Cerebral aneurysms.
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Aneurysm, Ruptured↗
Biomedical subjects
Vicente E Torres
Publications and source records attributed to Vicente E Torres.
Cyst number but not the rate of cystic growth is associated with the mutated gene in autosomal dominant polycystic kidney disease.
Data from serial renal magnetic resonance imaging of the Consortium of Radiologic Imaging Study of PKD (CRISP) autosomal dominant polycystic kidney disease (PKD) population showed that cystic expansion occurs at a consistent rate per individual, although it is heterogeneous in the population, and that larger kidneys are associated with more rapid disease progression. The significance of gene type to disease progression is analyzed in this study of the CRISP cohort. Gene type was determined in 183 families (219 cases); 156 (85.2%) had PKD1, and 27 (14.8%) had PKD2. PKD1 kidneys were significantly larger, but the rate of cystic growth (PKD1 5.68%/yr; PKD2 4.82%/yr) was not different (P = 0.24). Cyst number increased with age, and more cysts were detected in PKD1 kidneys (P < 0.0001). PKD1 is more severe because more cysts develop earlier, not because they grow faster, implicating the disease gene in cyst initiation but not expansion. These insights will inform the development of targeted therapies in autosomal dominant PKD.
Adolescent↗
Duodenal diverticulosis in autosomal dominant polycystic kidney disease.
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Aged↗
Water for ADPKD? Probably, yes.
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Animals↗
Volume progression in polycystic kidney disease.
BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive enlargement of cyst-filled kidneys. METHODS: In a three-year study, we measured the rates of change in total kidney volume, total cyst volume, and iothalamate clearance in patients with ADPKD. Of a total of 241 patients, in 232 patients without azotemia who were 15 to 46 years old at baseline we used magnetic-resonance imaging to correlate the total kidney volume and total cyst volume with iothalamate clearance. Statistical methods included analysis of variance, Pearson correlation, and multivariate regression analysis. RESULTS: Total kidney volume and total cyst volume increased exponentially, a result consistent with an expansion process dependent on growth. The mean (+/-SD) total kidney volume was 1060+/-642 ml at baseline and increased by a mean of 204+/-246 ml (5.27+/-3.92 percent per year, P<0.001) over a three-year period among 214 patients. Total cyst volume increased by 218+/-263 ml (P<0.001) during the same period among 210 patients. The baseline total kidney volume predicted the subsequent rate of increase in volume, independently of age. A baseline total kidney volume above 1500 ml in 51 patients was associated with a declining glomerular filtration rate (by 4.33+/-8.07 ml per minute per year, P<0.001). Total kidney volume increased more in 135 patients with PKD1 mutations (by 245+/-268 ml) than in 28 patients with PKD2 mutations (by 136+/-100 ml, P=0.03). CONCLUSIONS: Kidney enlargement resulting from the expansion of cysts in patients with ADPKD is continuous and quantifiable and is associated with the decline of renal function. Higher rates of kidney enlargement are associated with a more rapid decrease in renal function.
Adult↗
Comparison of methods for determining renal function decline in early autosomal dominant polycystic kidney disease: the consortium of radiologic imaging studies of polycystic kidney disease cohort.
A decline in renal function suggests progression of chronic kidney disease. This can be determined by measured GFR (e.g., iothalamate clearance), serum creatinine (SCr)-based GFR estimates, or creatinine clearance. A cohort of 234 patients with autosomal dominant polycystic kidney disease and baseline creatinine clearance>70 ml/min were followed annually for four visits. Iothalamate clearance, SCr, and creatinine clearance were obtained at each visit. Estimated GFR (eGFR) was determined with the Modification of Diet in Renal Disease (MDRD) and Cockcroft-Gault equations. Renal function slopes had a mean residual SD of 10.7% by iothalamate clearance, 8.2% by MDRD equation, 7.7% by Cockcroft-Gault equation, and 14.8% by creatinine clearance. By each method, a decline in renal function (lowest quintile slope) was compared among baseline predictors. Hypertension was associated with a decline in iothalamate clearance (odds ratio [OR] 5.8; 95% confidence interval [CI] 2.3 to 14), eGFR (OR [MDRD] 2.0 [95% CI 1.0 to 4.2] or OR [Cockcroft-Gault] 1.9 [95% CI 0.9 to 3.9]), and creatinine clearance (OR 2.0; 95% CI 1.0 to 4.2). Each doubling of kidney volume at baseline was associated with a decline in iothalamate clearance (OR 2.4; 95% CI 1.5 to 3.7), eGFR (OR 1.7 [95% CI 1.1 to 2.6] or 2.1 [95% CI 1.4 to 3.3]), and creatinine clearance (OR 1.7; 95% CI 1.1 to 2.5). Predictor associations were strongest with measured GFR. Misclassification from changes in non-GFR factors (e.g., creatinine production, tubular secretion) conservatively biased associations with eGFR. Misclassification from method imprecision attenuated associations with creatinine clearance.
Adolescent↗
The transmembrane protein meckelin (MKS3) is mutated in Meckel-Gruber syndrome and the wpk rat.
Meckel-Gruber syndrome is a severe autosomal, recessively inherited disorder characterized by bilateral renal cystic dysplasia, developmental defects of the central nervous system (most commonly occipital encephalocele), hepatic ductal dysplasia and cysts and polydactyly. MKS is genetically heterogeneous, with three loci mapped: MKS1, 17q21-24 (ref. 4); MKS2, 11q13 (ref. 5) and MKS3 (ref. 6). We have refined MKS3 mapping to a 12.67-Mb interval (8q21.13-q22.1) that is syntenic to the Wpk locus in rat, which is a model with polycystic kidney disease, agenesis of the corpus callosum and hydrocephalus. Positional cloning of the Wpk gene suggested a MKS3 candidate gene, TMEM67, for which we identified pathogenic mutations for five MKS3-linked consanguineous families. MKS3 is a previously uncharacterized, evolutionarily conserved gene that is expressed at moderate levels in fetal brain, liver and kidney but has widespread, low levels of expression. It encodes a 995-amino acid seven-transmembrane receptor protein of unknown function that we have called meckelin.
Abnormalities, Multiple↗
Autosomal recessive polycystic kidney disease and congenital hepatic fibrosis: summary statement of a first National Institutes of Health/Office of Rare Diseases conference.
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Angiotensin-Converting Enzyme Inhibitors↗
Mechanisms of Disease: autosomal dominant and recessive polycystic kidney diseases.
Autosomal dominant polycystic kidney disease and autosomal recessive polycystic kidney disease are the best known of a large family of inherited diseases characterized by the development of renal cysts of tubular epithelial cell origin. Autosomal dominant and recessive polycystic kidney diseases have overlapping but distinct pathogeneses. Identification of the causative mutated genes and elucidation of the function of their encoded proteins is shedding new light on the mechanisms that underlie tubular epithelial cell differentiation. This review summarizes recent literature on the role of primary cilia, intracellular calcium homeostasis, and signaling involving Wnt, cyclic AMP and Ras/MAPK, in the pathogenesis of polycystic kidney disease. Improved understanding of pathogenesis and the availability of animal models orthologous to the human diseases provide an excellent opportunity for the development of pathophysiology-based therapies. Some of these have proven effective in preclinical studies, and clinical trials have begun.
Animals↗
Clinical and molecular characterization defines a broadened spectrum of autosomal recessive polycystic kidney disease (ARPKD).
The autosomal recessive form of polycystic kidney disease (ARPKD) is generally considered an infantile disorder with the typical presentation of greatly enlarged echogenic kidneys detected in utero or within the neonatal period, often resulting in neonatal demise. However, there is an increasing realization that survivors often thrive into adulthood with complications of the ductal plate malformation, manifesting as congenital hepatic fibrosis and Caroli disease, becoming prominent. Previous natural history studies have concentrated almost exclusively on the infantile presenting group. However, developments in understanding the genetic basis of ARPKD, through identification of the disease gene, PKHD1, have allowed exploration of the etiology in patients with ARPKD-like disease or congenital hepatic fibrosis presenting later in childhood or as adults. In the current study we retrospectively reviewed the clinical records, and where possible performed PKHD1 mutation screening, in patients diagnosed with ARPKD or congenital hepatic fibrosis at the Mayo Clinic, Rochester, MN, from 1961 to 2004. Of a total of 133 cases reviewed, 65 were considered to meet the diagnostic criteria with an average duration of follow-up of 8.6 +/- 6.4 years. Fifty-five cases had ARPKD and 10 had isolated congenital hepatic fibrosis with no or minimal renal involvement. The patients were analyzed as 3 groups categorized by the age at diagnosis; <1 years (n = 22), 1-20 years (n = 23), and >20 years (n = 20). The presenting feature in the neonates was typically associated with renal enlargement, but in the older groups, more often involved manifestations of liver disease, including hepatosplenomegaly, hypersplenism, variceal bleeding, and cholangitis. During follow-up, 22 patients had renal insufficiency and 8 developed end-stage renal disease (ESRD), most from the neonatal group. Liver disease was evident on follow-up in all diagnostic groups but particularly prevalent in those diagnosed later in life. A total of 12 patients died, 6 in the neonatal period, but 86% of patients were alive at 40 years of age. The likelihood of being alive without ESRD differed significantly between the diagnostic groups with 36%, 80%, and 88% survival in the 3 diagnostic groups, respectively, 20 years after the diagnosis. Considerable evidence of intrafamilial phenotype variability was observed. Mutation analysis was performed in 31 families and at least 1 mutation was detected in 25 (81%), with 76% of mutant alleles detected in those cases. Consistent with the relatively mild disease manifestations in this population, the majority of changes were missense (79%) and no case had 2 truncating changes. Mutations were detected in all diagnostic groups, indicating that congenital hepatic fibrosis with minimal kidney involvement can result from PKHD1 mutation. The finding of 6 cases with no detected mutations may represent missed mutations or possible evidence of genetic heterogeneity. The current study indicates a broadened spectrum for the ARPKD phenotype and that later presenting cases with predominant liver disease should be considered part of ARPKD.
Adolescent↗
Understanding pathogenic mechanisms in polycystic kidney disease provides clues for therapy.
PURPOSE OF REVIEW: Polycystic kidney diseases are a group of inherited disorders that result in tubular dilatation and/or the development of fluid-filled cysts in the kidney. Identification and analysis of the primary defective protein in many of these diseases are providing insights into a common pathogenesis to polycystic kidney disease. This review explores this pathogenesis and determines the role that this knowledge is playing in the development of potential therapies. RECENT FINDINGS: Study of simple and syndromic forms of polycystic kidney disease has revealed that the defective proteins are localized to the primary cilia/basal body and that the pleiotropic phenotypes are often associated with defective ciliogenesis. Data indicating that the polycystins are involved in ciliary mechanosensation, and cellular changes in intracellular Ca and cAMP, have provided clues for possible therapeutic approaches that have proved highly effective in pre-clinical trials. SUMMARY: Polycystic kidney diseases are associated with defects to proteins involved in developing functional, sensory cilia in the kidney. While the primary defects in these disorders cannot be corrected at present, downsteam cellular changes can be targeted. Potential therapeutic agents are now being tested in patients, moving polycystic kidney disease research into a new and exciting phase.
Animals↗
[Ca2+]i reduction increases cellular proliferation and apoptosis in vascular smooth muscle cells: relevance to the ADPKD phenotype.
Cardiovascular complications are the leading cause of morbidity and mortality in autosomal dominant polycystic kidney disease. Pkd2+/- vascular smooth muscle cells (VSMCs) have an abnormal phenotype and defective intracellular Ca2+ ([Ca2+]i) regulation. We examined cAMP content in vascular smooth muscles from Pkd2+/- mice because cAMP is elevated in cystic renal epithelial cells. We found cAMP concentration was significantly increased in Pkd2+/- vessels compared with wild-type vessels. Furthermore, reducing the wild-type VSMC [Ca2+]i by Verapamil or BAPTA-AM significantly increased cellular cAMP concentration (mainly by phosphodiesterase [PDE] inhibition), the rate of VSMC proliferation (determined by direct cell counting, 3H-incorporation, FACS analysis of cells entering S phase, and quantitative Western PCNA and ERK1/2 analyses), and the rate of apoptosis (by Hoechst staining, FACS analysis of the Annexin-V positive cells, and quantitative Western Bax, cytochrome c, and activated caspase 9 and 3 analyses). The low [Ca2+]i induced VSMC proliferation was independent of cAMP/B-Raf signaling, while that of apoptosis was promoted by cAMP. In summary, Pkd2+/- VSMCs have elevated cAMP levels. This elevation can also be induced by reducing [Ca2+]i in wild-type VSMCs. The [Ca2+]i reduction and cAMP accumulation can cause an increase in both cellular proliferation and apoptosis, resembling Pkd mutant phenotype.
3',5'-Cyclic-AMP Phosphodiesterases↗
Effectiveness of vasopressin V2 receptor antagonists OPC-31260 and OPC-41061 on polycystic kidney disease development in the PCK rat.
cAMP plays a major role in cystogenesis. Recent in vitro studies suggested that cAMP stimulates B-Raf/ERK activation and proliferation of cyst-derived cells in a Ca(2+) inhibitable, Ras-dependent manner. OPC-31260, a vasopressin V2 receptor (VPV2) antagonist, was shown to lower renal cAMP and inhibit renal disease development and progression in models orthologous to human cystic diseases. Here it is shown that OPC-41061, an antagonist chosen for its potency and selectivity for human VPV2, is effective in PCK rats. PCK kidneys have increased Ras-GTP and phosphorylated ERK levels and 95-kD/68-kD B-Raf ratios, changes that are corrected by the administration of OPC-31260 or OPC-41061. These results support the importance of cAMP in the pathogenesis of polycystic kidney disease, confirm the effectiveness of a VPV2 antagonist to be used in clinical trials for this disease, and suggest that OPC-31260 and OPC-41061 inhibit Ras/mitogen-activated protein kinase signaling in polycystic kidneys.
Adenine↗
Haplotype analysis improves molecular diagnostics of autosomal recessive polycystic kidney disease.
BACKGROUND: Autosomal recessive polycystic kidney disease (ARPKD) is characterized by wide phenotypic variability, ranging from in utero detection with enlarged, echogenic kidneys to an adult presentation with congenital hepatic fibrosis. The ARPKD gene, PKHD1 , covers about 470 kb of DNA (67 exons), and mutation studies have found marked allelic heterogeneity with a high level of novel missense changes and neutral polymorphisms. To improve the prospects for molecular diagnostics and to study the origin of some relatively common mutations, the authors have developed a strategy for improved ARPKD haplotyping. METHODS: A protocol of multiplex PCR and fluorescence genotyping in a single capillary has been developed to assay 7 highly informative simple sequence repeat (SSR) markers that are intragenic or closely flanking PKHD1. RESULTS: Examples in which haplotype analysis, used in combination with mutation screening, improved the utility of molecular diagnostics, especially in families in which just a single PKHD1 mutation has been identified, are illustrated. The new markers also allow screening for larger DNA deletions, detecting unknown consanguinity and exploring the disease mechanism. Analysis of 8 recurring mutations has shown likely common haplotypes for each, and the divergence from the ancestral haplotype, by recombination, can be used to trace the history of the mutation. The common mutation, T36M, was found to have a single European origin, about 1,225 years ago. CONCLUSION: Improved haplotype analysis of ARPKD complements mutation-based diagnostics and helps trace the history of common PKHD1 mutations.
3' Flanking Region↗
Sonographic assessment of the severity and progression of autosomal dominant polycystic kidney disease: the Consortium of Renal Imaging Studies in Polycystic Kidney Disease (CRISP).
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.
Adolescent↗
Vasopressin antagonists in polycystic kidney disease.
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Adolescent↗
Mutations in SEC63 cause autosomal dominant polycystic liver disease.
Mutations in PRKCSH, encoding the beta-subunit of glucosidase II, an N-linked glycan-processing enzyme in the endoplasmic reticulum (ER), cause autosomal dominant polycystic liver disease. We found that mutations in SEC63, encoding a component of the protein translocation machinery in the ER, also cause this disease. These findings are suggestive of a role for cotranslational protein-processing pathways in maintaining epithelial luminal structure and implicate noncilial ER proteins in human polycystic disease.
Chromosomes, Human, Pair 6↗
Effective treatment of an orthologous model of autosomal dominant polycystic kidney disease.
Autosomal dominant polycystic kidney disease (ADPKD) is a leading cause of end-stage renal disease. The vasopressin V2 receptor (VPV2R) antagonist OPC31260 has been effective in two animal models of PKD with pathologies that are probably related. Here we show, in a mouse model of ADPKD (Pkd2(-/tm1Som)), a similar cellular phenotype and response to OPC31260 treatment, with reduction of renal cyclic AMP (cAMP) levels, prevention of renal enlargement, marked inhibition of cystogenesis and protection of renal function.
Animals↗