Congenital Kidney Research Articles

Angiotensin converting enzyme gene polymorphism in primary vesicoureteral reflux.

We studied the insertion/deletion (I/D) polymorphism of the angiotensin converting enzyme (ACE) gene in 78 patients with primary vesicoureteral reflux (VUR), and examined renal function by dimercaptosuccinate (DMSA) renoscintigraphy and diethylenetriamine-penta-acetic acid (DTPA) renogram in each genotype. Patients were classified into three genotypes according to the ACE gene I/D polymorphisms: 32 in II genotype, 36 in ID, and 10 in DD. The incidence of presumably congenital unilateral small kidneys was high in DD patients (70%). Glomerular filtration rate obtained from DTPA renogram was 120.7+/-35.7 ml/min (expressed as mean+/-SD) in II genotype, 111.7+/-33.3 in ID, and 88.0+/-18.0 in DD. The total quantitative DMSA tracer uptake of both kidneys was also low in patients with the D allele. This study shows that the D allele of ACE gene is closely related to small congenital kidneys with refluxing ureters in patients with primary VUR, and in accordance with previous reports, this allele is also related to the progression of reflux nephropathy.

Potential biological role of transforming growth factor-beta1 in human congenital kidney malformations.

Transformations between epithelial and mesenchymal cells are widespread during normal development and adult disease, and transforming growth factor-beta1 (TGF-beta1) has been implicated in some of these phenotypic switches. Dysplastic kidneys are a common cause of chronic kidney failure in young children and result from perturbed epithelial-mesenchymal interactions. In this study, we found that components of the TGF-beta1 axis were expressed in these malformations: TGF-beta1 mRNA and protein were up-regulated in dysplastic epithelia and surrounding mesenchymal cells, whereas TGF-beta receptors I and II were expressed in aberrant epithelia. We generated a dysplastic kidney epithelial-like cell line that expressed cytokeratin, ZO1, and MET, and found that exogenous TGF-beta1 inhibited proliferation and decreased expression of PAX2 and BCL2, molecules characterizing dysplastic tubules in vivo. Furthermore, addition of TGF-beta1 specifically induced morphological changes compatible with a shift to a mesenchymal phenotype, accompanied by loss of ZO1 at cell borders and up-regulation of the mesenchymal markers alpha-smooth muscle actin and fibronectin. The descriptive and functional data presented in this report potentially implicate TGF-beta1 in the pathobiology of dysplastic kidneys and our results provide preliminary evidence that an epithelial-to-mesenchymal phenotypic switch may be implicated in a clinically important developmental aberration.

Kidney Development: Regulatory Molecules Crucial to Both Mice and Men

Although the study of embryonic kidney development began in the 1950s, three decades passed until scientists began identifying the molecular controls of renal organogenesis. Most of these advances have come from mouse gene targeting and rodent kidney explant manipulation. Translation of the rodent data to human congenital kidney disease has only just begun. The activities of those regulatory molecules proven to be used in common appear remarkably similar in mouse and human renal development. Examples of these genes include glial cell line-derived neurotrophic factor (GDNF), RET, PAX2, Wilms tumor suppressor (WT1), and components in the renin–angiotensin pathway. Other factors that participate in mouse renal organogenesis, such as N-Myc, may later be proven important in human kidney development.

Detection of trisomy 18 on formalin-fixed and paraffin-embedded material by fluorescence in situ hybridization.

Formalin-fixed and paraffin-embedded autopsy material from 10 fetuses and infants with unknown karyotype and anomalies suggestive of trisomy 18 were subjected to fluorescence in situ hybridization (FISH). Nuclei were extracted from the tissues and hybridized with a chromosome 18-specific centromere probe. The hybridization was successful in 9 of 10 cases. Two cases showed three hybridization signals in most of the nuclei (74% and 85%). These had anomalies frequently occurring with trisomy 18 (congenital heart defect, omphalocele, and horseshoe kidney). Two cases showed a mixture of two and three signals (47%/49% and 59%/36%), suggesting the possibility of mosaicism. One of these cases had anomalies consistent with a trisomy 18 phenotype. In the other case intrauterine growth retardation and syndactylies suggested triploidy. Hybridization with a chromosome 8-specific probe gave a distribution of two and three signals (34% and 62%, respectively). This result strengthened the suspicion of a possible triploid mosaicism. In five of the cases most of the nuclei showed two signals (85% to 88%). However, as only one type of tissue was examined for enumeration of chromosome 18, the possibility of organ mosaicism or other chromosome aberrations cannot be excluded. The FISH technique is applicable on macerated and autolysed formalin-fixed tissue, making it possible to retrospectively analyze autopsy material from aborted and stillborn fetuses and infants. This analysis contributes to a better quality of perinatal autopsies and is helpful in parental counseling.

Murine forkhead/winged helix genes Foxc1 (Mf1) and Foxc2 (Mfh1) are required for the early organogenesis of the kidney and urinary tract.

The murine genes, Foxc1 and Foxc2 (previously, Mf1 and Mfh1), encode forkhead/winged helix transcription factors with virtually identical DNA-binding domains and overlapping expression patterns in various embryonic tissues. Foxc1/Mf1 is disrupted in the mutant, congenital hydrocephalus (Foxc1/Mf1(ch)), which has multiple developmental defects. We show here that, depending on the genetic background, most Foxc1 homozygous mutants are born with abnormalities of the metanephric kidney, including duplex kidneys and double ureters, one of which is a hydroureter. Analysis of embryos reveals that Foxc1 homozygotes have ectopic mesonephric tubules and ectopic anterior ureteric buds. Moreover, expression in the intermediate mesoderm of Glial cell-derived neurotrophic factor (Gdnf), a primary inducer of the ureteric bud, is expanded more anteriorly in Foxc1 homozygous mutants compared with wild type. These findings support the hypothesis of Mackie and Stephens concerning the etiology of duplex kidney and hydroureter in human infants with congenital kidney abnormalities (Mackie, G. G. and Stephens, F. G. (1975) J. Urol. 114, 274-280). Previous studies established that most Foxc1(lacZ )Foxc2(tm1) compound heterozygotes have the same spectrum of cardiovascular defects as single homozygous null mutants, demonstrating interaction between the two genes in the cardiovascular system. Here, we show that most compound heterozygotes have hypoplastic kidneys and a single hydroureter, while all heterozygotes are normal. This provides evidence that the two genes interact in kidney as well as heart development.

8 The Development of the Kidney

This chapter describes the earlier stages of development of the vertebrate metanephric kidney. It focuses on the mouse and descriptive morphology is used for considering both molecular mechanisms, underpinning kidney morphogenesis and differentiation, and the ways in which these processes can go awry and lead to congenital kidney disorders—particularly in humans. The mature kidney is a fairly complex organ attached to an arterial input vessel and two output vessels, the vein and the ureter. Inside, the artery and vein are connected by a complex network of capillaries that invade a large number of glomeruli, the proximal entrance to nephrons, which are filtration units that link to an arborized collecting-duct system that drains into the ureter. The ability of the kidney and isolated metanephrogenic mesenchyme, to develop in culture means that the developing tissues can be subjected to a wide variety of experimental procedures designed to investigate their molecular and cellular properties and to test hypotheses about developmental mechanisms.

Roles of growth factors in renal development.

The branching of the ureteric bud and the differentiation of renal mesenchyme into nephrons are interdependent processes. Experiments with organ culture and genetically engineered mice suggest that metanephric growth factors regulate these events. Renal mesenchyme produces glial cell line-derived neurotrophic factor, an essential molecule for ureteric bud growth, whereas multiple growth factors are required for nephron formation: these include fibroblast growth factor 2, Wnt4 and bone morphogenetic protein 7. Deregulation of growth factors may be implicated in the pathogenesis of congenital kidney malformations.

Erythropoietin concentrations and erythropoiesis in newborns suffering from renal agenesis and congenital kidney diseases.

We studied serum concentrations of erythropoietin (EPO) in the cord blood of 31 newborns. In patients with renal agenesis (n = 6), the EPO levels were 68.2 (23-177) mU/ml (median, range). These values are clearly above EPO levels in the reference groups (median/range: < 30 weeks 11.0 (5.5-17.5) mU/ml; 30-32 weeks 18.1 (5.5-136) mU/ml; 33-34 weeks 17.7 (8.3-423) mU/ml; 35-37 weeks 17.3 (5.5-272) mU/ml; > or = 38 weeks 17.8 (8.7-40.3) mU/ml). Neonates with polycystic kidney diseases (n = 12, EPO 23.5 (9.7-491) mU/ml) and with severe bilateral hydronephrosis due to obstructive uropathy (n = 13, 18.6 (7.5-30.7) mU/ml) showed no difference to the reference groups. In all groups there were only slight differences in haemoglobin/haematocrit values. In spite of renal agenesis and severe congenital kidney diseases, erythropoiesis is sufficiently maintained during fetal life. The liver of congenitally kidney-damaged fetuses is sufficiently able to compensate the reduction in--or lack of--renal EPO production.

Transvaginal sonographic assessment of the fetal urinary tract in early pregnancy.

Fetal renal size in the first trimester and the early second trimester of pregnancy was evaluated by high-frequency transvaginal sonography in 537 singleton fetuses at risk for cytogenetic abnormality but not at risk for congenital kidney disease. The percentage of visualization of both kidneys and bladder at different menstrual ages (11-16 weeks) is presented, and centile reference charts for evaluating kidney growth have been compiled. All kidney measurements were found to increase as pregnancy progressed. At 13 weeks, fetal kidneys and fetal urinary bladder were visualized in 92% of the cases screened. The incidence of pyelectasis was high in our population (4.5%), and this pathology was studied by other sonographic scans during pregnancy and postnatally. All fetuses had normal karyotypes. The results presented provide a reference for the assessment of normal renal morphology and growth in early pregnancy.

Effects of Long Term Administration of 2-Amino-4,5-Diphenylthiazole on Kidneys in Rats and N-Ethyl-N-Hydroxyethylnitrosamine-Treated Rats.

Changes in the kidneys were studied histopathologically and biochemically in F344 rats treated for long periods with 2-amino-4, 5-diphenylthiazole (DPT), with and without prior application of the renal carcinogen N-ethyl-N-hydroxyethylnitrosamine (EHEN). Experiment I: A total of 45 male 6-week-old F344 rats were divided into two groups; one receiving DPT at 1.06% in the diet (n=30) and the other being untreated (n=15). The observation period was 52 weeks. DPT caused cystic changes in the corticomedullary border, which were seen from the 4th week, progressed with time. Urine osmolarity began to decrease from the 6th week, however no biochemical signs of renal failure were noted before the 32nd week. High-performance liquid chromatography (HPLC) revealed 6 fractions, representing metabolites of DPT, in urine from DPT-treated rats. Experiment II: A total of 132 male 6-week-old F344 rats were divided into four groups: Group 1 (2-weeks 1, 000 ppm EHEN treatment followed by 1.06% DPT treatment), Group 2 (1.06% DPT treatment), Group 3 (2-weeks 1, 000 ppm EHEN treatment), and Group 4 (untreated controls). They were observed for 60 weeks. Cystic changes in the kidneys, as seen in Experiment I, were noted in Groups 1 and 2. Preneoplastic changes were seen only in Group 1, at incidences of 20% and 75% at weeks 48 and 60, respectively. Adenomas were seen in Groups 1 and 3, at incidences of 20% and 0%, and 25% and 20% at weeks 48 and 60, respectively. A carcinoma was diagnosed in 1 (20%) of the 5 rats from Group 1 in the 48th week. These results suggest that the DPT-treated rat can serve as a valid experimental model of congenital cystic kidney disease and chronic renal failure, and that DPT may promote EHEN-induced renal carcinogenesis.

Trisomy 16 fetus surviving into the second trimester

A 27-year-old gravida 4, para 3 was found to have anhydramnios at 14 weeks' gestation following a size/date discrepancy noted at her routine prenatal visit. A detailed ultrasound revealed multiple fetal anomalies including congenital heart defect, chest hypoplasia, and bilateral dysplastic kidneys. Karyotype revealed trisomy 16 in 15/15 cells from a tissue specimen obtained from the fetal cord insertion site following elective pregnancy termination.

Juvenile nephronophthisis: A case report

Nephronophthisis, or the deterioration of nephrons, is a classification of congenital kidney disorder that results in a medullary cystic disease. The three variations of genetic expression for this disease are: 1. Sporadic occurrences where family history is negative for renal disease. 2. Recessive inheritance with or without other associated abnormalities. 3. Transmitted inheritance that is dominant with probable autosomal, and possible X-linked trait.Nephronophthisis is reported to occur between the ages of 2 to 68 years of age, with most appearing in the first three decades of life. The most common clinical presentation is chronic renal failure, with a history of polyuria, and polydipsia. Children and adolescents may also exhibit enuresis, and chronic anemia.Light microscopic examination of kidney biopsy tissue reveals extensive tubular atrophy accompanied by glomerular sclerosis, and inflammation resembling pyelonephritis. Tubules that are cystically dilated may be observed primarily at the cortico-medullary junction, although this finding is dependent on the extent of the disease process.

Temporary perfusion of a congenital pelvic kidney during abdominal aortic aneurysm repair

Temporary perfusion of a congenital pelvic kidney during abdominal aortic aneurysm repair

The molecular basis of nephrogenesis and congenital kidney disease.

The molecular basis of nephrogenesis and congenital kidney disease.

Acquired Renal Cystic Disease Mimicking Adult Polycystic Kidney Disease in a Patient Undergoing Long-Term Hemodialysis

Acquired renal cystic disease (ARCD) is defined as the development of multiple cysts in the renal cortex and medulla in patients with chronic renal failure who are free from congenital polycystic kidney disease. ARCD develops generally in contracted kidneys. We report a case of grotesque enlargement of a single kidney in a patient who had been receiving hemodialysis for 18 years. Although the exact causes of ARCD are not known, 3 factors may contribute to the development of nephromegaly; the sex, the duration of hemodialysis and previous unilateral nephrectomy. As in polycystic disease, when the involved kidney reaches considerable size, ARCD may have a favorable effect on anemia caused by chronic renal failure.

Albrights syndrome—report of a case and review of literature

Albright’s Syndrome is a rare disease which occurs sporadically. Its aetiology is not known. It is extremely rare in males. To the best of our knowledge this Syndrome is not associated with any congenital visceral anomaly. We present a case of Albright’s Syndrome in a boy who also showed a congenital ectopic kidney. The literature of this syndrome is reviewed with a view to update the current knowledge.

Congenital Hepatic Fibrosis, Cystic Kidneys, Mental Retardation, and Facial Dysmorphy

This report concerns a boy with congenital hepatic fibrosis, cystic kidneys, mental retardation, and minor dysmorphic features. These symptoms have rarely been reported before and indicate that congenital hepatic fibrosis may not be a single clinical entity.

Transvaginal sonographic measurement of fetal kidneys in the first trimester of pregnancy

Fetal renal size late in the first trimester of pregnancy was evaluated by transvaginal ultrasonography in 50 patients not at risk for congenital kidney disease and whose pregnancies resulted in a normal outcome. Both kidneys were reliably identified in all patients scanned at 12 weeks, 13 weeks, and 14 weeks, menstrual age. Kidney diameter measurements obtained in this study are presented for reference in evaluating patients in late first trimester whose fetuses are at risk for kidney abnormalities.

The Marcus Gunn (jaw-winking) phenomenon: a case report

The clinical features of the Marcus Gunn (jaw-winking) phenomenon are described and a case is reported in a 23-year-old female who also had congenital left duplex kidneys and ureters.

Polycystic Kidney of Autosomal Dominant Inheritance, Polycystic Liver and Congenital Hepatic Fibrosis in a Single Kindred

A family with clear evidence of concomitant congenital hepatic fibrosis, polycystic liver and adult-type polycystic kidney is reported. The autosomal dominant inheritance of polycystic kidney in association with either liver cyst or hepatic fibrosis in this family suggests that various combinations of hepatic and renal fibrocystic lesions are possible to occur. Additionally, in the proband a very rare association of congenital hepatic fibrosis and cerebral aneurysm was present.