Maternal Chronic Disease and Congenital Anomalies of the Kidney and Urinary Tract in Offspring: A Japanese Cohort Study.

RATIONALE & OBJECTIVE: Several maternal chronic diseases have been reported as risk factors for congenital anomalies of the kidney and urinary tract (CAKUT) in offspring. However, these investigations used case-control designs, and cases with isolated genitourinary CAKUT were not distinguished from cases in which CAKUT were present with extrarenal congenital anomalies (complicated CAKUT). We examined the association of maternal diseases with isolated and complicated CAKUT in offspring using data from a prospective cohort study. STUDY DESIGN: A nationwide prospective birth cohort study. SETTING & PARTICIPANTS: 100,239 children enrolled in the Japan Environment and Children's Study between January 2011 and March 2014 at 15 research centers. Physicians' diagnoses in mothers and children were collected from medical record transcripts and questionnaires. EXPOSURES: Medical histories of maternal noncommunicable diseases, including obesity, hypertension, diabetes mellitus, kidney disease, hyperthyroidism, hypothyroidism, psychiatric disease, epilepsy, cancer, and autoimmune disease. OUTCOMES: CAKUT diagnosed during the first 3 years of life, classified as isolated or complicated. ANALYTICAL APPROACH: Multivariable Poisson regression with generalized estimating equations accounting for clustering by clinical center. RESULTS: Among the 100,239 children, 560 (0.6%) had CAKUT, comprising 454 (81%) isolated and 106 (19%) complicated forms. The risk of isolated CAKUT was increased in children of mothers who experienced kidney disease (adjusted risk ratio [RR], 1.80 [95% CI, 1.12-2.91]) or cancer (RR, 2.11 [95% CI, 1.15-3.86]). Furthermore, the risk of complicated CAKUT was increased in children of mothers with diabetes mellitus (RR, 3.04 [95% CI, 1.64-5.61]). LIMITATIONS: Lack of standardization or prespecification of clinical definitions, diagnostic criteria, measurements, and testing. Genetic testing was not performed. CONCLUSIONS: Isolated CAKUTs and complicated CAKUTs were associated with different maternal diseases. The results may inform clinical management of pregnancy and highlight potential differences in the genesis of isolated and complicated forms of CAKUT.

Widespread kidney anomalies in children with Down syndrome.

BACKGROUND: Rare autopsy studies have described smaller kidneys as well as urinary tract anomalies in Down syndrome. This observation has never been investigated in vivo and little is known about the possible consequences upon kidney function. Here we wish to confirm whether children with Down syndrome have smaller kidneys and to evaluate their kidney function in vivo. METHODS: This retrospective cohort study enrolled 49 children with Down syndrome, as well as 49 age- and sex-matched controls at the Queen Fabiola Children's University Hospital in Brussels, Belgium. Doppler and kidney ultrasonography, spot urine albumin to creatinine ratio, estimated glomerular filtration rate (eGFR), and anthropometric data were recorded. RESULTS: Kidney size in children with Down syndrome was smaller than age- and sex-matched controls in terms of length (p < 0.001) and volume (p < 0.001). Kidney function based on eGFR was also decreased in Down syndrome compared to historical normal. Twenty-one of the children with Down syndrome (42%) had eGFR < 90 mL/min/1.73 m2, with 5 of these (10%) having an eGFR < 75 mL/min/1.73 m2. In addition, 7 of the children with Down syndrome (14%) had anomalies of the kidney and/or urinary tract that had previously been undiagnosed. CONCLUSIONS: Children with Down syndrome have significantly smaller kidneys than age-matched controls as well as evidence of decreased kidney function. These findings, in addition to well-noted increased kidney and urologic anomalies, highlight the need for universal anatomical and functional assessment of all individuals with Down syndrome. A higher resolution version of the Graphical abstract is available as Supplementary information.

Targeted gene sequencing and whole-exome sequencing in autopsied fetuses with prenatally diagnosed kidney anomalies.

Identification of fetal kidney anomalies invites questions about underlying causes and recurrence risk in future pregnancies. We therefore investigated the diagnostic yield of next-generation sequencing in fetuses with bilateral kidney anomalies and the correlation between disrupted genes and fetal phenotypes. Fetuses with bilateral kidney anomalies were screened using an in-house-designed kidney-gene panel. In families where candidate variants were not identified, whole-exome sequencing was performed. Genes uncovered by this analysis were added to our kidney panel. We identified likely deleterious variants in 11 of 56 (20%) families. The kidney-gene analysis revealed likely deleterious variants in known kidney developmental genes in 6 fetuses and TMEM67 variants in 2 unrelated fetuses. Kidney histology was similar in the latter 2 fetuses-presenting a distinct prenatal form of nephronophthisis. Exome sequencing identified ROBO1 variants in one family and a GREB1L variant in another family. GREB1L and ROBO1 were added to our kidney-gene panel and additional variants were identified. Next-generation sequencing substantially contributes to identifying causes of fetal kidney anomalies. Genetic causes may be supported by histological examination of the kidneys. This is the first time that SLIT-ROBO signaling is implicated in human bilateral kidney agenesis.

Infants with prenatally diagnosed kidney anomalies have an increased risk of urinary tract infections.

AIM: This study estimated the urinary tract infection (UTI) risk in a nationwide cohort of infants prenatally diagnosed with parenchymal kidney anomalies compared with a comparison cohort. METHODS: A Danish population-based nationwide cohort of foetuses diagnosed with parenchymal kidney anomalies between 2007 and 2012 had previously been identified. These were compared with foetuses without kidney anomalies who were prenatally scanned the same year. Live born infants were followed from birth until the diagnosis of UTI, emigration, death or two years of age. Cumulative incidences of UTIs were computed. Mortality was estimated using the Kaplan-Meier method. RESULTS: We identified 412 foetuses with parenchymal kidney anomalies out of 362 069 who underwent ultrasound scans and 277 were born alive. The overall risk of a UTI before the age of two years was 19%, and it was 14% among infants without prenatally diagnosed co-occurring urinary tract malformations. The corresponding risk in the 4074 controls was 1%. After two years, mortality was 2.2% in infants with prenatally diagnosed parenchymal kidney anomalies and 0.2% in the controls. CONCLUSION: Infants prenatally diagnosed with parenchymal kidney anomalies had a substantially increased risk of UTI. Awareness of this increased risk may facilitate earlier diagnosis of UTIs in this population.

17q12 deletion and duplication syndrome in Denmark-A clinical cohort of 38 patients and review of the literature.

17q12 deletions and duplications are two distinct, recurrent chromosomal aberrations usually diagnosed by chromosomal microarray analysis (CMA). The aberrations encompass the genes, HNF1B, LHX1, and ACACA, among others. We here describe a large national cohort of 12 phenotyped patients with 17q12 deletions and 26 phenotyped patients with 17q12 duplications. The total cohort includes 19 index patients and 19 family members. We also reviewed the literature in order to further improve the basis for the counseling. We emphasize that renal disease, learning disability, behavioral abnormalities, epilepsy, autism, schizophrenia, structural brain abnormalities, facial dysmorphism, and joint laxity are features seen in both the 17q12 deletion syndrome and the reciprocal 17q12 duplication syndrome; and we extend the list of features seen in both patient categories to include strabismus, esophageal defects, and duodenal atresia. Delayed language development, learning disability, kidney involvement, and eye dysmorphism and strabismus were the most consistently shared features among patients with 17q12 deletion. Patients with 17q12 duplications were characterized by an extremely wide phenotypic spectrum, including a variable degree of learning disabilities, delayed language development, delayed motor milestones, and a broad range of psychiatric and neurological features. This patient group also included adults achieving an academic degree. Assessing index patients and non-index patients separately, our observations illustrate that an overall milder disease burden is seen, in particular in patients with 17q12 duplications who are ascertained on the duplication rather than the phenotype. This evidence may be useful in prenatal counseling. © 2016 Wiley Periodicals, Inc.

General Characteristics and Current State of Antibiotic Resistance in Pediatric Urinary Tract Infection-A Single Center Experience.

Urinary tract infection (UTI) represents one of the most common bacterial infections in children, mainly caused by Gram-negative bacteria. Empirical antibiotic treatment is based on international and national guidelines for treating UTIs in children and is individualized with local antibiotic resistance patterns. The aim of this study is to bring a clear view of present-day particularities of UTIs in children. METHODS: We analyzed 210 positive urine cultures identified in 141 pediatric patients admitted to the hospital over a 6-month period. RESULTS: The majority of patients were females (57%) with a median age of 5 years (IQR 12), while male patients revealed a median age of 2 (IQR 7). Most patients originated from urban areas (53%). Only 18 patients (12.76%) were identified with underlying Congenital Anomalies of the Kidney and Urinary Tract (CAKUT). Escherichia Coli was the most frequent pathogen. Increased antibiotic resistance was found in commonly-used antibiotics Ampicillin and Trimethoprim/Sulfamethoxazole, and in the case of patients with CAKUT. Suitable antibiotics for treating a Gram-negative UTI are aminoglycosides, Meropenem, third-generation Cephalosporins, and Nitrofurantoin. Vancomycin upholds efficacy in treating a Gram-positive pediatric UTI. CONCLUSION: Periodical analysis needs to be performed in order to constantly update clinicians on uropathogenic antibiotic resistance and optimal empirical treatment options.

Congenital anomalies of the kidney and urinary tract.

Congenital Anomalies of the Kidney and Urinary Tract (CAKUT) refer to a range of conditions that affect the kidney and urinary tract. These anomalies can be severe, such as kidney agenesis, or milder, such as vesicoureteral reflux. CAKUT affects over 1% of live births and accounts for 40-50% of cases of chronic kidney failure in children. The pathogenesis of CAKUT is caused by various environmental, genetic, and epigenetic factors that disrupt normal nephrogenesis. Environmental factors that can lead to CAKUT include maternal diabetes, obesity, malnutrition, alcohol consumption, or medications affecting kidneys development. Genetic factors can cause an imbalance in the metanephros and the ureteric bud interaction. Defects in specific genes such as PAX2, TBX18, NRIP1, REX, SIX2, BMP4, and chromosome 17 cause CAKUT. Over 50 genes have been identified as the root cause of this condition, with monogenetic variants causing up to 20% of all cases. CAKUTs can be diagnosed through fetal ultrasonography, but some anomalies may remain undetected. GWASs, Next Generation Sequencing for targeted and whole exome DNA sequencing may provide additional diagnostic methods. This review article highlights some the leading factors that cause CAKUT, which adversely affects kidney development and urinary tract function.

Maternal diseases and congenital anomalies of the kidney and urinary tract in offspring: a cohort study.

BACKGROUND: Congenital anomalies of the kidneys and urinary tract (CAKUT) are the most common cause of prenatally diagnosed developmental malformation. This study aimed to assess the relationship between maternal diseases and CAKUT in offspring. METHODS: This retrospective study enrolled all pregnant women registered from January 2020 to December 2022 at one medical center. Medical information on maternal noncommunicable diseases, including obesity, hypertension, diabetes mellitus, kidney disease, hyperthyroidism, hypothyroidism, psychiatric disease, epilepsy, cancer, and autoimmune disease was collected. Based on the records of ultrasound scanning during the third trimester, the diagnosis was classified as isolated urinary tract dilation (UTD) or kidney anomalies. Multivariate logistic regression was performed to establish models to predict antenatal CAKUT. RESULTS: Among the 19,656 pregnant women, perinatal ultrasound detected suspicious CAKUT in 114 (5.8/1000) fetuses, comprising 89 cases with isolated UTD and 25 cases with kidney anomalies. The risk of antenatal CAKUT was increased in the fetuses of mothers who experienced gestational diabetes, thyroid dysfunction, neuropsychiatric disease, anemia, ovarian and uterine disorders. A prediction model for isolated UTD was developed utilizing four confounding factors, namely gestational diabetes, gestational hypertension, maternal thyroid dysfunction, and hepatic disease. Similarly, a separate prediction model for kidney anomalies was established based on four distinct confounding factors, namely maternal thyroid dysfunction, gestational diabetes, disorders of ovarian/uterine, and kidney disease. CONCLUSIONS: Isolated UTD and kidney anomalies were associated with different maternal diseases. The results may inform the clinical management of pregnancy and highlight potential differences in the genesis of various subtypes of CAKUT.

Prenatal metal levels and congenital anomalies of the kidney and urinary tract: The Japan Environment and Children's Study.

BACKGROUND: Prenatal exposure to metal elements has been reported as a potential risk factor for congenital malformation. However, studies on the relationship with congenital anomalies of the kidney and urinary tract (CAKUT) are very scarce. METHODS: Participants of a prospective cohort from the Japan Environment and Children's Study, conducted at 15 research centers, were recruited between January 2011 and March 2014. The exposure factors were concentrations of lead (Pb), cadmium (Cd), mercury (Hg), selenium (Se), and manganese (Mn) measured from maternal whole blood in the second or third trimester. The primary outcome was CAKUT diagnosed during the first three years of life, which was classified into isolated cases and complicated cases accompanied by extrarenal congenital defects. To conduct a nested case-control design within the cohort, we selected 351 isolated cases with 1404 matched controls, and 79 complicated cases with 316 matched controls. RESULTS: A logistic regression model was used to examine the associations between individual metal concentrations and each subtype of CAKUT. A higher level of Se was associated with an increased risk of isolated CAKUT (adjusted odds ratio [95 % confidence interval]: 3.22 [1.33-7.77]). Meanwhile, higher levels of Pb and Mn were associated with a reduced risk of the complicated subtype (0.46 [0.24-0.90] and 0.33 [0.15-0.73], respectively). A Bayesian kernel machine regression model accounting for mixed effects of multiple metals further demonstrated that a higher level of Mn alone was significantly associated with a reduced occurrence of the complicated subtype. CONCLUSIONS: Using a stringent statistical approach, the present study demonstrated that a higher Mn concentration in the maternal blood was associated with a lower risk of complicated CAKUT in offspring. Further cohort and experimental studies are needed to verify the clinical impact of this finding.

Maternal risk factors for congenital anomalies of the kidney and urinary tract: A case-control study.

BACKGROUND: Congenital anomalies of the kidney and urinary tract (CAKUT) are significant causes of pediatric morbidity and mortality. The spectrum of CAKUT can be part of a syndrome, but most of these abnormalities occur as isolated and sporadic forms. The etiology of human CAKUT is unknown in the majority of cases. This case-control study aimed to investigate the association between maternal characteristics and the occurrence of CAKUT and specific CAKUT phenotypes. METHODS: In this case-control study, 29,653 newborns were evaluated consecutively in a tertiary neonatal unit using the Latin American Collaborative Study of Congenital Malformations (ECLAMC) registry. Newborns without congenital anomalies were matched to CAKUT cases by sex, date, and place of birth at a ratio of 3:1. For analysis purposes, the cases were stratified into four subgroups: upper tract abnormalities (UTA), including ureteropelvic junction obstruction, vesicoureteral reflux, primary megaureter and others (n = 239), lower urinary tract obstruction (LUTO) (n = 79), cystic diseases (n = 59) and agenesis/hypodysplasia (n = 28). Multivariable logistic regression analyses were used to calculate crude and adjusted odds ratios (ORs) with 95% confidence intervals (CIs) for associations between the maternal risk factors and the presence of CAKUT. RESULTS: The prevalence of non-syndromic CAKUT in our sample was 13 per 1000 live births. Data records allowed the analysis of 405 cases and 1208 controls. After adjustment by the binary regression logistic, three covariates remained associated as risk factors for the entire spectrum of CAKUT: consanguinity (Odds ratio [OR], 7.1, 95%CI, 2.4-20.4), family history of CAKUT (OR, 6.4, 95%CI, 1.9-21.3), and maternal chronic hypertension (OR, 14.69, 95%CI, 3.2-67.5) (Figure). These risk factors persisted consistently across the various CAKUT phenotypes with minor variations. Consanguinity was the only factor consistently associated with almost all CAKUT phenotypes. Maternal hypertension was associated with all phenotypes except for the agenesis/hypodysplasia group. The prevalence of CAKUT cases was 15 times higher in hypertensive mothers (3%) compared to normotensive mothers (0.2%). CONCLUSION: Our study suggests that an increased risk of CAKUT is associated with consanguinity, a positive family history of CAKUT, and maternal hypertension. However, the prevalence of these risk factors in our cohort was rare and most cases presented as sporadic forms.

Unilateral Kidney Agenesis and other Kidney Anomalies in Infertile Men with Congenital Bilateral Absence of Vas deferens: A Cross-Sectional Study.

BACKGROUND: We aim to determine the prevalence of renal anomalies in patients with congenital vas deferens agenesis referred for infertility assessment.
Materials and Methods: This cross-sectional study was carried out on eligible infertile men from 2016 to 2019. Infertile men who were suspected of obstructive azoospermia were referred to the Ultrasound ward and they were examined by abdominal ultrasound for detecting the genital and kidney anomalies. An informed consent form was filled out by patients. Data was entered into SPSS software 21. Patients were divided into two groups in terms of congenital bilateral absence of vas deferens (CBAVD) or congenital unilateral absence of the vas deferens (CUAVD). Using the Chi-square test kidney anomalies between groups were compared. The P<0.05 was considered significant.
Results: The mean age of participants was 33.05 ± 6.35. The frequency of CBAVD was 66 and the frequency of left side VD and right side VD were 23 and 21, respectively. The percentage of other comorbidities was calculated. Out of 110 cases, 12 (11%) men had coexistence of vas deferens and kidney agenesis. Other studies are in agreement with our findings. Although the percentage of CBAVD and CUAVD were 9.1% and 1.8% respectively, the difference was not significant (P=0.07).
Conclusion: Considering the fact that kidney agenesis is a remarkable congenital anomaly that coexists with the majority of vas deferens agenesis cases and could not be detected by routine laboratory tests or transrectal ultrasound
examination, it should be ruled out with transabdominal ultrasound examination after detection of vas deferens agenesis.

Loss of Planar Cell Polarity Effector Fuzzy Causes Renal Hypoplasia by Disrupting Several Signaling Pathways.

In vertebrates, the planar cell polarity (PCP) pathway regulates tissue morphogenesis during organogenesis, including the kidney. Mutations in human PCP effector proteins have been associated with severe syndromic ciliopathies. Importantly, renal hypoplasia has been reported in some patients. However, the developmental disturbance that causes renal hypoplasia is unknown. Here, we describe the early onset of profound renal hypoplasia in mice homozygous for null mutation of the PCP effector gene, Fuzzy. We found that this phenotype is caused by defective branching morphogenesis of the ureteric bud (UB) in the absence of defects in nephron progenitor specification or in early steps of nephrogenesis. By using various experimental approaches, we show that the loss of Fuzzy affects multiple signaling pathways. Specifically, we found mild involvement of GDNF/c-Ret pathway that drives UB branching. We noted the deficient expression of molecules belonging to the Bmp, Fgf and Shh pathways. Analysis of the primary cilia in the UB structures revealed a significant decrease in ciliary length. We conclude that renal hypoplasia in the mouse Fuzzy mutants is caused by defective UB branching associated with dysregulation of ciliary and non-ciliary signaling pathways. Our work suggests a PCP effector-dependent pathogenetic mechanism that contributes to renal hypoplasia in mice and humans.

Kidney and Inferior Vena Cava Abnormalities With Leg Thrombosis (KILT) Syndrome in a 24-Year-Old Man.

Here, we present a case of kidney and inferior vena cava abnormalities with leg thrombosis (KILT) syndrome, which consists of the triad of congenital kidney anomalies, inferior vena cava anomalies, and deep venous thrombosis. KILT syndrome is usually an incidental finding while investigating other conditions.

Congenital Anomalies of the Kidney and Urinary Tract: A Clinical Review.

PURPOSE OF REVIEW: This review highlights the most common congenital anomalies of the kidney and urinary tract (CAKUT) that are encountered in pediatric practices. CAKUT are the most common cause of prenatally diagnosed developmental malformations and encompass a spectrum of disorders impacting lower urinary tract development as well as kidney development and function. In pediatric and adolescent populations, developmental abnormalities are the leading cause of end-stage kidney disease. The goal of this review is to provide pediatric providers a framework for appropriate clinical management as well as highlight when referral to subspecialty care is needed. RECENT FINDINGS: While the exact etiologies of CAKUT are not completely defined, new evidence demonstrates that genetic and molecular changes impact embryonic kidney and urinary tract development. As a result, phenotypes and clinical outcomes may be affected. SUMMARY: Because pediatric providers provide front-line care to children and adolescents with developmental kidney and urinary tract anomalies, updated knowledge of CAKUT pathogenesis, embryology, clinical management, and patient outcomes is needed. This manuscript reviews CAKUT etiologies and essential diagnostic, prognostic, and management strategies.

Percutaneous nephrolithotomy of horseshoe kidney: Our institutional experience.

PURPOSE: To review our success in PCNL for managing large horse shoe kidney stones as primary treatment. METHOD: Between 2012 and 2016, a total of 23patients (24 renal units) underwent percutaneous renal surgery for stone dieses in horseshoe kidneys. Indications were HSK with stone more than 1 cm in size and failed ESWL. RESULTS: Mean age was 35.60 ± 10.10 years out of which 18 were males and 5 females. One patient had stone in both kidneys. Mean stone size was 22.03 ± 10.33 mm. Access site was upper calyceal and subcostal in all patients. In 2 patients an extra middle calyceal puncture were used for total clearance (8.69%). Mean operation time was 67.22 ± 7.63 minutes. One patient with staghorn stone was converted to open surgery because of inaccessibility of the stone and complexity of the renal calyceal system. Post operatively, 2 renal units with residual stone more than 8mm were cleared with ESWL. Complete clearance was achieved in 21 renal units with PCNL (87.50%). There was no significant intra operative complication. Post operatively 2 patients developed fever which was treated conservatively(clavien grade I). CONCLUSION: PCNL can be recommended as first line of management in the treatment of horseshoe kidneys with large stone burden considering its higher clearance rate and minimal complications.

Crossed fused renal ectopia: case report and review of the literature.

Crossed fused renal ectopia is a rare congenital anomaly, and is mostly detected incidentally. A 45-year-old man, during investigation for recurrent abdominal pain, was found to have an empty left renal fossa and right crossed renal ectopia with fusion on ultrasonography. In the present case, there were no abnormalities and/or alteration of the renal function. Abdominal tomography scan with contrast medium confirmed the diagnosis. Ectopic kidney is often associated with other abnormal situations such as agenesis, vascular malformation, incontinence, a palpable abdominal mass, urinary tract infection, high incidence of stone formation, and genital anomalies. Through this case report, we emphasize the importance of adequate imaging.

Associated nonurinary congenital anomalies among infants with congenital anomalies of kidney and urinary tract (CAKUT).

Infants with congenital anomalies of kidney and urinary tract (CAKUT) often have other associated anomalies. The purpose of this investigation was to assess the prevalence and the types of associated anomalies in CAKUT in a defined population from northeastern France. The associated anomalies in CAKUT were collected in all livebirths, stillbirths and terminations of pregnancy during 26 years in 346,831 consecutive births of known outcome in the area covered by our population based registry of congenital anomalies. Of the 1678 infants with CAKUT born during this period (prevalence at birth of 48.4 per 10,000), 563 (34%) had associated anomalies. There were 119 (7%) patients with chromosomal abnormalities including 33 trisomies 18 (2%), and 168 (10%) nonchromosomal recognized dysmorphic conditions. There were no predominant recognized dysmorphic conditions, but VA(C)TER(L) association (3%). However, other recognised dysmorphic conditions were registered including Meckel-Gruber syndrome (2%), and prune belly syndrome (1%). Two hundred seventy six (16%) of the patients had multiple congenital anomalies, non syndromic, non chromosomal (MCA). Anomalies in the musculoskeletal, the digestive, the cardiovascular and the central nervous systems were the most common other anomalies. Prenatal diagnosis was obtained in 71% of dysmorphic syndromes with CAKUT. In conclusion the overall prevalence of associated anomalies, which was one in three infants, emphasizes the need for a thorough investigation of infants with CAKUT. The most commonly associated major nonurinary anomalies involved the musculoskeletal system, followed by the digestive, the cardiovascular and the central nervous systems. A routine screening for other anomalies may be considered in infants and in fetuses with CAKUT. One should be aware that the anomalies associated with CAKUT can be classified into a recognizable anomaly syndrome or pattern in one out of six infants with CAKUT.