Renal Defects Research Articles

Apparent but unconfirmed digenism in an Iranian consanguineous family with syndromic Retinal Disease

BackgroundBardet-Biedl syndrome is an autosomal recessive disease characterized by rod-cone dystrophy, postaxial polydactyly, kidney defects, obesity, mental retardation and hypogonadism. Here, we report different genotypes in two Bardet-Biedl syndrome affected sisters with a different clinical phenotype regarding severity. Materials and methodsThe proband of the family was examined by Next Generation Sequencing (NGS) using clinical exome and filtering by syndromic and non-syndromic genes associated with retinal dystrophies. ResultsTargeted NGS revealed two novel variants in the MKKS and CEP290 genes in homozygosis state in the proband. Segregation analysis revealed the presence of the same MKKS homozygous variant in her younger affected sister but not the CEP290 variant. Both sisters presented different clinical manifestation, at different ages, with a more severe renal and retinal defect in the case of the sister carrying mutations in both genes. Another unaffected sister showed only homozygosity for the CEP290 variant, thus supporting the non-pathogenic role of this mutation in BBS phenotype. ConclusionsIn this study, NGS proved to be a powerful and efficient sequencing method to identify causal variants in different genes. However, it remarks the importance of the segregation analysis and clinical information to establish the pathogenicity of new variants. The two affected sisters present different genotypes and clinical manifestation, suggesting that the novel CEP290 variant could be acting as a modifier, making the phenotype more severe in the sister homozygote for MKKS and CEP290 genes. On the other hand, the difference in the age of both sisters highlight the important role of monitoring disease progression also to confirm the modifier role of genetic variants.

Comparison of Renal Ultrasonography and Technetium 99-M Dimercaptosuccinic acid Renal Cortical Scintigraphy in Identifying Renal Parenchymal Defects in Febrile Urinary Tract Infection In Children Less than Five Years Age

Comparison of Renal Ultrasonography and Technetium 99-M Dimercaptosuccinic acid Renal Cortical Scintigraphy in Identifying Renal Parenchymal Defects in Febrile Urinary Tract Infection In Children Less than Five Years Age

The Classification of VACTERL Association into 3 Groups According to the Limb Defect.

Summary:The VACTERL association (VA) is defined as the nonrandom co-occurrence of 6 anomalies: vertebral anomalies (V), Anal atresia (A), Cardiac defects (C), Tracheo-esophageal fistula (TE), Renal defects (R), and Limb anomalies (L). The current communication presents an argument that patients with VA should be classified into three district groups based on their limb defects: VACTERL1: patients with normal limbs; VACTERL2: patients with limb anomalies other than radial ray defects of the upper limbs; and VACTERL3: patients with radial ray defects of the upper limbs. The author will demonstrate that the rationale behind the L1-3 classification in patients in VA is based on the embryogenesis of the 6 affected anatomical areas in VA. The pathogenesis of VACTERL1 is secondary to perturbations of Sonic Hedgehog (SHH) interactions. SHH signaling is known to have a major role in the normal development of the vertebrae, ano-rectal area, heart, tracheo-esophageal area, and kidney. However, SHH is not involved in the development of the radial ray; hence, patients present with no limb defects. The pathogenesis of VACTERL2 is variable depending on the type of gene mutation. The pathogenesis of VACTERL3 is related to errors in a group of proteins (namely, the proteins of the TBX5-SALL4-SALL1 loop and the FGF8-FGF10 loop/ pathway). These proteins are essential for the normal development of the radial ray and they interact in the development of the other anatomical areas of VA including the heart and kidney. Hence, VACTERL3 patients present with radial ray deficiency.

Genetics of agenesis/hypoplasia of the uterus and vagina: narrowing down the number of candidate genes for Mayer-Rokitansky-Küster-Hauser Syndrome.

Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome consists of congenital absence of the uterus and vagina and is often associated with renal, skeletal, cardiac, and auditory defects. The genetic basis is largely unknown except for rare variants in several genes. Many candidate genes have been suggested by mouse models and human studies. The purpose of this study was to narrow down the number of candidate genes. Whole exome sequencing was performed on 111 unrelated individuals with MRKH; variant analysis focused on 72 genes suggested by mouse models, human studies of physiological candidates, or located near translocation breakpoints in t(3;16). Candidate variants (CV) predicted to be deleterious were confirmed by Sanger sequencing. Sanger sequencing verified 54 heterozygous CV from genes identified through mouse (13 CV in 6 genes), human (22 CV in seven genes), and translocation breakpoint (19 CV in 11 genes) studies. Twelve patients had ≥ 2 CVs, including four patients with two variants in the same gene. One likely digenic combination of LAMC1 and MMP14 was identified. We narrowed 72 candidate genes to 10 genes that appear more likely implicated. These candidate genes will require further investigation to elucidate their role in the development of MRKH.

Acquired Fanconi Syndrome from Ifosfamide

Fanconi syndrome is a renal proximal tubule defect that causes reabsorption defects of electrolytes. The clinical features of Fanconi syndrome are amino aciduria, proteinuria, hypophosphatemia, metabolic acidosis, and glycosuria. In children, it is usually resulting from a genetic defect, such as cystinosis, galactosemia, tyrosinemia, hereditary fructose intolerance, and Wilson disease [1]. However, in adults, it is usually resulting from medications, toxins, and kidney diseases such as light chain proximal tubulopathy and primary amyloidosis [1]. Ifosfamide is a chemotherapy agent that is well known in the literature to cause Fanconi syndrome. Herein, we present a case of a woman with cervical cancer who developed ifosfamide-induced Fanconi syndrome after her fifth cycle of chemotherapy.

Disorders of Acid-Base and Potassium Balance

Water accounts for approximately half of an adult human's body weight. Two thirds of body water is intracellular, and the remaining one third is contained in the extracellular fluid compartment, which includes intravascular (plasma) and interstitial fluid. Small amounts of water are also contained in bone, dense connective tissue, digestive secretions, and cerebrospinal fluid. To maintain stability of the internal milieu, body fluids are processed by the kidney, guided by intricate physiologic control systems that regulate fluid volume and composition. This chapter reviews the principles of body fluid hemostasis and discusses disorders of water excess (hyponatremia), water deficiency (hypernatremia), water conservation (diabetes insipidus), saltwater excess (edematous states), and saltwater deficiency (volume depletion). Figures illustrate the relation between the plasma hydrogen ion concentration and the blood pH, proximal tubular bicarbonate reabsorption, renal secretion of hydrogen ions, renal glutamine metabolism and ammonia diffusion, metabolic alkalosis, and the electrocardiographic changes in and approach to causes of hypokalemia and hyperkalemia. Tables describe causes of metabolic acidosis with a high and a normal ion gap; causes of type 1 renal tubular acidosis; causes of type 4 renal tubular acidosis and aldosterone resistance; causes of metabolic alkalosis, respiratory acidosis, and respiratory alkalosis; evaluation of the renal defect in hyperkalemia; and treatment of hyperkalemia. This chapter contains 10 figures, 12 tables, and 53 references.

Heterozygous loss of WBP11 function causes multiple congenital defects in humans and mice.

The genetic causes of multiple congenital anomalies are incompletely understood. Here, we report novel heterozygous predicted loss-of-function (LoF) and predicted damaging missense variants in the WW domain binding protein 11 (WBP11) gene in seven unrelated families with a variety of overlapping congenital malformations, including cardiac, vertebral, tracheo-esophageal, renal and limb defects. WBP11 encodes a component of the spliceosome with the ability to activate pre-messenger RNA splicing. We generated a Wbp11 null allele in mouse using CRISPR-Cas9 targeting. Wbp11 homozygous null embryos die prior to E8.5, indicating that Wbp11 is essential for development. Fewer Wbp11 heterozygous null mice are found than expected due to embryonic and postnatal death. Importantly, Wbp11 heterozygous null mice are small and exhibit defects in axial skeleton, kidneys and esophagus, similar to the affected individuals, supporting the role of WBP11 haploinsufficiency in the development of congenital malformations in humans. LoF WBP11 variants should be considered as a possible cause of VACTERL association as well as isolated Klippel-Feil syndrome, renal agenesis or esophageal atresia.

Genetic analysis diagnosed Bardet\u2013Biedl syndrome in a patient with a clinical diagnosis of Senior\u2013L\xf8ken syndrome

BackgroundSenior–Løken syndrome (SLS) and Bardet–Biedl syndrome (BBS) are ciliopathies. SLS is characterized by retinitis pigmentosa (RP) and familial nephronophthisis, leading to end-stage kidney disease, while BBS is characterized by six major symptoms: RP, polydactyly, obesity, genital abnormalities, learning difficulties, and renal defects. Ciliopathies have been diagnosed on a phenotypic basis, but diagnosis can now be established by genetic testing, using techniques such as next-generation sequencing. Here, we report a patient clinically diagnosed with SLS but diagnosed with BBS 13 years later using next-generation sequencing.Case presentationThe patient was diagnosed with RP at the age of 6 years. She had some difficulty in social interactions and pre-obesity, but no polydactyly. At the age of 8 years, she was diagnosed with chronic kidney disease, anemia, and liver dysfunction. Kidney and liver biopsy revealed renal tubule cysts, tubule membrane disruption, and liver fibrosis. Therefore, SLS was diagnosed but no NPHP1 mutations were detected. Peritoneal dialysis was started at the age of 9 years, and she underwent kidney transplantation with a graft from her father at the age of 13 years. At the age of 21 years, she again underwent genetic testing for most of the mutations associated with ciliopathy. This revealed a homozygous frameshift mutation in intron 11 of SDCCAG8.ConclusionsMutations in SDCCAG8 are known to be causative of SLS and BBS without polydactyly. The fact that the patient had RP, some difficulty in social interactions, pre-obesity, juvenile nephronophthisis, liver fibrosis, bronchial asthma, and otitis media suggested BBS. However, some of these are not specific symptoms for BBS and she had few typical symptoms of BBS. Therefore, a definitive diagnosis of BBS was difficult without genetic analysis. Because many more patients with SDCCAG8 mutations have extrarenal manifestations like the current patient than standard nephronophthisis patients, careful monitoring of extrarenal manifestations is needed to improve patient management.

O12 Pulseless electrical activity arrest in a young woman: could renal tubular acidosis due to Sjögren’s syndrome be the underlying cause?

O12 Pulseless electrical activity arrest in a young woman: could renal tubular acidosis due to Sjögren’s syndrome be the underlying cause?

Developmental Renal Glomerular Defects at the Origin of Glomerulocystic Disease

The architecture of renal glomeruli is acquired through intricate and still poorly understood developmental steps. In our study we identify a crucial glomerular morphogenetic event in nephrogenesis that drives the remodeling/separation of the prospective vascular pole (the future entrance of the glomerular arterioles) and the urinary pole (the tubular outflow). We demonstrate that this remodeling is genetically programmed. In fact, in mouse and human, the absence of HNF1B impairs the remodeling/separation of the two poles, leading to trapping and constriction of the tubular outflow inside the glomerulus. This aberration gives rise to obstructive glomerular dilations upon the initiation of primary urine production. In this context, we show that pharmacological decrease of glomerular filtration significantly contains cystic expansion. From a developmental point of view, our study discloses a crucial event on glomerular patterning affecting the "inside-outside" fate of the epithelia in the renal glomerulus.

Predictors of Acute Pyelonephritis in Infants Less Than 4 Months Old with Febrile Urinary Tract Infection

Background: Detecting early predictors of acute pyelonephritis (APN) is essential for the prognosis, but few studies have focused on young infants specifically. Objectives: The aim of our research was to determine the relationship between APN and laboratory parameters in the age group less than 4 months. Methods: This retrospective study included patients aged less than 4 months with first time febrile urinary tract infection (UTI) between January 2012 and December 2018. White blood cells (WBC), C-reactive protein (CRP), and blood neutrophil/lymphocyte ratio (NLR) were analyzed. Patients were divided into two groups according to the presence of renal defects on dimercaptosuccinic acid (DMSA) scans. Results: In total, 205 patients were screened; 107 patients were in the APN group, and 98 patients were in the non-APN group. Compared with the non-APN group, the APN group showed significant differences in therapeutic response time (TRT), CRP, and NLR (all P values < 0.001). Multiple logistic regression analysis revealed that CRP, NLR, and TRT were independent risk factors for APN (P ≤ 0.001, 0.003, and 0.004, respectively). The area under the receiver operating characteristic (ROC) curve was 0.774 for CRP (P < 0.001). The optimum cut-off value for CRP was 4.27 mg/dL, with the highest sensitivity and specificity (70.1% and 73.5%, respectively). Conclusions: In the age group less than 4 months, without the image diagnosis, we could treat the patients as APN for longer antibiotic duration if CRP ≥ 4.27 mg/dL.

Mutations of the Transcriptional Corepressor ZMYM2 Cause Syndromic Urinary Tract Malformations

Congenital anomalies of the kidney and urinary tract (CAKUT) constitute one of the most frequent birth defects and represent the most common cause of chronic kidney disease in the first three decades of life. Despite the discovery of dozens of monogenic causes of CAKUT, most pathogenic pathways remain elusive. We performed whole-exome sequencing (WES) in 551 individuals with CAKUT and identified a heterozygous de novo stop-gain variant in ZMYM2 in two different families with CAKUT. Through collaboration, we identified in total 14 different heterozygous loss-of-function mutations in ZMYM2 in 15 unrelated families. Most mutations occurred de novo, indicating possible interference with reproductive function. Human disease features are replicated in X.tropicalis larvae with morpholino knockdowns, in which expression of truncated ZMYM2 proteins, based on individual mutations, failed to rescue renal and craniofacial defects. Moreover, heterozygous Zmym2-deficient mice recapitulated features of CAKUT with high penetrance. The ZMYM2 protein is a component of a transcriptional corepressor complex recently linked to the silencing of developmentally regulated endogenous retrovirus elements. Using protein-protein interaction assays, we show that ZMYM2 interacts with additional epigenetic silencing complexes, as well as confirming that it binds to FOXP1, a transcription factor that has also been linked to CAKUT. In summary, our findings establish that loss-of-function mutations of ZMYM2, and potentially that of other proteins in its interactome, as causes of human CAKUT, offering new routes for studying the pathogenesis of the disorder.

Magnesium poisoning with analytical aspects and its management

Magnesium is an alkaline earth metal represented as Mg and has atomic number 12 and atomic mass 24. It is one of the most abundant metal found in the atmosphere of the earth and sea water. Magnesium acts as cofactor to various enzymes in the biological system and is very essential part of diet, several medications and health supplements. High concentration of magnesium and its compound in the blood serum results into toxicity and hypermagnesemia. Such condition is generally common in people with renal defects, hypothyroidism or accidental exposure to huge amount of magnesium and its salts. Magnesium poisoning can cause severe health issues including depression of CNS, neuromuscular and cardiovascular manifestation, with other symptoms including vomiting, nausea, paralysis etc. This paper discusses the general features, techniques of analysis, clinical diagnosis, symptoms and treatments related to the magnesium poisoning.

A mutation in NOTCH2 gene first associated with Hajdu-Cheney syndrome in a Greek family: diversity in phenotype and response to treatment.

Hajdu-Cheney Syndrome (HCS) is a rare genetic autosomal dominant disorder, characterized by distinctive facial features, acroosteolysis, and severe osteoporosis. Very rarely HCS is associated with polycystic kidney disease, splenomegaly or Crohn's disease (CD). It is caused by gain-of-function mutations in NOTCH2 gene. Treatment with bisphosphonates or denosumab is reported to result in BMD increase. We report a mutation in exon 34 of NOTCH2 gene, in a Greek pedigree, with diverse phenotypes among members. The 48-year-old mother had a history of a T12 vertebral fracture, postpartum at the age of 21 and two subsequent uneventful full-term pregnancies and never received treatment. Her 29-year-old son, presented with severe osteoporosis and multiple morphological vertebral fractures. Her 21-year-old daughter had recurrent vertebral fractures starting at 10 years of age. At 17 years, she developed severe CD, resistant to treatment with biologic agents, and functional hypothalamic hypogonadism. One male pedigree died of cystic fibrosis. All subjects bore the typical facial characteristics and acroosteolysis, while none had splenomegaly or renal defects. Zoledronate infusion led to BMD increase. Mutation in c.6758 G > A (NM_008163.1), leading to a Trp2253Ter replacement. This mutation has been reported as possibly pathogenic (SCV000620308), but not in association with HCS. Bone involvement can present with diverse severity in the same pedigree, ranging from low BMD to multiple fragility fractures. Antiresorptive therapy improves BMD, but its anti-fracture efficacy remains to be shown. The presence of CD might indicate the significant role of NOTCH2 signaling in different tissues.

Nephron Progenitor Maintenance Is Controlled through Fibroblast Growth Factors and Sprouty1 Interaction.

Nephron progenitor cells (NPCs) give rise to all segments of functional nephrons and are of great interest due to their potential as a source for novel treatment strategies for kidney disease. Fibroblast growth factor (FGF) signaling plays pivotal roles in generating and maintaining NPCs during kidney development, but little is known about the molecule(s) regulating FGF signaling during nephron development. Sprouty 1 (SPRY1) is an antagonist of receptor tyrosine kinases. Although SPRY1 antagonizes Ret-GDNF signaling, which modulates renal branching, its role in NPCs is not known. Spry1, Fgf9, and Fgf20 compound mutant animals were used to evaluate kidney phenotypes in mice to understand whether SPRY1 modulates FGF signaling in NPCs and whether FGF8 functions with FGF9 and FGF20 in maintaining NPCs. Loss of one copy of Spry1 counters effects of the loss of Fgf9 and Fgf20, rescuing bilateral renal agenesis premature NPC differentiation, NPC proliferation, and cell death defects. In the absence of SPRY1, FGF9, and FGF20, another FGF ligand, FGF8, promotes nephrogenesis. Deleting both Fgf8 and Fgf20 results in kidney agenesis, defects in NPC proliferation, and cell death. Deleting one copy of Fgf8 reversed the effect of deleting one copy of Spry1, which rescued the renal agenesis due to loss of Fgf9 and Fgf20. SPRY1 expressed in NPCs modulates the activity of FGF signaling and regulates NPC stemness. These findings indicate the importance of the balance between positive and negative signals during NPC maintenance.

Abstract IA25: Adult deletion of Lats1/2 leads to sarcomatoid renal cell carcinoma

Abstract Alterations of the Hippo signaling pathway have been found in patients with sarcomatoid renal cell carcinoma, a highly aggressive kidney disease with rapid progression and poor prognosis. It is unclear whether deregulated Hippo pathway is a primary cause of sarcomatoid cancers. To investigate whether conditional (kidney-specific) Hippo knockout leads to renal cancer development and/or sarcomatoid dedifferentiation, we conditionally inactivated both Lats1 and Lats2 from the adult renal proximal tubule epithelial cells. Mosaic deletion of Lats1 and Lats2 in the adult proximal tubules results in cell-autonomous sarcomatoid renal cell carcinoma ((54%) as early as 8 weeks after gene deletion) and lung metastasis. RNA sequencing of tumors compared to control renal cortices revealed massive transcriptional changes, with 2,292 genes significantly upregulated (FC>2) and 2261 genes significantly downregulated (FCË‚0.5). To visualize the cellular onset and progression of renal defects, we conducted histologic examination at different time points after induction of Lats1/2 deletion. Mutant kidneys displayed tubular atrophy with glomerular cysts. Loss of proximal tubule epithelial markers, and de novo expression of the mesenchymal marker vimentin, indicated that kidney epithelial cells had undergone an epithelial-to-mesenchymal transition (EMT). These studies demonstrate that loss of Lats1/2 rapidly leads to aggressive, metastatic sarcomatoid renal cell carcinoma. Citation Format: Antoine Reginensi, Sanjay Jain, Benjamin Humphreys, Jess Shen, Didier Hodzic, Jeff Wrana, Helen McNeill. Adult deletion of Lats1/2 leads to sarcomatoid renal cell carcinoma [abstract]. In: Proceedings of the AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; 2019 May 8-11; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(8_Suppl):Abstract nr IA25.

Sirenomelia with vertebral, anal, cardiac defect, tracheo-esophageal fistula, renal anomalies, limb abnormalities association: a case report

Sirenomelia is a rare congenital malformation, characterised by abnormal development of caudal part of body with variable degree of fusion of lower limbs. VACTERL is an acronym used for a group of sporadic non-random birth defects involving multiple organ systems, namely vertebral (V), anal (A), cardiac (C), tracheoesophageal (TE), renal (R) and limb (L) defects. Combination of both the anomalies is very rarely reported in literature. Survival is extremely rare and early prenatal diagnosis may allow for termination of pregnancy. Here we present a case of sirenomelia phenotype, with a complete spectrum of autopsy findings, suggestive of VACTERL association.

Urachal abscess in a child with single kidney and multiple anomalous vertebrae\u2014a case report and literature review

BackgroundUrachal anomalies (UAs) are rare in children; the most encountered are urachal cysts, urachal sinus, and urachal diverticulum. Other associated anomalies have been reported to include renal and abdominal wall defects. No skeletal anomalies have been reported to date.Case presentationWe present a case of a 20-month-old female patient, who presented to our emergency department with a fever of 2 weeks duration associated with colicky abdominal pain, a tender abdomen, and an infraumbilical mass. The suspicion of urachal sinus abscess was confirmed by ultrasound. The patient was also found to have a single left kidney and multiple vertebral segmental anomalies on a full-body computed tomography scan. The patient underwent open surgical excision of the urachal abscess without complications on follow-up.ConclusionUrachal abscess is rare in children. Associated anomalies include renal and abdominal wall defects. To our knowledge and based on our meticulous search through the literature, this is the first case to report a combination of renal and skeletal findings in a child. Whenever a urachal remnant is found in a patient, a radiological investigation should be made to rule out associated anomalies.

Ligase IV syndrome can present with microcephaly and radial ray anomalies similar to Fanconi anaemia plus fatal kidney malformations

Ligase IV (LIG4) syndrome is a rare disorder of DNA damage repair caused by biallelic, pathogenic variants in LIG4. This is a phenotypically heterogeneous condition with clinical presentation varying from lymphoreticular malignancies in developmentally normal individuals to significant microcephaly, primordial dwarfism, radiation hypersensitivity, severe combined immunodeficiency and early mortality. Renal defects have only rarely been described as part of the ligase IV disease spectrum.We identified a consanguineous family where three siblings presenting with antenatal growth retardation, microcephaly, severe renal anomalies and skeletal abnormalities, including radial ray defects. Autozygosity mapping and exome sequencing identified a novel homozygous frameshift variant in LIG4, c.597_600delTCAG, p.(Gln200LysfsTer33), which segregated in the family. LIG4 is encoded by a single exon and so this frameshift variant is predicted to result in a protein truncated by 678 amino acids. This is the shortest predicted LIG4 protein product reported and correlates with the most severe clinical phenotype described to date. We note the clinical overlap with Fanconi anemia and suggest that LIG4 syndrome is considered in the differential diagnosis of this severe developmental disorder.

Hypoparathyroidism, deafness, and renal dysplasia syndrome: 20 Years after the identification of the first GATA3 mutations.

The hypoparathyroidism, deafness, and renal dysplasia (HDR) syndrome is an autosomal dominant disorder caused by heterozygous mutations of the GATA3 gene. In the last 20 years, since the identification of the genetic cause of the HDR syndrome, GATA3 mutations have been reported in 124 families (177 patients). The clinical aspects and molecular genetics of the HDR syndrome are reviewed here together with the reported mutations and phenotypes. Reported mutations consist of 40% frameshift deletions or insertions, 23% missense mutations, 14% nonsense mutations, 6% splice-site mutations, 1% in-frame deletions or insertions, 15% whole-gene deletions, and 1% whole-gene duplication. Missense mutations were found to cluster in the regions encoding the two GATA3 zinc-finger domains. Patients showed great clinical variability and the penetrance of each HDR defect increased with age. The most frequently observed abnormality was deafness (93%), followed by hypoparathyroidism (87%) and renal defects (61%). The mean age of diagnosis of HDR was 15.3, 7.5, and 14.0 years, respectively. However, patients with whole-gene deletions and protein-truncating mutations were diagnosed earlier than patients with missense mutations.