses as compared to the group with rare relapses.
 Conclusion. Thus, the increase of HIF-1 alpha to the level of 185-205 a.u., which corresponds to the I-II degree of activity in children with NS can be used as a starting point and therapeutic window for specific anti-hypoxic and antioxidant interventions. Determination of HIF-1 alpha levels in children with NS can be used as a factor for stratification of the activity grade.

Development of a patient-reported outcome measure for the assessment of symptom burden in pediatric chronic kidney disease (PRO-Kid).

BackgroundChronic kidney disease (CKD) and kidney failure in childhood are associated with significant and life-altering morbidities and lower quality of life. Emerging evidence suggests that management should be guided in part by symptom burden; however, there is currently no standardized assessment tool for quantifying symptom burden in this pediatric population. This study aimed to develop and refine a patient-reported symptom assessment tool for children with CKD/kidney failure (PRO-Kid), to evaluate the frequency and impact of symptoms.MethodsThis was a prospective observational study of children and caregivers of children with CKD/kidney failure at two Canadian pediatric care centers. Building on previously published patient-reported outcome measures (PROs) for the assessment of symptom burden in other populations, we drafted a 13-item questionnaire. Cognitive interviews were performed with children and caregivers of children with CKD/kidney failure to iteratively refine the questionnaire.ResultsTwenty-four participants completed cognitive interviewing (11 children, 13 caregivers). The most common symptoms endorsed were feeling left out, feeling sad/depressed, inability to focus, tiredness, nausea, vomiting, not wanting to eat, and changes in the taste of food. Feeling left out was added to the questionnaire as almost all participants voiced this as a frequent and impactful symptom, resulting in a 14-item questionnaire.ConclusionsPRO-Kid is the first pediatric CKD/kidney failure-specific PRO tool to assess symptom burden. Future work should validate this tool in a larger cohort so that it may be used to improve the care of children living with CKD/kidney failure.Graphical abstractA higher resolution version of the Graphical abstract is available as Supplementary information Supplementary InformationThe online version contains supplementary material available at 10.1007/s00467-021-05269-4.

The causes and consequences of paediatric kidney disease on adult nephrology care.

Adult nephrologists often look after patients who have been diagnosed with kidney disease in childhood. This does present unique challenges to the adult nephrologist, who may be unfamiliar with the underlying cause of kidney disease as well as the complications of chronic kidney disease (CKD) that may have accumulated during childhood. This review discusses common causes of childhood CKD, in particular congenital anomalies of the kidney and urinary tract (CAKUT), autosomal dominant tubulointerstitial kidney disease (ADTKD), polycystic kidney disease, hereditary stone disease, nephrotic syndrome and atypical haemolytic uraemic syndrome. The long-term consequences of childhood CKD, such as the cardiovascular consequences, cognition and education as well as bone health, nutrition and growth are also discussed.

Clinical manifestations, prognosis, and treat-to-target assessment of pediatric lupus nephritis

BackgroundPediatric lupus nephritis (pLN) is one of the most refractory secondary kidney diseases in childhood. The treat-to-target (T2T) strategy has become the standard treatment for systemic lupus erythematosus (SLE). This study reviewed clinical features, overall remission status, and factors affecting prognosis, to guide pLN management according to T2T strategy.MethodsThis single-center retrospective study studied 220 children diagnosed with LN from January 2012 to December 2018, with > 6-month follow-up data on 173 and complete data on 137 patients. Primary outcome was treatment failure (deterioration or no response) at the latest follow-up.ResultsThe most common pLN manifestation was proteinuria (81.36%). Females presented more often with rash (P<0.001) and alopecia (P=0.026) than males. Class IV LN (33.33%) was the most common grade on kidney biopsy. Median follow-up was 27.20 months (IQR, 15.78–44.45 months). One-, 3-, and 5-year cumulative overall survival rates were 93.5%, 87.8%, and 86.5%, respectively. The 5-year cumulative kidney survival rate was 97.1%. Regarding initial therapy, efficacy of corticosteroids combined with immunosuppressive agents was significantly better than corticosteroids alone (P=0.010). Factors with P<0.05 in univariate analysis, including hypoalbuminemia, higher SCr at diagnosis, lower eGFR at diagnosis, anti-dsDNA positivity, heavy proteinuria, hypertension, nervous-system involvement, treatment non-compliance, and SLEDAI-2K score, were used for logistic regression analysis. Logistic regression analysis showed hypertension (OR=0.845, P=0.011), nervous-system involvement (OR=4.240, P=0.005), treatment non-compliance (OR=6.433, P=0.001), and lower estimated glomerular filtration rate at diagnosis (OR=1.020, P=0.021) affected prognosis. At end of follow-up, 34.31% achieved varying levels of remission, and 8.76% were in low disease activity state (LDAS).ConclusionspLN usually presented with proteinuria, and class IV LN was the dominant pathology. Hypertension, nervous-system involvement, treatment non-compliance, and lower eGFR at diagnosis were independent risk factors for poor prognosis of kidney outcomes. Compared with renal remission rate and cumulative overall survival rate, the proportion of targets achieved was not ideal, suggesting T2T strategy should be used to guide pLN management.Graphical abstractA higher resolution version of the Graphical abstract is available as Supplementary information.

Pathogenetic markers of diagnostics and prediction of chronic kidney disease in children

The authors present their own results of scientific research on the clinical and paraclinical characteristics of various stages of chronic kidney disease in children. They determine pathogenetic markers for the diagnosis and prognosis of chronic kidney disease in childhood with the assessment of the set of endothelial dysfunction markers. The authors proved diagnostic and prognostic value of a stepwise increase in arterial hypertension, urinary excretion of prosclerotic, pro-inflammatory cytokines and growth factors with a simultaneous decrease in urinary excretion of anti-inflammatory cytokines, an increase in the level of microalbuminuria, disturbances of urodynamics and intrarenal hemodynamics.The authors developed an algorithm for the diagnosis of chronic kidney disease in childhood, taking into account pathogenetic factors with an assessment of the complex of clinical and paraclinical, structural, functional parameters, hemodynamic changes in the kidneys in combination with the parameters of endothelial function and cytokine status.

Clinical profile of children with primary vesicoureteric reflux and its association with renal parenchymal scarring

Context: Vesicoureteric reflux (VUR) has been implicated in renal injury before birth as well as in postnatal occurrence of urinary tract infection (UTI) and further renal damage. About 30–49% of children with primary VUR may develop renal scarring called reflux nephropathy. About 5–10% of children with reflux nephropathy may progress to chronic kidney disease in late childhood. Objectives: The objectives of the study were to study the clinical profile of children with primary VUR and to assess the relationship with grades of primary VUR and renal parenchymal scarring. Materials and Methods: Fifty children of age 1 month–5 years, diagnosed to have Primary VUR, were included in this prospective observational study. Detailed history was taken; examination was carried out as per the study protocol. Investigations included urine analysis, renal function tests, urine culture, renal ultrasonography, micturating cystourethrogram, and 99mTc dimercaptosuccinic acid (DMSA) scintigraphy. For those who had UTI, DMSA was carried out after a minimum period of 6 months after UTI episode. Results: Among the 50 children, 21 (42%) were male and 29 (58%) were female with male-to-female ratio of 0.72:1. Mean age at diagnosis was 9 months, ranging from 1 to 40 months. The number of children presented with UTI was 43 (86%), and 7 children (14%) were asymptomatic and were evaluated in view of abnormality in prenatal ultrasound scan. Unilateral VUR was found in 21 patients (42%), and 29 patients (58%) had bilateral VUR. Of all 79 refluxing units (21 unilateral plus 58 bilateral), 4% had VUR of Grade I severity, 30% of Grade II, 34% of Grade III, 28% of Grade IV, and 4% of Grade V severity. Renal parenchymal scarring on DMSA scan was detected in 42 (54%) of 79 refluxing units including 33% of Grade II, 55% of Grade III, 71% of Grade IV, and 100% of Grade V refluxing units. Prevalence of scarring in complicated, recurrent, and simple UTI was 100%, 93%, and 22%, respectively. Conclusion: Risk of renal scarring increased progressively with increasing severity of primary VUR. Complicated and recurrent UTI were found to be statistically significant risk factors for renal scarring. Renal scarring was also seen in absence of UTI in a small percentage of children with primary VUR.

Mapping of the amniotic fluid proteome of fetuses with congenital anomalies of the kidney and urinary tract identifies plastin 3 as a protein involved in glomerular integrity.

Congenital anomalies of the kidney and the urinary tract (CAKUT) are the first cause of chronic kidney disease in childhood. Several genetic and environmental origins are associated with CAKUT, but most pathogenic pathways remain elusive. Considering the amniotic fluid (AF) composition as a proxy for fetal kidney development, we analyzed the AF proteome from non-severe CAKUT (n = 19), severe CAKUT (n = 14), and healthy control (n = 22) fetuses using LC-MS/MS. We identified 471 significant proteins that discriminated the three AF groups with 81% precision. Among them, eight proteins independent of gestational age (CSPG4, LMAN2, ENDOD1, ANGPTL2, PRSS8, NGFR, ROBO4, PLS3) were associated with both the presence and the severity of CAKUT. Among those, five were part of a protein-protein interaction network involving proteins previously identified as being potentially associated with CAKUT. The actin-bundling protein PLS3 (plastin 3) was the only protein displaying a gradually increased AF abundance from control, via non-severe, to severe CAKUT. Immunohistochemistry experiments showed that PLS3 was expressed in the human fetal as well as in both the fetal and the postnatal mouse kidney. In zebrafish embryos, depletion of PLS3 led to a general disruption of embryonic growth including reduced pronephros development. In postnatal Pls3-knockout mice, kidneys were macroscopically normal, but the glomerular ultrastructure showed thickening of the basement membrane and fusion of podocyte foot processes. These structural changes were associated with albuminuria and decreased expression of podocyte markers including Wilms' tumor-1 protein, nephrin, and podocalyxin. In conclusion, we provide the first map of the CAKUT AF proteome that will serve as a reference for future studies. Among the proteins strongly associated with CAKUT, PLS3 did surprisingly not specifically affect nephrogenesis but was found as a new contributor in the maintenance of normal kidney function, at least in part through the control of glomerular integrity. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Study of the Value of Urinary Vitamin D-Binding Protein as a Prognostic Biomarker in Cases of Childhood Idiopathic Nephrotic Syndrome and its Relation to Calcium /Phosphorus Metabolism.

Introduction: Nephrotic syndrome (NS) is a common chronic kidney disease in childhood and it is mostly idiopathic. Aim of the Study: To determine if uVDBP measurements can be used as a non-invasive prognostic biomarker in cases of childhood idiopathic NS and its relation to Ca/P metabolism. Methods: This prospective study was carried out on children who were newly diagnosed with idiopathic nephrotic syndrome presented to the pediatric nephrology unit, Ain Shams University hospitals during the period from November 2019 till May 2020. Results: The present study showed that levels of uVDBP were significantly higher in cases than in healthy control children. Conclusion: We can conclude that uVDBP measurements represent a non-invasive prognostic biomarker in cases of childhood idiopathic NS.

Genetic Architecture of Childhood Kidney and Urological Diseases in China

Kidney disease is manifested in a wide variety of phenotypes, many of which have an important hereditary component. To delineate the genotypic and phenotypic spectrum of pediatric nephropathy, a multicenter registration system is being implemented based on the Chinese Children Genetic Kidney Disease Database (CCGKDD). In this study, all the patients with kidney and urological diseases were recruited from 2014 to 2020. Genetic analysis was conducted using exome sequencing for families with multiple affected individuals with nephropathy or clinical suspicion of a genetic kidney disease owing to early-onset or extrarenal features. The genetic diagnosis was confirmed in 883 of 2256 (39.1%) patients from 23 provinces in China. Phenotypic profiles showed that the primary diagnosis included steroid-resistant nephrotic syndrome (SRNS, 23.5%), glomerulonephritis (GN, 32.2%), congenital anomalies of the kidney and urinary tract (CAKUT, 21.2%), cystic renal disease (3.9%), renal calcinosis/stone (3.6%), tubulopathy (9.7%), and chronic kidney disease of unknown etiology (CKDu, 5.8%). The pathogenic variants of 105 monogenetic disorders were identified. Ten distinct genomic disorders were identified as pathogenic copy number variants (CNVs) in 11 patients. The diagnostic yield differed by subgroups, and was highest in those with cystic renal disease (66.3%), followed by tubulopathy (58.4%), GN (57.7%), CKDu (43.5%), SRNS (29.2%), renal calcinosis /stone (29.3%) and CAKUT (8.6%). Reverse phenotyping permitted correct identification in 40 cases with clinical reassessment and unexpected genetic conditions. We present the results of the largest cohort of children with kidney disease in China where diagnostic exome sequencing was performed. Our data demonstrate the utility of family-based exome sequencing, and indicate that the combined analysis of genotype and phenotype based on the national patient registry is pivotal to the genetic diagnosis of kidney disease.

Renal and Skeletal Anomalies in a Cohort of Individuals With Clinically Presumed Hereditary Nephropathy Analyzed by Molecular Genetic Testing.

Background: Chronic kidney disease (CKD) in childhood and adolescence occurs with a median incidence of 9 per million of the age-related population. Over 70% of CKD cases under the age of 25 years can be attributed to a hereditary kidney disease. Among these are hereditary podocytopathies, ciliopathies and (monogenic) congenital anomalies of the kidney and urinary tract (CAKUT). These disease entities can present with a vast variety of extrarenal manifestations. So far, skeletal anomalies (SA) have been infrequently described as extrarenal manifestation in these entities. The aim of this study was to retrospectively investigate a cohort of individuals with hereditary podocytopathies, ciliopathies or CAKUT, in which molecular genetic testing had been performed, for the extrarenal manifestation of SA.Material and Methods: A cohort of 65 unrelated individuals with a clinically presumed hereditary podocytopathy (focal segmental glomerulosclerosis, steroid resistant nephrotic syndrome), ciliopathy (nephronophthisis, Bardet-Biedl syndrome, autosomal recessive/dominant polycystic kidney disease), or CAKUT was screened for SA. Data was acquired using a standardized questionnaire and medical reports. 57/65 (88%) of the index cases were analyzed using exome sequencing (ES).Results: 8/65 (12%) index individuals presented with a hereditary podocytopathy, ciliopathy, or CAKUT and an additional skeletal phenotype. In 5/8 families (63%), pathogenic variants in known disease-associated genes (1x BBS1, 1x MAFB, 2x PBX1, 1x SIX2) could be identified.Conclusions: This study highlights the genetic heterogeneity and clinical variability of hereditary nephropathies in respect of skeletal anomalies as extrarenal manifestation.

Palliative care for children and young people with stage\xa05 chronic kidney disease

Death from stage 5 chronic kidney disease (CKD 5) in childhood or adolescence is rare, but something that all paediatric renal physicians and most paediatricians will encounter. In this paper, we present the literature on three key areas of palliative care practice essential to good clinical management: shared decision-making, advance care planning, and symptom management, with particular reference to CKD 5 where kidney transplant is not an option and where a decision has been made to withdraw or withhold dialysis. Some areas of care, particularly with regard to symptom management, have not been well-studied in children and young people (CYP) with CKD 5 and recommendations with regard to drug choice and dose modification are based on adult literature, known pharmacokinetics, and clinical experience.

Incidence and predictors of vascular events following end-stage kidney disease in childhood.

Cardiovascular death is a leading cause of mortality in paediatric end-stage kidney disease (ESKD). There is however little known about the clinically relevant vascular disease in this population. We aimed to describe the incidence of new onset vascular disease and vascular death in Australian children receiving renal replacement therapy (RRT). We also aimed to identify demographic or childhood risk factors for these endpoints, and whether vascular disease predicts mortality. Data on Australian patients who commenced RRT at <18 years of age from 1991 to 2017 were extracted from the Australian and New Zealand Dialysis and Transplant Registry (ANZDATA). Multivariable competing risks regression was used to identify factors associated with vascular events. A cohort of 1268 patients were followed up for a median of 10.31 years. Vascular disease was reported in 5.4%, and vascular death in 4.1%. The cumulative incidence of any vascular event, that is, disease or death, at 10 and 20 years was 5.5% and 12.8%, respectively. Childhood vascular events were associated with non-Caucasian, non-Indigenous ethnicity, and for the 804 patients followed up after 18 years of age, vascular events were associated with lack of childhood transplantation, longer childhood dialysis duration and Indigenous ethnicity. Vascular disease was only reported for 25.49% of patients who had a vascular death, and although a significant risk factor for mortality, it had limited ability to predict mortality. Cumulative incidence of vascular events is significant after commencing RRT during childhood and is associated with ethnicity, longer childhood dialysis duration and lack of childhood transplantation.

Assessment of Clinical Spectrum of Renal Diseases in children – A Descriptive Study at Benazir Bhutto Hospital, Rawalpindi

Introduction: Childhood kidney diseases are a frequent presentation. Most of the affected pediatric populations are from under-developed and developing countries. Noting the epidemiology of childhood renal diseases is very important as it helps in health planning, allows for adequate resource allocation, and enables adequate renal services provision. This study aimed to determine the etiological spectrum of renal disease in pediatric patients. Material and Methods: A descriptive study was conducted in Benazir Bhutto Hospital, Rawalpindi over a period of 6 months. Ethical clearance was taken from the institutional review board and written informed consent was administered before enrollment of subject per study criteria. A total of 100 children of both genders, aged up to 12 years with the diagnosis of any renal disease condition were included in the study. Patients having other comorbidities like chronic liver disease and heart diseases were excluded. The study information as age, sex, detailed history, and physical examination, and details of laboratory investigations. Statistical analysis was conducted in SPSS version 20.0. Results: Mean age of patients was 2.1 years. Most patients had a fever, edema, burning micturition, and high blood pressure. In two-thirds of the children RFTs were deranged and 19.0% had positive urinary culture reports. The common kidney diseases were UTI (42.0%), nephrotic syndrome (29.0%), acute kidney injury/ disease (19.0%), and chronic kidney disease (6.0%). Conclusion: UTIs and nephrotic syndrome along with acute kidney injury were the main kidney conditions. Females were more likely to have UTIs whereas nephrotic syndrome was common in male children.&#x0D;

Trends in the Epidemiology of Childhood Nephrotic Syndrome in Africa: A Systematic Review

Background: Childhood nephrotic syndrome, if left untreated, leads to progressive kidney disease or death. We quantified the prevalence of steroid-sensitive nephrotic syndrome, steroid-resistant nephrotic syndrome and histological types as the epidemiology of nephrotic syndrome in Africa remains unknown, yet impacts outcomes. Methods: We searched MEDLINE, Embase, African Journals Online and WHO Global Health Library for articles in English or French reporting on childhood nephrotic syndrome in Africa from January 1, 1946 to July 1, 2020. Primary outcomes included steroid response, biopsy defined minimal change disease, and focal segmental glomerulosclerosis (FSGS) by both pooled and individual proportions across regions and overall. Findings: There were 81 papers from 17 countries included. Majority of 8,131 children were steroid-sensitive (64% [95% CI: 63-66%]) and the remaining were steroid-resistant (34% [95% CI: 33-35%]). Of children biopsied, pathological findings were 38% [95% CI: 36-40%] minimal change, 24% [95% CI: 22-25%] FSGS, and 38% [95% CI: 36-40%] secondary causes of nephrotic syndrome. Interpretation: Few African countries reported on the prevalence of childhood nephrotic syndrome. Steroid-sensitive disease is more common than steroid-resistant disease although prevalence of steroid-resistant nephrotic syndrome is higher than reported in European populations. Pathology findings suggest minimal change and secondary causes are common. Scarcity of data in Africa prevents appropriate healthcare resource allocation to diagnose and treat this treatable childhood kidney disease to prevent poor health outcomes. Funding Statement: Funding was provided by the Canadian Institute for Health Research (CIHR) and the National Institute of Health (NIH) for the H3 Africa Kidney Disease Research Network. This research was undertaken, in part, from the Canada Research Chairs program. Declaration of Interests: The authors have no competing interests or conflicts to declare.

Congenital Anomalies of the Kidney and Urinary Tract and Adulthood risk of Urinary Tract Cancer

IntroductionCongenital anomalies of the kidney and urinary tract (CAKUT) are the most common kidney diseases in childhood. Alterations in genes governing nephrogenesis may cause CAKUT, and in some cases may contribute to development of urinary tract (UT) tumors later in life. We aimed to assess the association between CAKUT and UT cancer in adulthood.MethodsWe conducted a population-based historical cohort study encompassing 1,510,042 recruits to the Israeli army between 1967 and 1997. CAKUT exposure was determined by army medical coding of CAKUT in childhood. Incidence of UT cancer (kidney, ureter, or bladder) was available through record linkage with the Israeli Cancer Registry. Recruits were followed from the prerecruitment assessment until cancer diagnosis, death, or study termination, in 2012. Cox proportional hazards models were constructed to estimate the hazard ratios (HRs) for UT cancer in participants with vs. without CAKUT.ResultsDuring a mean follow-up of 30.4 years, 2959 participants (2573 men and 386 women) developed UT cancer. Men with CAKUT exhibited an increased risk of UT cancer compared with men without CAKUT, yielding an adjusted HR of 1.98 (95% confidence interval [CI] 1.03-3.82). Among women CAKUT was associated with a HR of 5.88 (95% CI 2.19-15.76). Notably, upon stratification according to age of cancer diagnosis, the association between CAKUT and UT cancer was statistically significant only before 45 years of age in women and only after 45 years of age in men.ConclusionCAKUT is associated with a significantly increased risk of UT cancer, although the incidence and absolute risk remained quite low.

小児腎臓疾患の今と昔 ： IgA 腎症の発症病態からみた治療の進歩

小児腎臓疾患の今と昔 ： IgA 腎症の発症病態からみた治療の進歩

Steroid-resistant Nephrotic Syndrome in Children: A Mini-review on Genetic Mechanisms, Predictive Biomarkers and Pharmacotherapy Strategies.

Steroid-resistant nephrotic syndrome (SRNS) constitutes the second most frequent cause of chronic kidney disease in childhood. The etiology of SRNS remains largely unknown and no standardized treatment exists. Recent advances in genomics have helped to build understanding of the molecular mechanisms and pathogenesis of the disease. The genetic polymorphisms in genes encoding proteins which are involved in the pharmacokinetics and pharmacodynamics of glucocorticoids (GCs) partially account for the different responses between patients with nephrotic syndrome. More importantly, single-gene causation in podocytes-associated proteins was found in approximately 30% of SRNS patients. Some potential biomarkers have been tested for their abilities to discriminate against pediatric patients who are sensitive to GCs treatment and patients who are resistant to the same therapy. This article reviews the recent findings on genetic mechanisms, predictive biomarkers and current therapies for SRNS with the goal to improve the management of children with this syndrome.

Phenotype expansion of heterozygous FOXC1 pathogenic variants toward involvement of congenital anomalies of the kidneys and urinary tract (CAKUT)

PurposeCongenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of chronic kidney disease in childhood and adolescence. We aim to identify novel monogenic causes of CAKUT. MethodsExome sequencing was performed in 550 CAKUT-affected families. ResultsWe discovered seven FOXC1 heterozygous likely pathogenic variants within eight CAKUT families. These variants are either never reported, or present in <5 alleles in the gnomAD database with ~141,456 controls. FOXC1 is a causal gene for Axenfeld–Rieger syndrome type 3 and anterior segment dysgenesis 3. Pathogenic variants in FOXC1 have not been detected in patients with CAKUT yet. Interestingly, mouse models for Foxc1 show severe CAKUT phenotypes with incomplete penetrance and variable expressivity. The FOXC1 variants are enriched in the CAKUT cohort compared with the control. Genotype–phenotype correlations showed that Axenfeld–Rieger syndrome or anterior segment dysgenesis can be caused by both truncating and missense pathogenic variants, and the missense variants are located at the forkhead domain. In contrast, for CAKUT, there is no truncating pathogenic variant, and all variants except one are located outside the forkhead domain. ConclusionWe thereby expanded the phenotype of FOXC1 pathogenic variants toward involvement of CAKUT, which can potentially be explained by allelism.

A homozygous HOXA11 variation as a potential novel cause of autosomal recessive congenital anomalies of the kidney and urinary tract.

Congenital anomalies of the kidney and urinary tract (CAKUT) is the leading cause of end-stage kidney disease in children. Until now, more than 50 monogenic causes for CAKUT have been described, all of which only explain 10% to 20% of all patients with CAKUT, suggesting the presence of additional genes that cause CAKUT when mutated. Herein, we report two siblings of a consanguineous family with CAKUT, both of which rapidly progressed to chronic kidney disease in early childhood. Whole-exome sequencing followed by homozygosity mapping identified a homozygous variation in HOXA11. We therefore showed for the first time an association between a homozygous HOXA11 variation with CAKUT in humans, expanding the genetic spectrum of the disease.