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Meral Gunayaygun - One of the best experts on this subject based on the ideXlab platform.
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prospective evaluation of Kidney and liver disease in autosomal recessive polycystic Kidney disease congenital hepatic fibrosis
Molecular Genetics and Metabolism, 2020Co-Authors: Nehna Abdul Majeed, Esperanza Fontmontgomery, Linda Lukose, Joy Bryant, Theo Heller, Peter L Choyke, Peter Veppumthara, Ismail B Turkbey, William A Gahl, Meral GunayaygunAbstract:Abstract Background and objectives We have previously published the characteristics of Kidney and liver disease in a cohort of 73 individuals with molecularly confirmed autosomal recessive polycystic Kidney disease-congenital hepatic fibrosis, based upon cross-sectional data. Here, we present prospective data on the same cohort. Design, setting, participants, and measurements Comprehensive biochemical and imaging data on progression of Kidney and liver disease in 60 of the 73 patients were prospectively collected at the NIH Clinical Center on multiple visits between 2003 and 2019. Results and conclusions Of the 73 patients, 23 received a renal allograft at an average age of 17.5 years and 10 underwent liver transplantation at an average age of 20.3 years. Patients who presented perinatally and those who had corticomedullary disease required Kidney transplantation significantly earlier. The mean eGFR slope in patients with corticomedullary disease was −1.6 ml/min/1.73 m2/y, in comparison to −0.6 ml/min/1.73 m2/y in those with medullary disease. Kidney Size remained the same over time and normalized to the upper limit of normal by 20–25 years of age. The extent of renal disease on ultrasound remained largely unchanged; no patient progressed from the “medullary” to the “corticomedullary” group. There was no correlation between eGFR slope and Kidney Size. The synthetic function of the liver remained largely intact even in patients with advanced portal hypertension. Based on spleen length/height ratio, two thirds of patients had portal hypertension which remained stable in 39% and worsened in 61%. Patients with portal hypertension had lower platelet counts and relatively higher levels of AST, GGT, direct bilirubin and ammonia. The progression rates of Kidney and liver disease were independent of each other. Patients with bi-allelic non-truncating PKHD1 variants had similar progression of Kidney and liver disease in comparison to those who were compound heterozygous for a non-truncating and a truncating variant.
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correlation of Kidney function volume and imaging findings and pkhd1 mutations in 73 patients with autosomal recessive polycystic Kidney disease
Clinical Journal of The American Society of Nephrology, 2010Co-Authors: Meral Gunayaygun, Esperanza Fontmontgomery, Linda Lukose, Joy Bryant, Maya Tuchman, Jennifer Graf, Robert Kleta, Angelica Garcia, Hailey Edwards, Katie PiwnicawormsAbstract:Background and objectives: Renal function and imaging findings have not been comprehensively and prospectively characterized in a broad age range of patients with molecularly confirmed autosomal recessive polycystic Kidney disease (ARPKD). Design, setting, participants, & measurements: Ninety potential ARPKD patients were examined at the National Institutes of Health Clinical Center. Seventy-three fulfilled clinical diagnostic criteria, had at least one PKHD1 mutation, and were prospectively evaluated using magnetic resonance imaging (MRI), high-resolution ultrasonography (HR-USG), and measures of glomerular and tubular function. Results: Among 31 perinatally symptomatic patients, 25% required renal replacement therapy by age 11 years; among 42 patients who became symptomatic beyond 1 month (nonperinatal), 25% required Kidney transplantation by age 32 years. Creatinine clearance (CrCl) for nonperinatal patients (103 ± 54 ml/min/1.73 m2) was greater than for perinatal patients (62 ± 33) (P = 0.002). Corticomedullary involvement on HR-USG was associated with a significantly worse mean CrCl (61 ± 32) in comparison with medullary involvement only (131 ± 46) (P < 0.0001). Among children with enlarged Kidneys, volume correlated inversely with function, although with wide variability. Severity of PKHD1 mutations did not determine Kidney Size or function. In 35% of patients with medullary-only abnormalities, standard ultrasound was normal and the pathology was detectable with HR-USG. Conclusions: In ARPKD, perinatal presentation and corticomedullary involvement are associated with faster progression of Kidney disease. Mild ARPKD is best detected by HR-USG. Considerable variability occurs that is not explained by the type of PKHD1 mutation.
Paul Goodyer - One of the best experts on this subject based on the ideXlab platform.
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a variant osr1 allele which disturbs osr1 mrna expression in renal progenitor cells is associated with reduction of newborn Kidney Size and function
Human Molecular Genetics, 2011Co-Authors: Zhao Zhang, Diana M Iglesias, Nicoletta Eliopoulos, Reyhan El Kares, Leelee Chu, Paola Romagnani, Paul GoodyerAbstract:Human nephrons are formed during fetal life through an interaction between the branching ureteric bud and progenitor cells. The wide variation in final nephron number has been attributed to allelic variants of genes regulating ureteric bud arborization. Here, we hypotheSize that dysfunctional variants of the Odd-Skipped Related 1 (OSR1) gene which compromise the renal progenitor cell pool might also limit newborn Kidney Size and function. We show that OSR1 is expressed in human mesenchymal stem cells, the blastemal component of Wilms tumors and CD24+/CD133+ progenitor cells isolated from the mature Kidney. We identified an OSR1(rs12329305(T)) allele in 6% of normal Caucasians which alters an exon2 splice enhancer. This variant is predicted to reduce spliceosome-binding affinity and stability of the OSR1 mRNA. In cultured cells, the OSR1(rs12329305)(T) allele produced no identifiable transcript. Normal Caucasian newborns from Montreal with the OSR1(rs12329305)(T) allele had Kidney volume 11.8% smaller (P= 0.006) and cord blood cystatin C levels 12.6% higher (P = 0.005) than those with wild-type genotype. Effects of the OSR1(rs12329305)(T) allele are additive with genes that alter ureteric bud branching. Kidney volume was reduced more in newborns bearing both RET(rs1800860)(A) and OSR1(rs12329305)(T) alleles (22%, P= 0.0008) and cystatin C was increased by 17% (P= 0.006) versus newborns with wild-type alleles. Although only two subjects had PAX2(rs11599825)(A) and OSR1(rs12329305)(T) alleles, Kidney Size was reduced by 27% and cystatin C was increased by 14% versus wild-types (P= NS).
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a human aldh1a2 gene variant is associated with increased newborn Kidney Size and serum retinoic acid
Kidney International, 2010Co-Authors: Reyhan El Kares, Zhao Zhang, Daniel C Manolescu, Lajmi Lakhalchaieb, Alexandre Montpetit, Pangala V Bhat, Paul GoodyerAbstract:Nephron number varies widely between 0.3 and 1.3 million per Kidney in humans. During fetal life, the rate of nephrogenesis is influenced by local retinoic acid (RA) level such that even moderate maternal vitamin A deficiency limits the final nephron number in rodents. Inactivation of genes in the RA pathway causes renal agenesis in mice; however, the impact of retinoids on human Kidney development is unknown. To resolve this, we tested for associations between variants of genes involved in RA metabolism (ALDH1A2, CYP26A1, and CYP26B1) and Kidney Size among normal newborns. Homozygosity for a common (1 in 5) variant, rs7169289(G), within an Sp1 transcription factor motif of the ALDH1A2 gene, showed a significant 22% increase in newborn Kidney volume when adjusted for body surface area. Infants bearing this allele had higher umbilical cord blood RA levels compared to those with homozygous wild-type ALDH1A2 rs7169289(A) alleles. Furthermore, the effect of the rs7169289(G) variant was evident in subgroups with or without a previously reported hypomorphic RET 1476(A) proto-oncogene allele that is critical in determining final nephron number. As maternal vitamin A deficiency is widespread in developing countries and may compromise availability of retinol for fetal RA synthesis, our study suggests that the ALDH1A2 rs7169289(G) variant might be protective for such individuals.
Paul Thompson - One of the best experts on this subject based on the ideXlab platform.
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sonographic assessment of the severity and progression of autosomal dominant polycystic Kidney disease the consortium of renal imaging studies in polycystic Kidney disease crisp
American Journal of Kidney Diseases, 2005Co-Authors: Charles W Oneill, Lisa M Guaywoodford, Michelle L Robbin, Kyongtae T Bae, Jared J Grantham, Arlene B Chapman, Vicente E Torres, Bernard Francis King, Louis H Wetzel, Paul ThompsonAbstract:Background: The accuracy and precision of ultrasonography (US) in assessing the severity of autosomal dominant polycystic Kidney disease (ADPKD) is unknown. Methods: US and magnetic resonance imaging (MRI) were performed at baseline and 1 year on 230 subjects with ADPKD. Ellipsoid volume was calculated from US length, width, and depth, and sequential transverse images were used to measure total and cystic volume directly. These were compared with MRI measurements of Kidney volume and cystic volume. Results: Variability between different sonographers ranged from 18% to 42%. Correlations between US and MRI volume were 0.88 and 0.89. The SD of the discrepancy from MRI ranged from 21% to 33% and was unrelated to Kidney Size or body mass. Kidney length was the most reproducible measurement, and its correlation with MRI volume was 0.84. All patients with an US volume less than 700 cm3 had an MRI volume less than 1,000 cm3, and all patients with an US volume greater than 1,700 cm3 had an MRI volume greater than 1,000 cm3. Increases in volume after 1 year were 12% ± 36% for the ellipsoid method, 6% ± 29% for the direct method, and 4.2% ± 7.2% for MRI. Correlation between US and MRI measurement of fractional cyst volume was 0.80. Conclusion: Sonographic measurement of Kidney volume in patients with ADPKD is inaccurate and lacks the precision necessary to measure short-term disease progression. However, sonography can provide an estimate of Kidney volume that reflects severity and prognosis in individual patients.
Joy Bryant - One of the best experts on this subject based on the ideXlab platform.
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prospective evaluation of Kidney and liver disease in autosomal recessive polycystic Kidney disease congenital hepatic fibrosis
Molecular Genetics and Metabolism, 2020Co-Authors: Nehna Abdul Majeed, Esperanza Fontmontgomery, Linda Lukose, Joy Bryant, Theo Heller, Peter L Choyke, Peter Veppumthara, Ismail B Turkbey, William A Gahl, Meral GunayaygunAbstract:Abstract Background and objectives We have previously published the characteristics of Kidney and liver disease in a cohort of 73 individuals with molecularly confirmed autosomal recessive polycystic Kidney disease-congenital hepatic fibrosis, based upon cross-sectional data. Here, we present prospective data on the same cohort. Design, setting, participants, and measurements Comprehensive biochemical and imaging data on progression of Kidney and liver disease in 60 of the 73 patients were prospectively collected at the NIH Clinical Center on multiple visits between 2003 and 2019. Results and conclusions Of the 73 patients, 23 received a renal allograft at an average age of 17.5 years and 10 underwent liver transplantation at an average age of 20.3 years. Patients who presented perinatally and those who had corticomedullary disease required Kidney transplantation significantly earlier. The mean eGFR slope in patients with corticomedullary disease was −1.6 ml/min/1.73 m2/y, in comparison to −0.6 ml/min/1.73 m2/y in those with medullary disease. Kidney Size remained the same over time and normalized to the upper limit of normal by 20–25 years of age. The extent of renal disease on ultrasound remained largely unchanged; no patient progressed from the “medullary” to the “corticomedullary” group. There was no correlation between eGFR slope and Kidney Size. The synthetic function of the liver remained largely intact even in patients with advanced portal hypertension. Based on spleen length/height ratio, two thirds of patients had portal hypertension which remained stable in 39% and worsened in 61%. Patients with portal hypertension had lower platelet counts and relatively higher levels of AST, GGT, direct bilirubin and ammonia. The progression rates of Kidney and liver disease were independent of each other. Patients with bi-allelic non-truncating PKHD1 variants had similar progression of Kidney and liver disease in comparison to those who were compound heterozygous for a non-truncating and a truncating variant.
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correlation of Kidney function volume and imaging findings and pkhd1 mutations in 73 patients with autosomal recessive polycystic Kidney disease
Clinical Journal of The American Society of Nephrology, 2010Co-Authors: Meral Gunayaygun, Esperanza Fontmontgomery, Linda Lukose, Joy Bryant, Maya Tuchman, Jennifer Graf, Robert Kleta, Angelica Garcia, Hailey Edwards, Katie PiwnicawormsAbstract:Background and objectives: Renal function and imaging findings have not been comprehensively and prospectively characterized in a broad age range of patients with molecularly confirmed autosomal recessive polycystic Kidney disease (ARPKD). Design, setting, participants, & measurements: Ninety potential ARPKD patients were examined at the National Institutes of Health Clinical Center. Seventy-three fulfilled clinical diagnostic criteria, had at least one PKHD1 mutation, and were prospectively evaluated using magnetic resonance imaging (MRI), high-resolution ultrasonography (HR-USG), and measures of glomerular and tubular function. Results: Among 31 perinatally symptomatic patients, 25% required renal replacement therapy by age 11 years; among 42 patients who became symptomatic beyond 1 month (nonperinatal), 25% required Kidney transplantation by age 32 years. Creatinine clearance (CrCl) for nonperinatal patients (103 ± 54 ml/min/1.73 m2) was greater than for perinatal patients (62 ± 33) (P = 0.002). Corticomedullary involvement on HR-USG was associated with a significantly worse mean CrCl (61 ± 32) in comparison with medullary involvement only (131 ± 46) (P < 0.0001). Among children with enlarged Kidneys, volume correlated inversely with function, although with wide variability. Severity of PKHD1 mutations did not determine Kidney Size or function. In 35% of patients with medullary-only abnormalities, standard ultrasound was normal and the pathology was detectable with HR-USG. Conclusions: In ARPKD, perinatal presentation and corticomedullary involvement are associated with faster progression of Kidney disease. Mild ARPKD is best detected by HR-USG. Considerable variability occurs that is not explained by the type of PKHD1 mutation.
Linda Lukose - One of the best experts on this subject based on the ideXlab platform.
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prospective evaluation of Kidney and liver disease in autosomal recessive polycystic Kidney disease congenital hepatic fibrosis
Molecular Genetics and Metabolism, 2020Co-Authors: Nehna Abdul Majeed, Esperanza Fontmontgomery, Linda Lukose, Joy Bryant, Theo Heller, Peter L Choyke, Peter Veppumthara, Ismail B Turkbey, William A Gahl, Meral GunayaygunAbstract:Abstract Background and objectives We have previously published the characteristics of Kidney and liver disease in a cohort of 73 individuals with molecularly confirmed autosomal recessive polycystic Kidney disease-congenital hepatic fibrosis, based upon cross-sectional data. Here, we present prospective data on the same cohort. Design, setting, participants, and measurements Comprehensive biochemical and imaging data on progression of Kidney and liver disease in 60 of the 73 patients were prospectively collected at the NIH Clinical Center on multiple visits between 2003 and 2019. Results and conclusions Of the 73 patients, 23 received a renal allograft at an average age of 17.5 years and 10 underwent liver transplantation at an average age of 20.3 years. Patients who presented perinatally and those who had corticomedullary disease required Kidney transplantation significantly earlier. The mean eGFR slope in patients with corticomedullary disease was −1.6 ml/min/1.73 m2/y, in comparison to −0.6 ml/min/1.73 m2/y in those with medullary disease. Kidney Size remained the same over time and normalized to the upper limit of normal by 20–25 years of age. The extent of renal disease on ultrasound remained largely unchanged; no patient progressed from the “medullary” to the “corticomedullary” group. There was no correlation between eGFR slope and Kidney Size. The synthetic function of the liver remained largely intact even in patients with advanced portal hypertension. Based on spleen length/height ratio, two thirds of patients had portal hypertension which remained stable in 39% and worsened in 61%. Patients with portal hypertension had lower platelet counts and relatively higher levels of AST, GGT, direct bilirubin and ammonia. The progression rates of Kidney and liver disease were independent of each other. Patients with bi-allelic non-truncating PKHD1 variants had similar progression of Kidney and liver disease in comparison to those who were compound heterozygous for a non-truncating and a truncating variant.
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correlation of Kidney function volume and imaging findings and pkhd1 mutations in 73 patients with autosomal recessive polycystic Kidney disease
Clinical Journal of The American Society of Nephrology, 2010Co-Authors: Meral Gunayaygun, Esperanza Fontmontgomery, Linda Lukose, Joy Bryant, Maya Tuchman, Jennifer Graf, Robert Kleta, Angelica Garcia, Hailey Edwards, Katie PiwnicawormsAbstract:Background and objectives: Renal function and imaging findings have not been comprehensively and prospectively characterized in a broad age range of patients with molecularly confirmed autosomal recessive polycystic Kidney disease (ARPKD). Design, setting, participants, & measurements: Ninety potential ARPKD patients were examined at the National Institutes of Health Clinical Center. Seventy-three fulfilled clinical diagnostic criteria, had at least one PKHD1 mutation, and were prospectively evaluated using magnetic resonance imaging (MRI), high-resolution ultrasonography (HR-USG), and measures of glomerular and tubular function. Results: Among 31 perinatally symptomatic patients, 25% required renal replacement therapy by age 11 years; among 42 patients who became symptomatic beyond 1 month (nonperinatal), 25% required Kidney transplantation by age 32 years. Creatinine clearance (CrCl) for nonperinatal patients (103 ± 54 ml/min/1.73 m2) was greater than for perinatal patients (62 ± 33) (P = 0.002). Corticomedullary involvement on HR-USG was associated with a significantly worse mean CrCl (61 ± 32) in comparison with medullary involvement only (131 ± 46) (P < 0.0001). Among children with enlarged Kidneys, volume correlated inversely with function, although with wide variability. Severity of PKHD1 mutations did not determine Kidney Size or function. In 35% of patients with medullary-only abnormalities, standard ultrasound was normal and the pathology was detectable with HR-USG. Conclusions: In ARPKD, perinatal presentation and corticomedullary involvement are associated with faster progression of Kidney disease. Mild ARPKD is best detected by HR-USG. Considerable variability occurs that is not explained by the type of PKHD1 mutation.
