Vicente E Torres

Publications (111)1015.87 Total impact

• Source

  Available from: Sandro Rossetti

  Dataset: Rossetti S 2012 suppl

  Sandro Rossetti, Katharina Hopp, Robert A Sikkink, Jamie L Sundsbak, Yean Kit Lee, Vickie Kubly, Bruce W Eckloff, Christopher J Ward, Christopher G Winearls, Vicente E Torres, Peter C Harris
• Article: Segmentation of Individual Renal Cysts from MR Images in Patients with Autosomal Dominant Polycystic Kidney Disease.

  Kyungsoo Bae, Bumwoo Park, Hongliang Sun, Jinhong Wang, Cheng Tao, Arlene B Chapman, Vicente E Torres, Jared J Grantham, Michal Mrug, William M Bennett, Michael F Flessner, Doug P Landsittel, Kyongtae T Bae
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  ABSTRACT: OBJECTIVE: To evaluate the performance of a semi-automated method for the segmentation of individual renal cysts from magnetic resonance (MR) images in patients with autosomal dominant polycystic kidney disease (ADPKD). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This semi-automated method was based on a morphologic watershed technique with shape-detection level set for segmentation of renal cysts from MR images. T2-weighted MR image sets of 40 kidneys were selected from 20 patients with mild to moderate renal cyst burden (kidney volume < 1500 ml) in the Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP). The performance of the semi-automated method was assessed in terms of two reference metrics in each kidney: the total number of cysts measured by manual counting and the total volume of cysts measured with a region-based thresholding method. The proposed and reference measurements were compared using intraclass correlation coefficient (ICC) and Bland-Altman analysis. RESULTS: Individual renal cysts were successfully segmented with the semi-automated method in all 20 cases. The total number of cysts in each kidney measured with the two methods correlated well (ICC, 0.99), with a very small relative bias (0.3% increase with the semi-automated method; limits of agreement, 15.2% reduction to 17.2% increase). The total volume of cysts measured using both methods also correlated well (ICC, 1.00), with a small relative bias of <10% (9.0% decrease in the semi-automated method; limits of agreement, 17.1% increase to 43.3% decrease). CONCLUSION: This semi-automated method to segment individual renal cysts in ADPKD kidneys provides a quantitative indicator of severity in early and moderate stages of the disease.
  Clinical Journal of the American Society of Nephrology 03/2013; · 5.23 Impact Factor
• Article: Polycystin-2 mutations lead to impaired calcium cycling in the heart and predispose to dilated cardiomyopathy.

  Jere Paavola, Simon Schliffke, Sandro Rossetti, Ivana Y-T Kuo, Shiaulou Yuan, Zhaoxia Sun, Peter C Harris, Vicente E Torres, Barbara E Ehrlich
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  ABSTRACT: Mutations in PKD1 and PKD2, the genes encoding the proteins polycystin-1 (PC1) and polycystin-2 (PC2), cause autosomal dominant polycystic kidney disease (ADPKD). Although the leading cause of mortality in ADPKD is cardiovascular disease, the relationship between these conditions remains poorly understood. PC2 is an intracellular calcium channel expressed in renal epithelial cells and in cardiomyocytes, and is thus hypothesized to modulate intracellular calcium signaling and affect cardiac function. Our first aim was to study cardiac function in a zebrafish model lacking PC2 (pkd2 mutants). Next, we aimed to explore the relevance of this zebrafish model to human ADPKD by examining the Mayo Clinic's ADPKD database for an association between ADPKD and idiopathic dilated cardiomyopathy (IDCM). Pkd2 mutant zebrafish showed low cardiac output and atrioventricular block. Isolated pkd2 mutant hearts displayed impaired intracellular calcium cycling and calcium alternans. These results indicate heart failure in the pkd2 mutants. In human ADPKD patients, we found IDCM to coexist frequently with ADPKD. This association was strongest in patients with PKD2 mutations. Our results demonstrate that PC2 modulates intracellular calcium cycling, contributing to the development of heart failure. In human subjects we found an association between ADPKD and IDCM and suggest that PKD mutations contribute to the development of heart failure.
  Journal of Molecular and Cellular Cardiology 01/2013; · 5.17 Impact Factor
• Article: Urinary proteomic biomarkers for diagnosis and risk stratification of autosomal dominant polycystic kidney disease: a multicentric study.

  Andreas D Kistler, Andreas L Serra, Justyna Siwy, Diane Poster, Fabienne Krauer, Vicente E Torres, Michal Mrug, Jared J Grantham, Kyongtae T Bae, James E Bost, William Mullen, Rudolf P Wüthrich, Harald Mischak, Arlene B Chapman
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  ABSTRACT: Treatment options for autosomal dominant polycystic kidney disease (ADPKD) will likely become available in the near future, hence reliable diagnostic and prognostic biomarkers for the disease are strongly needed. Here, we aimed to define urinary proteomic patterns in ADPKD patients, which aid diagnosis and risk stratification. By capillary electrophoresis online coupled to mass spectrometry (CE-MS), we compared the urinary peptidome of 41 ADPKD patients to 189 healthy controls and identified 657 peptides with significantly altered excretion, of which 209 could be sequenced using tandem mass spectrometry. A support-vector-machine based diagnostic biomarker model based on the 142 most consistent peptide markers achieved a diagnostic sensitivity of 84.5% and specificity of 94.2% in an independent validation cohort, consisting of 251 ADPKD patients from five different centers and 86 healthy controls. The proteomic alterations in ADPKD included, but were not limited to markers previously associated with acute kidney injury (AKI). The diagnostic biomarker model was highly specific for ADPKD when tested in a cohort consisting of 481 patients with a variety of renal and extrarenal diseases, including AKI. Similar to ultrasound, sensitivity and specificity of the diagnostic score depended on patient age and genotype. We were furthermore able to identify biomarkers for disease severity and progression. A proteomic severity score was developed to predict height adjusted total kidney volume (htTKV) based on proteomic analysis of 134 ADPKD patients and showed a correlation of r = 0.415 (p<0.0001) with htTKV in an independent validation cohort consisting of 158 ADPKD patients. In conclusion, the performance of peptidomic biomarker scores is superior to any other biochemical markers of ADPKD and the proteomic biomarker patterns are a promising tool for prognostic evaluation of ADPKD.
  PLoS ONE 01/2013; 8(1):e53016. · 4.09 Impact Factor
• Source

  Available from: Esther Meijer

  Dataset: TEMPO rationale and design AJKD

  Vicente E Torres, Ronald D Perrone, Jared J Grantham, Arlene B Chapman, Holly B Krasa, Olivier Devuyst, Esther Meijer, Ron T Gansevoort, Eiji Higashihara, Kyongtae T Bae, John J Ouyang, Frank S Czerwiec
• Source

  Available from: Sandro Rossetti

  Dataset: Hopp K supplemental

  Samih H Nasr, Cynthia J Hommerding, Vicente E Torres, Katharina Hopp, Han-Fang Tuan, Vladimir G Gainullin, Christopher J Ward, Peter C Harris, Sandro Rossetti
• Article: Pasireotide is more effective than Octreotide in reducing hepato-renal cystogenesis in rodents with polycystic kidney and liver diseases.

  Tatyana V Masyuk, Brynn N Radtke, Angela J Stroope, Jesús M Banales, Sergio A Gradilone, Bing Huang, Anatoliy I Masyuk, Marie C Hogan, Vicente E Torres, Nicholas F Larusso
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  ABSTRACT: In polycystic liver (PLD) and kidney (PKD) diseases, increased cAMP levels trigger hepato-renal cystogenesis. We previously reported that reduction of elevated cAMP by targeting somatostatin receptors (SSTRs) with Octreotide (OCT; a somatostatin analogue that preferentially binds to SSTR2), inhibits cyst growth. We now compare effects of OCT to Pasireotide (PAS; a more potent somatostatin analogue with broader receptor specificity) on: (i) cAMP levels, cell cycle, proliferation and cyst expansion in vitro using cholangiocytes derived from control and PCK rats (a model of autosomal recessive PKD [ARPKD]), healthy human beings and patients with autosomal dominant PKD (ADPKD); and (ii) hepato-renal cystogenesis in vivo in PCK rats and Pkd2(WS25/-) mice (a model of ADPKD). Expression of SSTRs was assessed in control and cystic cholangiocytes of rodents and human beings. Concentrations of IGF and VEGF (both involved in indirect action of somatostatin analogs), and expression and localization of SSTRs after treatment were evaluated. We showed that PAS was more potent (by 30-45%) than OCT in reducing cAMP and cell proliferation, affecting cell cycle distribution, decreasing growth of cultured cysts in vitro and inhibiting hepato-renal cystogenesis in vivo in PCK rats and Pkd2(WS25/-) mice. The levels of IGF1 (but not VEGF) were reduced only in response to PAS. Expression of SSTR1 and SSTR2 (but not SSTR3 and SSTR5) was decreased in cystic cholangiocytes compared to control. While both OCT and PAS increased immunoreactivity of SSTR2, only PAS up-regulated SSTR1; neither drug affected cellular localization of SSTRs. Conclusion: PAS is more effective than OCT in reducing hepato-renal cystogenesis in rodent models; therefore it might be more beneficial for the treatment of PKD and PLD. (HEPATOLOGY 2012.).
  Hepatology 11/2012; · 11.66 Impact Factor
• Article: Tolvaptan in Patients with Autosomal Dominant Polycystic Kidney Disease.

  Vicente E Torres, Arlene B Chapman, Olivier Devuyst, Ron T Gansevoort, Jared J Grantham, Eiji Higashihara, Ronald D Perrone, Holly B Krasa, John Ouyang, Frank S Czerwiec
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  ABSTRACT: Background The course of autosomal dominant polycystic kidney disease (ADPKD) is often associated with pain, hypertension, and kidney failure. Preclinical studies indicated that vasopressin V(2)-receptor antagonists inhibit cyst growth and slow the decline of kidney function. Methods In this phase 3, multicenter, double-blind, placebo-controlled, 3-year trial, we randomly assigned 1445 patients, 18 to 50 years of age, who had ADPKD with a total kidney volume of 750 ml or more and an estimated creatinine clearance of 60 ml per minute or more, in a 2:1 ratio to receive tolvaptan, a V(2)-receptor antagonist, at the highest of three twice-daily dose regimens that the patient found tolerable, or placebo. The primary outcome was the annual rate of change in the total kidney volume. Sequential secondary end points included a composite of time to clinical progression (defined as worsening kidney function, kidney pain, hypertension, and albuminuria) and rate of kidney-function decline. Results Over a 3-year period, the increase in total kidney volume in the tolvaptan group was 2.8% per year (95% confidence interval [CI], 2.5 to 3.1), versus 5.5% per year in the placebo group (95% CI, 5.1 to 6.0; P<0.001). The composite end point favored tolvaptan over placebo (44 vs. 50 events per 100 follow-up-years, P=0.01), with lower rates of worsening kidney function (2 vs. 5 events per 100 person-years of follow-up, P<0.001) and kidney pain (5 vs. 7 events per 100 person-years of follow-up, P=0.007). Tolvaptan was associated with a slower decline in kidney function (reciprocal of the serum creatinine level, -2.61 [mg per milliliter](-1) per year vs. -3.81 [mg per milliliter](-1) per year; P<0.001). There were fewer ADPKD-related adverse events in the tolvaptan group but more events related to aquaresis (excretion of electrolyte-free water) and hepatic adverse events unrelated to ADPKD, contributing to a higher discontinuation rate (23%, vs. 14% in the placebo group). Conclusions Tolvaptan, as compared with placebo, slowed the increase in total kidney volume and the decline in kidney function over a 3-year period in patients with ADPKD but was associated with a higher discontinuation rate, owing to adverse events. (Funded by Otsuka Pharmaceuticals and Otsuka Pharmaceutical Development and Commercialization; TEMPO 3:4 ClinicalTrials.gov number, NCT00428948 .).
  New England Journal of Medicine 11/2012; · 53.30 Impact Factor
• Article: Relationship of Copeptin, a Surrogate Marker for Arginine Vasopressin, With Change in Total Kidney Volume and GFR Decline in Autosomal Dominant Polycystic Kidney Disease: Results From the CRISP Cohort.

  Wendy E Boertien, Esther Meijer, Jie Li, James E Bost, Joachim Struck, Michael F Flessner, Ron T Gansevoort, Vicente E Torres
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  ABSTRACT: BACKGROUND: Experimental studies indicate that arginine vasopressin (AVP) may have deleterious effects in the pathogenesis of autosomal dominant polycystic kidney disease (ADPKD). However, the significance of AVP in human ADPKD is unclear. STUDY DESIGN: Longitudinal observational study with 8.5 (IQR, 7.7-9.0) years' follow-up (CRISP [Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease]). SETTING & PARTICIPANTS: 241 patients with ADPKD with creatinine clearance >70 mL/min. PREDICTOR: Plasma copeptin concentration, a surrogate marker for AVP. OUTCOMES: Change in measured glomerular filtration rate (mGFR, assessed by iothalamate clearance) and total kidney volume (measured by magnetic resonance imaging). MEASUREMENTS: Baseline copeptin level, plasma and urinary osmolality, and measurements of total kidney volume and mGFR during follow-up. RESULTS: In these patients (median age, 34 [IQR, 25-40] years; 38% men; median mGFR, 94 [IQR, 79-145] mL/min/1.73 m(2); median total kidney volume, 859 [IQR, 577-1,299] mL), median copeptin level was 2.9 (IQR, 1.8-5.1) pmol/L. Copeptin was not associated with plasma osmolality (P = 0.3), the physiologic stimulus for AVP release, but was associated significantly with change in total kidney volume during follow-up (P < 0.001). This association remained significant after adjusting for sex, age, cardiovascular risk factors, and diuretic use (P = 0.03). Copeptin level was associated borderline significantly with change in mGFR after adjusting for these variables (P = 0.09). LIMITATIONS: No standardization of hydration status at time of copeptin measurement. CONCLUSIONS: These data show that in ADPKD, copeptin level, as a marker for AVP, is not correlated with plasma osmolality. Most importantly, high copeptin levels are associated independently with disease progression in early ADPKD. This is in line with experimental studies that indicate a disease-promoting role for AVP.
  American Journal of Kidney Diseases 10/2012; · 5.43 Impact Factor
• Source

  Available from: Sandro Rossetti

  Article: Functional polycystin-1 dosage governs autosomal dominant polycystic kidney disease severity.

  Katharina Hopp, Christopher J Ward, Cynthia J Hommerding, Samih H Nasr, Han-Fang Tuan, Vladimir G Gainullin, Sandro Rossetti, Vicente E Torres, Peter C Harris
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  ABSTRACT: Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations to PKD1 or PKD2, triggering progressive cystogenesis and typically leading to end-stage renal disease in midlife. The phenotypic spectrum, however, ranges from in utero onset to adequate renal function at old age. Recent patient data suggest that the disease is dosage dependent, where incompletely penetrant alleles influence disease severity. Here, we have developed a knockin mouse model matching a likely disease variant, PKD1 p.R3277C (RC), and have proved that its functionally hypomorphic nature modifies the ADPKD phenotype. While Pkd1+/null mice are normal, Pkd1RC/null mice have rapidly progressive disease, and Pkd1RC/RC animals develop gradual cystogenesis. These models effectively mimic the pathophysiological features of in utero-onset and typical ADPKD, respectively, correlating the level of functional Pkd1 product with disease severity, highlighting the dosage dependence of cystogenesis. Additionally, molecular analyses identified p.R3277C as a temperature-sensitive folding/trafficking mutant, and length defects in collecting duct primary cilia, the organelle central to PKD pathogenesis, were clearly detected for the first time to our knowledge in PKD1. Altogether, this study highlights the role that in trans variants at the disease locus can play in phenotypic modification of dominant diseases and provides a truly orthologous PKD1 model, optimal for therapeutic testing.
  The Journal of clinical investigation 10/2012; · 15.39 Impact Factor
• Article: Somatostatin analog therapy for severe polycystic liver disease: results after 2 years.

  Marie C Hogan, Tetyana V Masyuk, Linda Page, David R Holmes, Xujian Li, Eric J Bergstralh, Maria V Irazabal, Bohyun Kim, Bernard F King, James F Glockner, Nicholas F Larusso, Vicente E Torres
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  ABSTRACT: We showed in a randomized double-blinded placebo-controlled clinical trial that octreotide long-acting repeatable depot.® (OctLAR(®)) for 12 months reduces kidney and liver growth in autosomal dominant polycystic kidney patients with severe polycystic liver disease (PLD) and liver growth in patients with severe isolated PLD. We have now completed an open-label extension for one additional year to assess safety and clinical benefits of continued use of OctLAR for 2 years (O → O) and examined drug effect in the placebo group who crossed over to OctLAR in Year 2 (P → O). The primary end point was change in total liver volume (TLV) measured by magnetic resonance imaging (MRI); secondary end points were changes in total kidney volume (TKV) measured by MRI, glomerular filtration rate (GFR), quality of life (QOL), safety, vital signs and laboratory parameters. Forty-one of 42 patients received OctLAR (n = 28) or placebo (n = 14) in Year 1 and received OctLAR in Year 2 (maximum dose 40 mg). Patients originally randomized to placebo (P → O) showed substantial reduction in TLV after treatment with OctLAR in Year 2 (Δ% -7.66 ± 9.69%, P = 0.011). The initial reduction of TLV in the OctLAR group (O → O) was maintained for 2 years (Δ% -5.96 ± 8.90%), although did not change significantly during Year 2 (Δ% -0.77 ± 6.82%). OctLAR inhibited renal enlargement during Year 1 (Δ% +0.42 ± 7.61%) in the (O → O) group and during Year 2 (Δ% -0.41 ± 9.45%) in the (P → O) group, but not throughout Year 2 (Δ% +6.49 ± 7.08%) in the (O → O) group. Using pooled analyses of all individuals who received OctLAR for 12 months, i.e. in Year 1 for O → O patients and Year 2 for P → O patients, average reduction in TLV was -6.08 ± 7.58% (P = 0.001) compared to net growth of 0.9 ± 8.35% in the original placebo group. OctLAR-treated individuals continued to experience improvements in QOL in Year 2, although overall physical and mental improvements were not significant during Year 2 compared to Year 1. Changes in GFR were similar in both groups. Over 2 years, OctLAR significantly reduced the rate of increase in TLV and possibly the rate of increase in TKV.
  Nephrology Dialysis Transplantation 07/2012; 27(9):3532-9. · 3.40 Impact Factor
• Article: Characteristics of renal cystic and solid lesions based on contrast-enhanced computed tomography of potential kidney donors.

  Andrew D Rule, Kewalee Sasiwimonphan, John C Lieske, Mira T Keddis, Vicente E Torres, Terri J Vrtiska
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  ABSTRACT: The presence of a few renal cysts is considered of little relevance in healthy adults, although acquired renal cystic disease occurs in advanced kidney failure. The objective of this study was to detail renal cystic and solid lesions and identify any association with clinical characteristics. Clinical-pathologic correlation. Potential kidney donors undergoing a standardized evaluation at the Mayo Clinic in 2000-2008. Age, kidney function, and chronic kidney disease risk factors. Renal cystic and solid lesions by contrast-enhanced computed tomographic images. Cyst number, diameter, and location. After excluding 8 with cystic disease, 7 of whom had autosomal dominant polycystic kidney disease, there were 1,948 potential kidney donors (42% men; mean age, 43 years). A cortical, medullary, or parapelvic cyst ≥5 mm was present in 12%, 14%, or 2.8%. For ages 19-49 years, 39%, 22%, 7.9%, and 1.6% had a cortical or medullary cyst ≥2, ≥5, ≥10, and ≥20 mm in diameter. For ages 50-75 years, 63%, 43%, 22%, and 7.8% had a cortical or medullary cyst ≥2, ≥5, ≥10, and ≥20 mm in diameter. The 97.5th percentile for number of cortical and medullary cysts ≥5 mm increased with age (10 for men and 4 for women in the 60- to 69-year group). After age and sex adjustment, cortical and medullary cysts ≥5 mm were associated with higher 24-hour urine albumin excretion, as well as increased body surface area, hypertension, and higher glomerular filtration rate in some analyses. Angiomyolipomas, hyperdense cysts, and enhancing masses or cysts with concerning features for malignancy occurred in 2.2%, 1.2%, and 0.6% and were associated with older age (P ≤ 0.05 for each). Persons with known chronic kidney disease were excluded. Renal cysts are common, particularly in older men, and may be a marker of early kidney injury because they associate with albuminuria, hypertension, and hyperfiltration.
  American Journal of Kidney Diseases 03/2012; 59(5):611-8. · 5.43 Impact Factor
• Article: Kidney volume and functional outcomes in autosomal dominant polycystic kidney disease.

  Arlene B Chapman, James E Bost, Vicente E Torres, Lisa Guay-Woodford, Kyongtae Ty Bae, Douglas Landsittel, Jie Li, Bernard F King, Diego Martin, Louis H Wetzel, Mark E Lockhart, Peter C Harris, Marva Moxey-Mims, Mike Flessner, William M Bennett, Jared J Grantham
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  ABSTRACT: Autosomal dominant polycystic kidney disease (ADPKD) is characterized by increased total kidney volume (TKV) and renal failure. This study aimed to determine if height-adjusted TKV (htTKV) predicts the onset of renal insufficiency. This prospective, observational, longitudinal, multicenter study included 241 adults with ADPKD and preserved renal function. Magnetic resonance imaging and iothalamate clearance were used to measure htTKV and GFR, respectively. The association between baseline htTKV and the attainment of stage 3 CKD (GFR <60 ml/min per 1.73 m(2)) during follow-up was determined. After a mean follow-up of 7.9 years, stage 3 CKD was attained in 30.7% of the enrollees. Using baseline htTKV, negative correlations with GFR increased from -0.22 at baseline to -0.65 at year 8. In multivariable analysis, a baseline htTKV increase of 100 cc/m significantly predicted the development of CKD within 8 years with an odds ratio of 1.48 (95% confidence interval: 1.29, 1.70). In receiver operator characteristic curve analysis, baseline htTKV of 600 cc/m most accurately defined the risk of developing stage 3 CKD within 8 years with an area under the curve of 0.84 (95% confidence interval: 0.79, 0.90). htTKV was a better predictor than baseline age, serum creatinine, BUN, urinary albumin, or monocyte chemotactic protein-1 excretion (P<0.05). Baseline htTKV ≥600 cc/m predicted the risk of developing renal insufficiency in ADPKD patients at high risk for renal disease progression within 8 years of follow-up, qualifying htTKV as a prognostic biomarker in ADPKD.
  Clinical Journal of the American Society of Nephrology 03/2012; 7(3):479-86. · 5.23 Impact Factor
• Source

  Available from: Sandro Rossetti

  Article: Identification of gene mutations in autosomal dominant polycystic kidney disease through targeted resequencing.

  Sandro Rossetti, Katharina Hopp, Robert A Sikkink, Jamie L Sundsbak, Yean Kit Lee, Vickie Kubly, Bruce W Eckloff, Christopher J Ward, Christopher G Winearls, Vicente E Torres, Peter C Harris
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  ABSTRACT: Mutations in two large multi-exon genes, PKD1 and PKD2, cause autosomal dominant polycystic kidney disease (ADPKD). The duplication of PKD1 exons 1-32 as six pseudogenes on chromosome 16, the high level of allelic heterogeneity, and the cost of Sanger sequencing complicate mutation analysis, which can aid diagnostics of ADPKD. We developed and validated a strategy to analyze both the PKD1 and PKD2 genes using next-generation sequencing by pooling long-range PCR amplicons and multiplexing bar-coded libraries. We used this approach to characterize a cohort of 230 patients with ADPKD. This process detected definitely and likely pathogenic variants in 115 (63%) of 183 patients with typical ADPKD. In addition, we identified atypical mutations, a gene conversion, and one missed mutation resulting from allele dropout, and we characterized the pattern of deep intronic variation for both genes. In summary, this strategy involving next-generation sequencing is a model for future genetic characterization of large ADPKD populations.
  Journal of the American Society of Nephrology 03/2012; 23(5):915-33. · 9.66 Impact Factor
• Article: Analysis of baseline parameters in the HALT polycystic kidney disease trials.

  Vicente E Torres, Arlene B Chapman, Ronald D Perrone, K Ty Bae, Kaleab Z Abebe, James E Bost, Dana C Miskulin, Theodore I Steinman, William E Braun, Franz T Winklhofer, [......], Neil J Halin, Diego R Martin, Erick Remer, Nayana Patel, Ivan Pedrosa, Louis H Wetzel, Paul A Thompson, J Philip Miller, Catherine M Meyers, Robert W Schrier
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  ABSTRACT: HALT PKD consists of two ongoing randomized trials with the largest cohort of systematically studied patients with autosomal dominant polycystic kidney disease to date. Study A will compare combined treatment with an angiotensin-converting inhibitor and receptor blocker to inhibitor alone and standard compared with low blood pressure targets in 558 early-stage disease patients with an eGFR over 60 ml/min per 1.73 m(2). Study B will compare inhibitor-blocker treatment to the inhibitor alone in 486 late-stage patients with eGFR 25-60 ml/min per 1.73 m(2). We used correlation and multiple regression cross-sectional analyses to determine associations of baseline parameters with total kidney, liver, or liver cyst volumes measured by MRI in Study A and eGFR in both studies. Lower eGFR and higher natural log-transformed urine albumin excretion were independently associated with a larger natural log-transformed total kidney volume adjusted for height (ln(HtTKV)). Higher body surface area was independently associated with a higher ln(HtTKV) and lower eGFR. Men had larger height-adjusted total kidney volume and smaller liver cyst volumes than women. A weak correlation was found between the ln(HtTKV) and natural log-transformed total liver volume adjusted for height or natural log liver cyst volume in women only. Women had higher urine aldosterone excretion and lower plasma potassium. Thus, our analysis (1) confirms a strong association between renal volume and functional parameters, (2) shows that gender and other factors differentially affect the development of polycystic disease in the kidney and liver, and (3) suggests an association between anthropomorphic measures reflecting prenatal and/or postnatal growth and disease severity.
  Kidney International 12/2011; 81(6):577-85. · 6.61 Impact Factor
• Article: Polycystic kidney disease in 2011: Connecting the dots toward a polycystic kidney disease therapy.

  Vicente E Torres, Peter C Harris
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  ABSTRACT: Understanding the complex interactions between the various pathways disrupted in polycystic kidney and liver disease is essential to identify and optimize therapies for these disorders. Studies published in the past year have demonstrated a functional interaction between the main proteins implicated in these diseases and identified novel therapeutic approaches.
  Nature Reviews Nephrology 12/2011; 8(2):66-8. · 7.09 Impact Factor
• Article: Epitope-tagged Pkhd1 tracks the processing, secretion, and localization of fibrocystin.

  Jason L Bakeberg, Rachaneekorn Tammachote, John R Woollard, Marie C Hogan, Han-Fang Tuan, Ming Li, Jan M van Deursen, Yanhong Wu, Bing Q Huang, Vicente E Torres, Peter C Harris, Christopher J Ward
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  ABSTRACT: Mutations in the PKHD1 gene, which encodes fibrocystin, cause autosomal recessive polycystic kidney disease (ARPKD). Unfortunately, the lack of specific antibodies to the mouse protein impairs the study of splicing, post-translational processing, shedding, and temporal and spatial expression of endogenous fibrocystin at the cellular and subcellular level. Here, we report using a knock-in strategy to generate a null Pkhd1 strain and a strain that expresses fibrocystin along with two SV5-Pk epitope tags engineered in-frame into the third exon, immediately C-terminal to the signal-peptide cleavage site in a poorly conserved region. By 6 mo of age, the Pkhd1-null mouse develops massive cystic hepatomegaly and proximal tubule dilation, whereas the mouse with epitope-tagged fibrocystin has histologically normal liver and kidneys at 14 mo. Although Pkhd1 was believed to generate many splice forms, our western analysis resolved fibrocystin as a 500 kD product without other forms in the 15-550 kD range. Western analysis also revealed that exosome-like vesicles (ELVs) secrete the bulk of fibrocystin in its mature cleaved form, and scanning electron microscopy identified that fibrocystin on ELVs attached to cilia. Furthermore, the addition of ELVs with epitope-tagged fibrocystin to wild-type cells showed that label transferred to primary cilia within 5 min. In summary, tagging of the endogenous Pkhd1 gene facilitates the study of the glycosylation, proteolytic cleavage, and shedding of fibrocystin.
  Journal of the American Society of Nephrology 12/2011; 22(12):2266-77. · 9.66 Impact Factor
• Article: Cardiac magnetic resonance assessment of left ventricular mass in autosomal dominant polycystic kidney disease.

  Ronald D Perrone, Kaleab Z Abebe, Robert W Schrier, Arlene B Chapman, Vicente E Torres, James Bost, Diana Kaya, Dana C Miskulin, Theodore I Steinman, William Braun, [......], Neil J Halin, Diego Martin, Erick Remer, Nayana Patel, Ivan Pedrosa, Louis H Wetzel, Paul A Thompson, J Philip Miller, K Ty Bae, Catherine M Meyers
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  ABSTRACT: Autosomal dominant polycystic kidney disease (ADPKD) is associated with a substantial cardiovascular disease burden including early onset hypertension, intracranial aneurysms, and left ventricular hypertrophy (LVH). A 41% prevalence of LVH has been reported in ADPKD, using echocardiographic assessment of LV mass (LVM). The HALT PKD study was designed to assess the effect of intensive angiotensin blockade on progression of total kidney volume and LVM. Measurements of LVM were performed using cardiac magnetic resonance (MR). Five hundred forty-three hypertensive patients with GFR >60 ml/min per 1.73 m(2) underwent MR assessment of LVM at baseline. LVM was adjusted for body surface area and expressed as LVM index (LVMI; g/m(2)). Baseline BP was 125.1 ± 14.5/79.3 ± 11.6 mmHg. Average duration of hypertension was 5.79 years. Prior use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers was present in 59.5% of patients. The prevalence of LVH assessed using nonindexed LVM (g) was 3.9% (n = 21, eight men and 13 women) and 0.93% (n = 5, one man and four women) using LVMI (g/m(2)). In exploratory analyses, the prevalence of LVH using LVM indexed to H(2.7), and the allometric index ppLVmass(HW), ranged from 0.74% to 2.23% (n = 4 to 12). Multivariate regression showed significant direct associations of LVMI with systolic BP, serum creatinine, and albuminuria; significant inverse associations with LVMI were found with age and female gender. The prevalence of LVH in hypertensive ADPKD patients <50 years of age with short duration of hypertension, and prior use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers is low. Early BP intervention in ADPKD may have decreased LVH and may potentially decrease cardiovascular mortality.
  Clinical Journal of the American Society of Nephrology 09/2011; 6(10):2508-15. · 5.23 Impact Factor
• Article: Tolvaptan in autosomal dominant polycystic kidney disease: three years' experience.

  Eiji Higashihara, Vicente E Torres, Arlene B Chapman, Jared J Grantham, Kyongtae Bae, Terry J Watnick, Shigeo Horie, Kikuo Nutahara, John Ouyang, Holly B Krasa, Frank S Czerwiec
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  ABSTRACT: Autosomal dominant polycystic kidney disease (ADPKD), a frequent cause of end-stage renal disease, has no cure. V2-specific vasopressin receptor antagonists delay disease progression in animal models. This is a prospectively designed analysis of annual total kidney volume (TKV) and thrice annual estimated GFR (eGFR) measurements, from two 3-year studies of tolvaptan in 63 ADPKD subjects randomly matched 1:2 to historical controls by gender, hypertension, age, and baseline TKV or eGFR. Prespecified end points were group differences in log-TKV (primary) and eGFR (secondary) slopes for month 36 completers, using linear mixed model (LMM) analysis. Sensitivity analyses of primary and secondary end points included LMM using all subject data and mixed model repeated measures (MMRM) of change from baseline at each year. Pearson correlation tested the association between log-TKV and eGFR changes. Fifty-one subjects (81%) completed 3 years of tolvaptan therapy; all experienced adverse events (AEs), with AEs accounting for six of 12 withdrawals. Baseline TKV (controls 1422, tolvaptan 1635 ml) and eGFR (both 62 ml/min per 1.73 m(2)) were similar. Control TKV increased 5.8% versus 1.7%/yr for tolvaptan (P < 0.001, estimated ratio of geometric mean 0.96 [95% confidence interval 0.95 to 0.97]). Corresponding annualized eGFR declined: -2.1 versus -0.71 ml/min per 1.73 m(2)/yr (P = 0.01, LMM group difference 1.1 ml/min per 1.73 m(2)/yr [95% confidence interval 0.24 to 1.9]). Sensitivity analyses including withdrawn subjects were similar, whereas MMRM analyses were significant at each year for TKV and nonsignificant for eGFR. Increasing TKV correlated with decreasing eGFR (r = -0.21, P < 0.01). ADPKD cyst growth progresses more slowly with tolvaptan than in historical controls, but AEs are common.
  Clinical Journal of the American Society of Nephrology 09/2011; 6(10):2499-507. · 5.23 Impact Factor
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  Article: Fibrosis, regeneration, and aging: playing chess with evolution.

  Vicente E Torres, Edward B Leof
  Journal of the American Society of Nephrology 08/2011; 22(8):1393-6. · 9.66 Impact Factor