Skip to main content

Main menu

  • Home
  • Content
    • Published Ahead of Print
    • Current Issue
    • Subject Collections
    • JASN Podcasts
    • Archives
    • Saved Searches
    • ASN Meeting Abstracts
  • Authors
    • Submit a Manuscript
    • Author Resources
  • Editorial Team
  • Subscriptions
  • More
    • About JASN
    • Alerts
    • Advertising
    • Editorial Fellowship Program
    • Feedback
    • Reprints
    • Impact Factor
  • ASN Kidney News
  • Other
    • CJASN
    • Kidney360
    • Kidney News Online
    • American Society of Nephrology

User menu

  • Subscribe
  • My alerts
  • Log in
  • My Cart

Search

  • Advanced search
American Society of Nephrology
  • Other
    • CJASN
    • Kidney360
    • Kidney News Online
    • American Society of Nephrology
  • Subscribe
  • My alerts
  • Log in
  • My Cart
Advertisement
American Society of Nephrology

Advanced Search

  • Home
  • Content
    • Published Ahead of Print
    • Current Issue
    • Subject Collections
    • JASN Podcasts
    • Archives
    • Saved Searches
    • ASN Meeting Abstracts
  • Authors
    • Submit a Manuscript
    • Author Resources
  • Editorial Team
  • Subscriptions
  • More
    • About JASN
    • Alerts
    • Advertising
    • Editorial Fellowship Program
    • Feedback
    • Reprints
    • Impact Factor
  • ASN Kidney News
  • Follow JASN on Twitter
  • Visit ASN on Facebook
  • Follow JASN on RSS
  • Community Forum
Fast Track
You have accessRestricted Access

Cyst Number but Not the Rate of Cystic Growth Is Associated with the Mutated Gene in Autosomal Dominant Polycystic Kidney Disease

Peter C. Harris, Kyongtae T. Bae, Sandro Rossetti, Vicente E. Torres, Jared J. Grantham, Arlene B. Chapman, Lisa M. Guay-Woodford, Bernard F. King, Louis H. Wetzel, Deborah A. Baumgarten, Philip J. Kenney, Mark Consugar, Saulo Klahr, William M. Bennett, Catherine M. Meyers, Qin (Jean) Zhang, Paul A. Thompson, Fang Zhu, J. Philip Miller and and the CRISP Consortium
JASN November 2006, 17 (11) 3013-3019; DOI: https://doi.org/10.1681/ASN.2006080835
Peter C. Harris
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kyongtae T. Bae
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Sandro Rossetti
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Vicente E. Torres
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jared J. Grantham
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Arlene B. Chapman
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Lisa M. Guay-Woodford
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Bernard F. King
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Louis H. Wetzel
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Deborah A. Baumgarten
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Philip J. Kenney
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Mark Consugar
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Saulo Klahr
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
William M. Bennett
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Catherine M. Meyers
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Qin (Jean) Zhang
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Paul A. Thompson
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Fang Zhu
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
J. Philip Miller
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data Supps
  • Info & Metrics
  • View PDF
Loading

Abstract

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.

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive cyst development and expansion, resulting in ESRD in the majority of patients (1,2). ADPKD is genetically heterogeneous with two loci identified—PKD1 (16p13.3) and PKD2 (4q21)—that encode the proteins polycystin-1 and polycystin-2 (3–5). The majority of patients (approximately 85%) have PKD1, with PKD2 accounting for most of the remainder (6–8). Genetic modifying factors, as well as the environment, also significantly influence the course of this disease (9,10). On the basis of detected somatic mutations in isolated cystic linings and cell lines that are derived from single cysts, plus animal models, it has been proposed that cyst initiation is a two-hit process (11–15). However, dosage changes of a polycystin molecule also may result in cyst development (16–20), and heterogeneity of a developing cyst questions whether a second hit is always necessary as an initiating event (21).

PKD2 is consistently a milder disease as evidenced in age at ESRD (PKD1 54.3 yr; PKD2 74 yr) and age at diagnosis of the disease and of hypertension (7,22,23). The Consortium of Radiologic Imaging Study of PKD (CRISP) was established to determine from a prospective, longitudinal study whether radiologic measures of kidney and cyst volumes by magnetic resonance imaging (MRI) could be used as an early means to monitor disease progression (24). This study showed that kidney and cyst volumes increase in most patients and that larger kidneys are associated with a decline in renal function (25). Previously, no significant difference was found between PKD1 and PKD2 kidneys by ultrasound analysis (7,26), but preliminary data from the CRISP study (before the genotyping was complete) showed that PKD1 kidneys are significantly larger than PKD2, consistent with correlations between renal size and function (25). Here, with completed genotyping data, PKD1 and PKD2 kidneys are compared in more detail, and insights are provided about the process of cystogenesis.

Materials and Methods

Radiologic and Statistical Analyses

Detailed descriptions of the structure of this study, the baseline characteristics of the cohort, and details of evaluations during the course of the study have been published previously (24,25,27). Patients who had ADPKD (n = 241), were 15 to 46 yr of age, and had a GFR of >70 ml/min at enrollment were evaluated at baseline and annually over 3 yr for renal function and MRI of the kidney with coronal T1- and T2-weighted images to calculate renal and cyst volumes. Volumes were measured on a 3-mm slice-by-slice basis by two analysts who were blinded to genotype, as described previously in detail (24). The annual percentage change of total kidney and cyst volume was determined by regressing log-transformed (on a base-10 scale) against time (baseline to year 3) for individuals using a mixed linear model. To count the number of cysts, we chose a middle section of the left kidney on coronal T2-weighted images, and any cyst with a diameter of ≥4 mm was recorded by a single analyst who was blinded to genotype.

The percentage change of corrected iothalamate clearance was calculated by dividing the slope estimate by the intercept value to measure GFR. Logistic regression was used to evaluate hypertension in PKD1 and PKD2 groups after adjustment for gender and age. Statistical methods used in this study included mixed-model ANOVA (and t test). Cross-tabulation comparisons were examined using χ2 methods.

Genotyping Analysis

Details of the genetic study will be described elsewhere. Briefly, samples for genotyping were available from 239 patients from 202 different families. The PKD1 and PKD2 genes were screened in each family by denaturing HPLC (28), and mutation-negative cases (plus controls) were analyzed using a commercial diagnostic test (Athena Diagnostics, Worcester, MA) that uses direct sequencing. Larger deletion mutations also were sought by field inversion gel electrophoresis (29). The overall detection rate was 90.1%. Linkage analysis with markers flanking PKD1 and PKD2 also was used to identify gene type in three large families in whom no mutation was detected.

Results

Mutation analysis of the CRISP cohort identified likely pathogenic changes in 180 pedigrees (211 patients) with linkage identifying the gene in three more families (eight patients). Twenty-seven (14.8%) pedigrees (34 patients) had PKD2, and 156 (85.2%) pedigrees (185 patients) had PKD1, a distribution similar to that previously found in clinical ADPKD populations (6,7). Despite that the patients with PKD2 were significantly older, they were less likely to be hypertensive and had smaller kidney and cyst volumes at baseline (Table 1, Figure 1, A and B). The age- and gender-adjusted PKD2 kidney and cyst volumes were, respectively, 59.8 and 43.2% of their PKD1 counterparts. Although there was no difference in GFR or renal blood flow (another early marker of kidney function [30]) between PKD1 and PKD2 at baseline, there was significantly more urinary albumin in PKD1 cases (Table 1). Kidney and cyst volumes consistently increased in both the PKD1 and PKD2 populations, and the absolute rate of change was greater in PKD1 (25) (Figure 1, A through D, Table 1). However, this was due to the larger baseline sizes of the kidneys; the rates of growth for kidney and cyst volume were not significantly different (Table 1, Figure 1, A through D). This indicates that gene type does not strongly influence the size of ADPKD kidneys by modulating the relative rate of cyst growth. Gender, however, was associated with both the absolute and relative rates of kidney and cystic expansion in the ADPKD population, with male patients showing more rapid expansion (Table 2).

Figure 1.
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 1.

Plot of kidney (a and c) or cyst volume (b and d) on a linear (a and b) or log scale (c and d) versus age for all genotyped Consortium of Radiologic Imaging Study of PKD (CRISP) participants comparing patients with PKD1 (red asterisks) and PKD2 (blue circles). Patients with PKD2 generally have smaller kidney and cyst volumes, but the rate of increase (c and d) is similar to that of patients with PKD1. Cyst number compared with age (e) or kidney volume (f) in the PKD1 and PKD2 populations. Patients with PKD2 generally have lower cyst numbers. Regression lines (e) show that the relative rate of development of new cysts in the PKD1 and PKD2 populations is similar but that more cysts develop in PKD1 at a younger age.

View this table:
  • View inline
  • View popup
Table 1.

Comparison of PKD1 versus PKD2 imaging/clinical parametersa

View this table:
  • View inline
  • View popup
Table 2.

Comparison of gender with baseline values and measures of disease progression in the total ADPKD populationa

Analysis of cyst number at baseline in all patients showed that PKD2 kidneys have significantly fewer cysts (55.9% of those found in PKD1 kidneys) and that there is a correlation between cyst number and kidney volume (Figure 1, E and F, Table 1; see the Materials and Methods section for details). In both PKD1 and PKD2, the number of cysts was correlated with the age of the patient, illustrating that new cysts develop during the course of the disease. Although the slopes of the regression lines that depict the relationship between age and cyst number are not significantly different between the PKD1 and PKD2 populations (P = 0.77; Figure 1E), the intersect to the y axis is significantly lower for PKD2 (approximately 14 cysts per MRI section; P < 0.0001), suggesting more aggressive early onset of cystogenesis in PKD1. Representative MRI images showing examples of younger and older PKD1 and PKD2 kidneys illustrate the differences in terms of cyst number, as well as total cystic volume (Figure 2), although there is considerable heterogeneity within each of the genic populations (Figure 1, E and F). Overall, these data indicate that PKD2 kidneys are smaller because they develop fewer cysts, especially at the early stages of the disease.

Figure 2.
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 2.

Coronal T2-weighted, single-shot fast spin echo magnetic resonance images from patients with PKD1 (a and b) and PKD2 (c and d) at 18 yr (a and c) and 41 yr (b and d). Renal cysts in PKD1 are more numerous, diffusely distributed, and heterogeneous in size than those in PKD2.

Discussion

Hypertension and urinary albumin excretion were significantly more common in PKD1 than PKD2, consistent with these variables’ being associated with more severe disease (24,25). However, the major new conclusion from this study is that the genic effect is at the level of cyst initiation; the rate of cystic enlargement is not modulated by the disease gene. Although it is logical that the disease mutation is involved in cyst initiation, similar rates of cystic growth in the two disorders has not been shown previously. Therefore, two distinct phases to cystogenesis, a disease gene–related initiation phase and a gene-independent cyst enlargement phase, have been defined.

Gender was associated with the rate of cyst expansion in the total cohort. Previously, male individuals have been associated with more severe disease in ADPKD (2), and although this has been demonstrated in PKD2 (31), recent data on PKD1 have not shown a significant difference (22,32) in age at ESRD. Our data indicate that gender may be important, however, to the rate of cystic expansion, suggesting a hormonal influence on the process. The faster expansion of cyst volume in male individuals is consistent with the stimulating effect of testosterone on cAMP accumulation and chloride and fluid secretion by MDCK cells (33). A hormonal effect was identified previously in polycystic liver disease, in which more severe disease in women is thought to be promoted by estrogen exposure (34,35).

Our data lead us to suggest that new cysts develop during the life of the patient, although the expansion of microscopic cysts initiated in utero (36) to a level where they are recorded (≥4 mm), may be significant; and differential rates of growth of PKD1 and PKD2 microcysts cannot be ruled out. That cysts continue to develop in childhood and adulthood also is indicated because, although the rate of cystic expansion is similar in both kidneys in an individual (25), there is considerable heterogeneity in cyst size (Figure 2). These concepts are presently being tested in conditional mouse models of ADPKD (37) and by further observations of the CRISP cohort. Because PKD1 kidneys have more cysts even at young ages (Figure 1, E and F), the rate of cyst initiation at early ages, including in the fetus, may be important.

The reason that fewer cysts develop in PKD2 is not known, but it seems to fit neatly with the concept that cystogenesis is a two-hit process that requires a somatic mutation for cyst initiation (11). Several factors suggest that the PKD1 gene may sustain a higher level of somatic insults than PKD2. Most notable among these is the larger size of the coding region (approximately 12.9 kb compared with approximately 3 kb) and the GC richness of the DNA, resulting in a higher level of CpG dinucleotides that are known warm spots for mutations (38). In addition, special factors, such as a polypyrimidine tract in IVS21 and six pseudogenes that match much of the 5′ two thirds of PKD1, may increase the somatic mutation level at PKD1 (29,39,40). A significant level of de novo germline mutations at PKD1 emphasize that new mutations occur at a significant level at this locus (38). It is possible, however, that there are other reasons that a PKD1 germline mutation might be more likely to result in cyst development. For example, polycystin-1 may be more important during renal development than polycystin-2, or some PKD1 mutations may generate stable proteins that can act as dominant negatives and thus have an enhanced detrimental effect.

A comparison of patients within the PKD1 or PKD2 populations show that there is considerable variability in the rate at which cysts grow (Figure 1, C and D), although similar individual rates are found for the right and left kidneys (25). This rate seems to be independent of the disease gene and reflects genetic modifying effects, as well as environmental influences and gender. Similarly, considerable variation in cyst number is seen within the PKD1 and PKD2 populations (Figure 1, E and F), probably influenced by allelic effects, genetic modifiers, the environment, and stochastic factors on the rate of cyst initiation. These findings have implications for identifying quantitative trait loci that modulate disease severity and the development of effective therapeutics.

Conclusion

We have defined cystogenesis as a two-phase process: Cyst initiation, associated with the disease mutation, and cyst expansion, which is disease gene independent. Both phases vary between individuals. Therefore, quantitative trait loci or potential therapies may have an influence on the rate of cyst formation by preventing somatic mutations or by regulating the growth of cysts. Assuming that the downstream changes that are associated with cystogenesis as a result of disruption of the polycystin complex are similar in PKD1 and PKD2, it is likely that factors that target cystic growth may be equally effective in both disorders. Most therapies that presently are under consideration, such as the clinical evaluation of vasopressin receptor antagonists (41), fall into this second group.

Acknowledgments

This study was supported by National Institute of Diabetes and Digestive and Kidney Diseases cooperative agreements (DK56934, DK56956, DK56957, and DK56961), with additional support for this ancillary study (DK56957-S1) for genetic analysis. The CRISP study also was supported by General Clinical Research Centers at each institution.

The study has been accepted as an abstract to the annual meeting of the American Society of Nephrology; November 17, 2006; San Diego, CA.

We thank the study coordinators Jody Mahan, Beth Stafford, Lorna Stevens, Kristin Cornwell, Vickie Kubly, Diane Watkins, Sharon Langley, and Pam Trull and Mary Virginia Gaines for managerial support. John McAuliffe, William Seltzer, Lynne Leclair, and Mark Smith at Athena Diagnostic are thanked for assistance in the fee-for-service direct sequence mutation analysis.

Footnotes

  • Published online ahead of print. Publication date available at www.jasn.org.

  • © 2006 American Society of Nephrology

References

  1. ↵
    Grantham JJ, Chapman AB, Torres VE: Volume progression in autosomal dominant polycystic kidney disease: The major factor determining clinical outcomes. Clin J Am Soc Nephrol 1 : 148 –157, 2006
    OpenUrlCrossRef
  2. ↵
    Gabow PA, Johnson AM, Kaehny WD, Kimberling WJ, Lezotte DC, Duley IT, Jones RH: Factors affecting the progression of renal disease in autosomal-dominant polycystic kidney disease. Kidney Int 41 : 1311 –1319, 1992
    OpenUrlCrossRefPubMed
  3. ↵
    International Polycystic Kidney Disease Consortium: Polycystic kidney disease: The complete structure of the PKD1 gene and its protein. Cell 81 : 289 –298, 1995
    OpenUrl
  4. Hughes J, Ward CJ, Peral B, Aspinwall R, Clark K, San Millan JL, Gamble V, Harris PC: The polycystic kidney disease 1 (PKD1) gene encodes a novel protein with multiple cell recognition domains. Nat Genet 10 : 151 –160, 1995
    OpenUrlCrossRefPubMed
  5. ↵
    Mochizuki T, Wu G, Hayashi T, Xenophontos SL, Veldhusien B, Saris JJ, Reynolds DM, Cai Y, Gabow PA, Pierides A, Kimberling WJ, Breuning MH, Deltas CC, Peters DJM, Somlo S: PKD2, a gene for polycystic kidney disease that encodes an integral membrane protein. Science 272 : 1339 –1342, 1996
    OpenUrlAbstract
  6. ↵
    Peters DJM, Sandkuijl LA: Genetic heterogeneity of polycystic kidney disease in Europe. Contrib Nephrol 97 : 128 –139, 1992
    OpenUrlCrossRefPubMed
  7. ↵
    Torra R, Badenas C, Darnell A, Nicolau C, Volpini V, Revert L, Estivill X: Linkage, clinical features, and prognosis of autosomal dominant polycystic kidney disease types 1 and 2. J Am Soc Nephrol 7 : 2142 –2151, 1996
    OpenUrlAbstract
  8. ↵
    Daoust MC, Reynolds DM, Bichet DG, Somlo S: Evidence for a third genetic locus for autosomal dominant polycystic kidney disease. Genomics 25 : 733 –736, 1995
    OpenUrlCrossRefPubMed
  9. ↵
    Paterson AD, Magistroni R, He N, Wang K, Johnson A, Fain PR, Dicks E, Parfrey P, St George-Hyslop P, Pei Y: Progressive loss of renal function is an age-dependent heritable trait in type 1 autosomal dominant polycystic kidney disease. J Am Soc Nephrol 16 : 755 –762, 2005
    OpenUrlAbstract/FREE Full Text
  10. ↵
    Fain PR, McFann KK, Taylor MR, Tison M, Johnson AM, Reed B, Schrier RW: Modifier genes play a significant role in the phenotypic expression of PKD1. Kidney Int 67 : 1256 –1267, 2005
    OpenUrlCrossRefPubMed
  11. ↵
    Qian F, Watnick TJ, Onuchic LF, Germino GG: The molecular basis of focal cyst formation in human autosomal dominant polycystic kidney disease type 1. Cell 87 : 979 –987, 1996
    OpenUrlCrossRefPubMed
  12. Brasier JL, Henske EP: Loss of the polycystic kidney disease (PKD1) region of chromosome 16p13 in renal cyst cells supports a loss-of-function model for cyst pathogenesis. J Clin Invest 99 : 194 –199, 1997
    OpenUrlCrossRefPubMed
  13. Watnick TJ, Torres VE, Gandolph MA, Qian F, Onuchic LF, Klinger KW, Landes G, Germino GG: Somatic mutation in individual liver cysts supports a two-hit model of cystogenesis in autosomal dominant polycystic kidney disease. Mol Cell 2 : 247 –251, 1998
    OpenUrlCrossRefPubMed
  14. Nauli SM, Rossetti S, Kolb RJ, Alenghat FJ, Consugar MB, Harris PC, Ingber DE, Loghman-Adham M, Zhou J: Loss of polycystin-1 in human cyst-lining epithelia leads to ciliary dysfunction. J Am Soc Nephrol 17 : 1015 –1025, 2006
    OpenUrlAbstract/FREE Full Text
  15. ↵
    Wu G, D’Agati V, Cai Y, Markowitz G, Park JH, Reynolds DM, Maeda Y, Le TC, Hou J Jr, Kucherlapati R, Edelmann W, Somlo S: Somatic inactivation of Pkd2 results in polycystic kidney disease. Cell 93 : 177 –188, 1998
    OpenUrlCrossRefPubMed
  16. ↵
    Jiang ST, Chiou YY, Wang E, Lin HK, Lin YT, Chi YC, Wang CK, Tang MJ, Li H: Defining a link with autosomal-dominant polycystic kidney disease in mice with congenitally low expression of Pkd1. Am J Pathol 168 : 205 –220, 2006
    OpenUrlCrossRefPubMed
  17. Lantinga-van Leeuwen IS, Dauwerse JG, Baelde HJ, Leonhard WN, van de Wal A, Ward CJ, Verbeek S, DeRuiter MC, Breuning MH, de Heer E, Peters DJM: Lowering of Pkd1 expression is sufficient to cause polycystic kidney disease. Hum Mol Genet 13 : 3069 –3077, 2004
    OpenUrlCrossRefPubMed
  18. Thivierge C, Kurbegovic A, Couillard M, Guillaume R, Cote O, Trudel M: Overexpression of PKD1 causes polycystic kidney disease. Mol Cell Biol 26 : 1538 –1548, 2006
    OpenUrlAbstract/FREE Full Text
  19. Pritchard L, Sloane-Stanley JA, Sharpe J, Aspinwall R, Lu W, Buckle V, Strmecki L, Walker D, Ward CJ, Alpers CE, Zhou J, Wood WG, Harris PC: A human PKD1 transgene generates functional polycystin-1 in mice and is associated with a cystic phenotype. Hum Mol Genet 9 : 2617 –2627, 2000
    OpenUrlCrossRefPubMed
  20. ↵
    Qian Q, Hunter LW, Li M, Marin-Padilla M, Prakash YS, Harris PC, Somlo S, Torres VE, Sieck GC: PKD2 haploinsufficiency alters intracellular calcium in vascular smooth muscle cells. Hum Mol Genet 12 : 1875 –1880, 2003
    OpenUrlCrossRefPubMed
  21. ↵
    Nishio S, Hatano M, Nagata M, Horie S, Koike T, Tokuhisa T, Mochizuki T: Pkd1 regulates immortalized proliferation of renal tubular epithelial cells through p53 induction and JNK activation. J Clin Invest 115 : 910 –918, 2005
    OpenUrlCrossRefPubMed
  22. ↵
    Hateboer N, van Dijk MA, Bogdanova N, Coto E, Saggar-Malik AK, San Millan JL, Torra R, Breuning M, Ravine D: Comparison of phenotypes of polycystic kidney disease types 1 and 2. Lancet 353 : 103 –107, 1999
    OpenUrlCrossRefPubMed
  23. ↵
    Torra R, Badenas C, Perez-Oller L, Luis J, Millan S, Nicolau C, Oppenheimer F, Mila M, Darnell A: Increased prevalence of polycystic kidney disease type 2 among elderly polycystic patients. Am J Kidney Dis 36 : 728 –734, 2000
    OpenUrlPubMed
  24. ↵
    Chapman AB, Guay-Woodford LM, Grantham JJ, Torres VE, Bae KT, Baumgarten DA, Kenney PJ, King BF Jr, Glockner JF, Wetzel LH, Brummer ME, O’Neill WC, Robbin ML, Bennett WM, Klahr S, Hirschman GH, Kimmel PL, Thompson PA, Miller JP: Renal structure in early autosomal-dominant polycystic kidney disease (ADPKD): The Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) cohort. Kidney Int 64 : 1035 –1045, 2003
    OpenUrlCrossRefPubMed
  25. ↵
    Grantham JJ, Torres VE, Chapman AB, Guay-Woodford LM, Bae KT, King BF Jr, Wetzel LH, Baumgarten DA, Kenney PJ, Harris PC, Klahr S, Bennett WM, Hirschman GN, Meyers CM, Zhang X, Zhu F, Miller JP: Volume progression in polycystic kidney disease. N Engl J Med 354 : 2122 –2130, 2006
    OpenUrlCrossRefPubMed
  26. ↵
    O’Neill WC, Robbin ML, Bae KT, Grantham JJ, Chapman AB, Guay-Woodford LM, Torres VE, King BF, Wetzel LH, Thompson PA, Miller JP: Sonographic assessment of the severity and progression of autosomal dominant polycystic kidney disease: The Consortium of Renal Imaging Studies in Polycystic Kidney Disease (CRISP). Am J Kidney Dis 46 : 1058 –1064, 2005
    OpenUrlCrossRefPubMed
  27. ↵
    Bae KT, Commean PK, Lee J: Volumetric measurement of renal cysts and parenchyma using MRI: Phantoms and patients with polycystic kidney disease. J Comput Assisted Tomogr 24 : 614 –619, 2000
    OpenUrlCrossRefPubMed
  28. ↵
    Rossetti S, Chauveau D, Walker D, Saggar-Malik A, Winearls CG, Torres VE, Harris PC: A complete mutation screen of the ADPKD genes by DHPLC. Kidney Int 61 : 1588 –1599, 2002
    OpenUrlCrossRefPubMed
  29. ↵
    European Polycystic Kidney Disease Consortium: The polycystic kidney disease 1 gene encodes a 14 kb transcript and lies within a duplicated region on chromosome 16. Cell 77 : 881 –894, 1994
    OpenUrlCrossRefPubMed
  30. ↵
    King BF, Torres VE, Brummer ME, Chapman AB, Bae KT, Glockner JF, Arya K, Felmlee JP, Grantham JJ, Guay-Woodford LM, Bennett WM, Klahr S, Hirschman GH, Kimmel PL, Thompson PA, Miller JP: Magnetic resonance measurements of renal blood flow as a marker of disease severity in autosomal-dominant polycystic kidney disease. Kidney Int 64 : 2214 –2221, 2003
    OpenUrlCrossRefPubMed
  31. ↵
    Magistroni R, He N, Wang K, Andrew R, Johnson A, Gabow P, Dicks E, Parfrey P, Torra R, San-Millan JL, Coto E, Van Dijk M, Breuning M, Peters D, Bogdanova N, Ligabue G, Albertazzi A, Hateboer N, Demetriou K, Pierides A, Deltas C, St George-Hyslop P, Ravine D, Pei Y: Genotype-renal function correlation in type 2 autosomal dominant polycystic kidney disease. J Am Soc Nephrol 14 : 1164 –1174, 2003
    OpenUrlAbstract/FREE Full Text
  32. ↵
    Rossetti S, Burton S, Strmecki L, Pond GR, San Millan JL, Zerres K, Barratt TM, Ozen S, Torres VE, Bergstralh EJ, Winearls CG, Harris PC: The position of the polycystic kidney disease 1 (PKD1) gene mutation correlates with the severity of renal disease. J Am Soc Nephrol 13 : 1230 –1237, 2002
    OpenUrlAbstract/FREE Full Text
  33. ↵
    Sandhu S, Silbiger SR, Lei J, Neugarten J: Effects of sex hormones on fluid and solute transport in Madin-Darby canine kidney cells. Kidney Int 51 : 1535 –1539, 1997
    OpenUrlPubMed
  34. ↵
    Sherstha R, McKinley C, Russ P, Scherzinger A, Bronner T, Showalter R, Everson GT: Postmenopausal estrogen therapy selectively stimulates hepatic enlargement in women with autosomal dominant polycystic kidney disease. Hepatology 26 : 1282 –1286, 1997
    OpenUrlPubMed
  35. ↵
    Gabow PA, Johnson AM, Kaehny WD, Manco-Johnson ML, Duley IT, Everson GT: Risk factors for the development of hepatic cysts in autosomal dominant polycystic kidney disease. Hepatology 11 : 1033 –1037, 1990
    OpenUrlCrossRefPubMed
  36. ↵
    Reeders ST, Zerres K, Gal A, Hogenkamp T, Propping P, Schmidt W, Waldherr R, Dolata MM, Davies KE, Weatherall DJ: Prenatal diagnosis of autosomal dominant polycystic kidney disease with a DNA probe. Lancet 2 : 6 –8, 1986
    OpenUrlPubMed
  37. ↵
    Piontek KB, Huso DL, Grinberg A, Liu L, Bedja D, Zhao H, Gabrielson K, Qian F, Mei C, Westphal H, Germino GG: A functional floxed allele of Pkd1 that can be conditionally inactivated in vivo. J Am Soc Nephrol 15 : 3035 –3043, 2004
    OpenUrlAbstract/FREE Full Text
  38. ↵
    Rossetti S, Strmecki L, Gamble V, Burton S, Sneddon V, Peral B, Roy S, Bakkaloglu A, Komel R, Winearls CG, Harris PC: Mutation analysis of the entire PKD1 gene: Genetic and diagnostic implications. Am J Hum Genet 68 : 46 –63, 2001
    OpenUrlCrossRefPubMed
  39. ↵
    Burn TC, Connors TD, Dackowski WR, Petry LR, Van Raay TJ, Millholland JM, Venet M, Miller G, Hakim RM, Landes GM, Klinger KW, Qian F, Onuchic LF, Watnick T, Germino GG, Doggett NA: Analysis of the genomic sequence for the autosomal dominant polycystic kidney disease (PKD1) gene predicts the presence of a leucine-rich repeat. Hum Mol Genet 4 : 575 –582, 1995
    OpenUrlCrossRefPubMed
  40. ↵
    Watnick TJ, Gandolph MA, Weber H, Neumann HPH, Germino GG: Gene conversion is a likely cause of mutation in PKD1. Hum Mol Genet 7 : 1239 –1243, 1998
    OpenUrlCrossRefPubMed
  41. ↵
    Torres VE, Wang X, Qian Q, Somlo S, Harris PC, Gattone VH: Effective treatment of an orthologous model of autosomal dominant polycystic kidney disease. Nature Med 10 : 363 –364, 2004
    OpenUrlCrossRefPubMed
View Abstract
PreviousNext
Back to top

In this issue

Journal of the American Society of Nephrology: 17 (11)
Journal of the American Society of Nephrology
Vol. 17, Issue 11
November 2006
  • Table of Contents
  • Table of Contents (PDF)
  • Index by author
View Selected Citations (0)
Print
Download PDF
Sign up for Alerts
Email Article
Thank you for your help in sharing the high-quality science in JASN.
Enter multiple addresses on separate lines or separate them with commas.
Cyst Number but Not the Rate of Cystic Growth Is Associated with the Mutated Gene in Autosomal Dominant Polycystic Kidney Disease
(Your Name) has sent you a message from American Society of Nephrology
(Your Name) thought you would like to see the American Society of Nephrology web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Cyst Number but Not the Rate of Cystic Growth Is Associated with the Mutated Gene in Autosomal Dominant Polycystic Kidney Disease
Peter C. Harris, Kyongtae T. Bae, Sandro Rossetti, Vicente E. Torres, Jared J. Grantham, Arlene B. Chapman, Lisa M. Guay-Woodford, Bernard F. King, Louis H. Wetzel, Deborah A. Baumgarten, Philip J. Kenney, Mark Consugar, Saulo Klahr, William M. Bennett, Catherine M. Meyers, Qin (Jean) Zhang, Paul A. Thompson, Fang Zhu, J. Philip Miller, and the CRISP Consortium
JASN Nov 2006, 17 (11) 3013-3019; DOI: 10.1681/ASN.2006080835

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Request Permissions
Share
Cyst Number but Not the Rate of Cystic Growth Is Associated with the Mutated Gene in Autosomal Dominant Polycystic Kidney Disease
Peter C. Harris, Kyongtae T. Bae, Sandro Rossetti, Vicente E. Torres, Jared J. Grantham, Arlene B. Chapman, Lisa M. Guay-Woodford, Bernard F. King, Louis H. Wetzel, Deborah A. Baumgarten, Philip J. Kenney, Mark Consugar, Saulo Klahr, William M. Bennett, Catherine M. Meyers, Qin (Jean) Zhang, Paul A. Thompson, Fang Zhu, J. Philip Miller, and the CRISP Consortium
JASN Nov 2006, 17 (11) 3013-3019; DOI: 10.1681/ASN.2006080835
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like

Jump to section

  • Article
    • Abstract
    • Materials and Methods
    • Results
    • Discussion
    • Conclusion
    • Acknowledgments
    • Footnotes
    • References
  • Figures & Data Supps
  • Info & Metrics
  • View PDF

More in this TOC Section

  • Induction of TRPC6 Channel in Acquired Forms of Proteinuric Kidney Disease
  • Prorenin and Angiotensin-Dependent Renal Vasoconstriction in Type 1 and Type 2 Diabetes
Show more Fast Track

Cited By...

  • Growth Pattern of Kidney Cyst Number and Volume in Autosomal Dominant Polycystic Kidney Disease
  • Prevalence Estimates of Polycystic Kidney and Liver Disease by Population Sequencing
  • Genetic Complexity of Autosomal Dominant Polycystic Kidney and Liver Diseases
  • Ciliary Mechanisms of Cyst Formation in Polycystic Kidney Disease
  • Polycystic Kidney Disease without an Apparent Family History
  • Predicted Mutation Strength of Nontruncating PKD1 Mutations Aids Genotype-Phenotype Correlations in Autosomal Dominant Polycystic Kidney Disease
  • Refining Genotype-Phenotype Correlation in Autosomal Dominant Polycystic Kidney Disease
  • Inactivation of Integrin-{beta}1 Prevents the Development of Polycystic Kidney Disease after the Loss of Polycystin-1
  • Imaging-Based Diagnosis of Autosomal Dominant Polycystic Kidney Disease
  • Imaging Classification of Autosomal Dominant Polycystic Kidney Disease: A Simple Model for Selecting Patients for Clinical Trials
  • Predictors of Autosomal Dominant Polycystic Kidney Disease Progression
  • Low-Dose Rapamycin (Sirolimus) Effects in Autosomal Dominant Polycystic Kidney Disease: An Open-Label Randomized Controlled Pilot Study
  • Renal Relevant Radiology: Radiologic Imaging in Autosomal Dominant Polycystic Kidney Disease
  • Segmentation of Individual Renal Cysts from MR Images in Patients with Autosomal Dominant Polycystic Kidney Disease
  • Detected Renal Cysts Are Tips of the Iceberg in Adults with ADPKD
  • Kidney Volume and Functional Outcomes in Autosomal Dominant Polycystic Kidney Disease
  • Improved Prognosis in Patients with Autosomal Dominant Polycystic Kidney Disease in Denmark
  • Genetic Variation of DKK3 May Modify Renal Disease Severity in ADPKD
  • Evidence of Extraordinary Growth in the Progressive Enlargement of Renal Cysts
  • Family History of Renal Disease Severity Predicts the Mutated Gene in ADPKD
  • 2008 Homer W. Smith Award: Insights into the Pathogenesis of Polycystic Kidney Disease from Gene Discovery
  • Unified Criteria for Ultrasonographic Diagnosis of ADPKD
  • Unified Ultrasonographic Diagnostic Criteria for Polycystic Kidney Disease
  • Targeting Cyst Initiation in ADPKD
  • Triptolide Reduces Cystogenesis in a Model of ADPKD
  • Approaches to Testing New Treatments in Autosomal Dominant Polycystic Kidney Disease: Insights from the CRISP and HALT-PKD Studies
  • Vasopressin Directly Regulates Cyst Growth in Polycystic Kidney Disease
  • Comprehensive Molecular Diagnostics in Autosomal Dominant Polycystic Kidney Disease
  • Autosomal Dominant Polycystic Kidney Disease: Time for a Change?
  • Genotype-Phenotype Correlations in Autosomal Dominant and Autosomal Recessive Polycystic Kidney Disease
  • Google Scholar

Similar Articles

Related Articles

  • No related articles found.
  • PubMed
  • Google Scholar

Articles

  • Current Issue
  • Early Access
  • Subject Collections
  • Article Archive
  • ASN Annual Meeting Abstracts

Information for Authors

  • Submit a Manuscript
  • Author Resources
  • Editorial Fellowship Program
  • ASN Journal Policies
  • Reuse/Reprint Policy

About

  • JASN
  • ASN
  • ASN Journals
  • ASN Kidney News

Journal Information

  • About JASN
  • JASN Email Alerts
  • JASN Key Impact Information
  • JASN Podcasts
  • JASN RSS Feeds
  • Editorial Board

More Information

  • Advertise
  • ASN Podcasts
  • ASN Publications
  • Become an ASN Member
  • Feedback
  • Follow on Twitter
  • Password/Email Address Changes
  • Subscribe

© 2021 American Society of Nephrology

Print ISSN - 1046-6673 Online ISSN - 1533-3450

Powered by HighWire