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Polycystic Kidney Disease
What is it?
Polycystic kidney disease (PKD) is a group of diseases characterized by dilatation of the tubular units of the kidney. The kidney tubules process the 140 liters of fluid filtered by the glomerulus into the final urine volume (0.5-2.0 liters) that is made daily. Cystic tubules are unable to perform this function properly, resulting in fluid retention, high blood pressure and kidney failure requiring dialysis or transplantation. In some forms of this disease, the dilated segments of tubules expand so much that they pinch off from the adjacent tubules and form very large, fluid filled structures that further damage the kidney and cause significant problems for patients (pain, infection, hemorrhage, kidney stones). The name “PKD” really is a misnomer, however, in that many individuals also have significant liver disease (sometimes necessitating liver transplant) and cardiovascular disease (resulting in hypertension, strokes, aneurysms of the blood vessels of the brain and aorta, and cardiac valvular disorders).
PKD is an important health care problem. One form of PKD, called autosomal dominant polycystic kidney disease (ADPKD), is among the most common of all inherited diseases of humans, affecting between 1/500 and 1/2000 people. It is responsible for ~4% of all individuals with end stage kidney failure in the United States.
What are the different types of PKD?
A number of acquired and genetic diseases can result in polycystic kidney and liver disease. The various forms differ with respect to the way in which they are inherited (autosomal dominant, autosomal recessive or X-linked), the range of renal and extra-renal manifestations that accompany the cystic disease, the age at which renal failure most commonly presents (childhood vs adult), and the mutant gene responsible for causing the disorder.
Some of diseases most commonly associated with PKD are listed below:
How do you treat PKD?
There are presently no known treatments. Our efforts are primarily directed at managing complications of the various forms of the disease, such as treating hypertension or infections. Several experimental drugs have been shown to slow the progression of PKD in some mice models but not in others.
What type of research in PKD is currently being conducted at Johns Hopkins?
PKD poses special challenges for investigators seeking therapies. It is frequently a slowly progressive disease that evolves over decades. The risk of a therapy must be less than the potential benefit. The JHU team is tackling the problem on two parallel tracks. In the first, the investigators seek to define the pathophysiology of the disease as a means of identifying steps for possible intervention. The second approach is aimed at determining the normal functions of the PKD proteins, seeking to identify ways that their activity may be replaced in disease tissue. We are pursuing these aims through the following NIH-, foundation- and private donor-sponsored projects:
1) Johns Hopkins is one of four NIH-sponsored PKD Centers of Excellence. The group includes eight faculty, a number of senior scientists, post-doctoral fellows, graduate students and technical staff. The group is focused primarily on understanding fundamental aspects of PKD biology, using a variety of simple model systems as a means of establishing the foundation for rational therapy.
2) Genotype-Phenotype Correlation: JHU investigators developed some of the first DNA tests for ADPKD and ARPKD. We are presently using these tests to define the molecular cause of disease in patients with disease of variable severity. This information may help us to determine why some individuals are more severely affected than others.
3) Engineer and manipulate mouse models of human PKD: The JHU team has used transgenic technologies to produce mice with disease very similar to that which affects humans (both ADPKD and ARPKD).
4) Identify PKD signaling pathways: Most PKD genes encode proteins that sit on the surface of cells and transmit information across the cell boundary into the cell interior. The cell uses this information to respond to its environment. In PKD, the cell is either unable to acquire this information because the sensor is defective, or is unable to respond properly to the signal. JHU researchers are seeking to define the types of information that PKD proteins sense and the pathways inside the cell that PKD proteins regulate.
Although we have made significant progress in the 9 years since the JHU team helped to discover the first human PKD gene, significant questions remain. We still do not know why some patients develop severe disease or aneurysms while family members with the same mutation do not. Are there other underlying genetic factors that determine the severity of disease or its rate of progression? Why do some mutations result in severe disease more frequently? How does loss of PKD proteins cause the vascular manifestations that are observed? How do dietary or lifestyle factors affect progression of disease? Do any of the experimental therapies used in other forms of mouse PKD work in the form that most commonly affects humans? Future NIH clinical studies propose to use changes in the amount of kidney tissue as a means of assessing response to therapy. Is this really a suitable surrogate marker for functional response?
1) Longitudinal Cohort Study:
Dr. Terry Watnick, Director of the JHU Hereditary Renal Disease Clinic, follows over 150 individuals with PKD from the Mid-Atlantic region. Working with investigators at the Johns Hopkins Welch Center, she developed a preliminary clinical database as a pilot project. She has now established collaborations with investigators at the University of Virginia (Charlottesville, VA), University of Richmond (VA), the Rogeson Institute at Cornell University (New York City), University of Sao Paulo (Brazil), University of Toronto, University of Santiago de Compostela Galeras (Spain) and Universite Catholique de Louvain (Brussels, Belgium). Their goal is to establish a data base that records relevant clinical information and PKD genotype, when available. The ultimate goal of the database is to identify groups of patients for clinical intervention trials.
2) Determine how PKD proteins help to preserve normal blood vessel structure and function:
The cardiovascular complications of PKD are an important cause of premature death and morbidity. Studies of patients with ADPKD and of mouse models of human ADPKD made at JHU show that PKD proteins are essential for normal blood vessels. Both humans and mice with PKD mutations develop hemorrhages. In pilot studies done by JHU nephrology faculty in collaboration with Dr. Hal Dietz of the Howard Hughes Institute at JHU, they have identified a signaling pathway that may be altered in ADPKD. The proposed studies aim to understand this process in the hope that future treatments may be directed at preventing these complications.
3) Develop methods for assessing progression of PKD in mouse forms of human PKD and then use them to assess response to therapies:
While our communal goal is to define therapies that are effective in humans, these studies are expensive, require many participants and take many years to complete. The large cost limits the number of different interventions that can be tested at any given time. The newly developed JHU mouse models are extremely powerful tools that can be used to test multiple novel interventions in a very cost effective and timely manner. They have the added advantage that a comprehensive analysis of mouse tissues can be performed to confirm that agents are acting in the manner that is predicted. JHU has a new, state-of-the-art mouse facility that will have a Mouse Phenotyping Core with veterinary pathologists, resources for hematology and clinical chemistry analyses, and an on-site imaging facility with a full line of imaging instrumentation to do mouse MRI, CT, SPECT, PET and even some optical imaging. JHU nephrologists propose to collaborate with other investigators at JHU who are experts in small animal imaging to identify the best methods for assessing disease progression using the least number of animals in the most time-effective manner. They will then use these methods to assess response to various interventions.
4) Determine how PKD mutations cause disease:
It is widely known that mutations of the DNA sequence of PKD genes result in disease, the mechanism by which this is occurs is poorly understood. Moreover, there are innumerable variants of PKD genes that are of unknown significance, severely limiting the utility of DNA testing in the management of PKD patients. The proposed studies seek to develop methods that can be used to assess the pathogenic properties of these variants and then determine how those, which in fact are disease-causing, do so.
5) Determine the function of the ARPKD protein (called polyductin):
JHU investigators led an international consortium of investigators that identified the gene responsible for causing ARPKD. The JHU team has recently developed animal and cell culture systems that can be used to model the human disease and the ARPKD protein’s function. Preliminary studies at JHU suggest that the protein is clipped from the cell surface where it is made and then activates adjacent cells. A piece of the ARPKD protein appears to be retained in the cell where it has regulatory properties. The proposed studies will seek to identify the function of each component, the signaling pathways by which each exerts its effects and the factors that regulate the release of the cleaved extra-cellular fragment. In parallel, JHU investigators are proposing to study mice engineered to have the human form of ARPKD to better determine the in vivo function of polyductin and to establish a foundation for intervention trials.
6) Identify novel Bardet-Biedl candidate genes.
JHU investigators in the Institute of Molecular Medicine have identified several genes that cause Bardet-Biedl when mutated. Genetic studies of humans suggest that there may be up to an additional 40 genes that can result in this disease when mutated. The small size of most families precludes the use of standard genetic approaches. In such situations, geneticists frequently turn to simple organisms such as the fruit fly or round worm for clues. A JHU nephrologist has developed a fruit fly with mutations of several of the known Bardet-Biedl genes and now proposes to use this simple system to identify the others. This information can be used to understand the function of this highly conserved system and to guide development of better mouse models by the other JHU team.
7) Establishment of a National PKD Reagent Core:
Many of the PKD genes and proteins are technically very difficult to analyze and manipulate. These technical difficulties have posed large hurdles to investigators and significantly slowed progress in the field. Moreover, many of the reagents in common use are incompletely characterized, thus yielding potentially incorrect results. JHU researchers have overcome many of these obstacles and are presently the only group that can easily manipulate and express all of the major PKD proteins. The JHU team also has carefully validated antibodies that can be used to track PKD proteins and a variety of novel mouse models that mimic human disease. The JHU team proposes to scale up production and development of these resources in a manner that will allow them to provide them to the community at large in a ready-to-use format. The Core proposes to develop a variety of methods that can be used to introduce PKD proteins into cells and animals. It also will develop a wide range of modified forms of the protein that can be used to test various functional elements. It seeks to continue to develop additional mouse models that can be used to define the pathophysiology of the disease, the function of PKD protein domains, and to identify novel therapies. Finally, the Core will work with other investigators to validate already available antibodies as well as generate and characterize new reagents that will then be freely shared with the community-at-large. It is envisaged that the JHU PKD Reagent Core will serve as the ultimate resource for both established PKD groups as well as other scientists with an interest in a question related to PKD biology but without the necessary infra-structure to answer it.
Polycystic Kidney Disease Publications from Johns Hopkins Nephrology:
1. Germino GG, Somlo S. A positional cloning approach to inherited renal disease. Sem Nephrol , 12:541-553, 1992
2. Germino GG, Somlo S. Inherited diseases of the kidney. Current Opinion in Nephrology and Hypertension: Renal Immunology and pathology, 2, May, 1993.
3. Somlo S, Germino GG. Adult Polycystic Kidney Disease. Chapter in Molecular Biology in Health and Disease, Schlondorff D, and Bonventre J, editors; pp. 821-838, 1995.
4. Germino GG. Progress in the cloning of ADPKD. Kidney Int, 47:729-730, 1995.
5. The American Polycystic Kidney Disease Consortium (APKD1): (Burn TJ, Connors TD, Dackowski WR, Petry LR, Van Raay TJ, Millholland JM, Venet M, Miller G, Hakim RH, Landes GM, Klinger KW, Qian F, Onuchic LF, Watnick T, Germino GG, Doggett N) The autosomal dominant polycystic kidney disease (PKD1) gene product contains a leucine-rich repeat. Hum Mol Genet, 4:575-582, 1995.
6. Harris P, Germino G, Klinger K, Landes G, Van Adelsberg J. The PKD1 gene product. Nature Medicine, 1:493, 1995.
7. Guay-Woodford LM, Muecher G, Hopkins SD, Avner ED, Germino GG, Guillot AP, Herrin J, Holloman R, Irons DA, Primack W, Thomson PD, Waldo FB, Lunt PW, Zerres K. The severe perinatal form of autosomal recessive polycystic kidney disease (ARPKD) maps to chromosome 6p21.1-p12: implications for genetic counseling. Am J Hum Genet, 5:1101-1107, 1995.
8. Germino, GG. Cloning Strategies and Genetics of Type 1 Autosomal Dominant Polycystic Kidney Disease. Chapter in Polycystic Kidney Disease, Watson M, Torres V, editors; Oxford University Press; pp. 356-390, 1996.
9. Qian F*, Watnick TJ*, Onuchic LF, Germino GG. The molecular basis of focal cyst formation in human autosomal dominant polycystic kidney disease type I. Cell, 87:979-987, 1996. (*Co-authors, listed alphabetically).
10. Van Raay TJ, Burn TC, Connors TD, Petry LR, Germino GG, Klinger KW, Landes GM. A 2.5kb polypyrimidine tract in the PKD1 gene contains at least 23 H-DNA forming sequences. Genome Sci Tech, 1:317-327, 1996.
11. APRKD Consortium: Lens XM, Onuchic LF, Daoust M, Bichet D, Germino GG (corresponding author), Wu G, Hayashi T, Mochizuki T Santarina LB, Somlo S, Guay-Woodford L, Zerres K, Mucher G, Becker J, Avner ED, Sweeny WE. An integrated genetic and physical map of the autosomal recessive polycystic kidney disease region. Genomics, 41:463-466, 1997.
12. Qian F, Germino FJ, Cai Y, Zhang X, Somlo S, Germino GG. PKD1 interacts with PKD2 through a probable coiled-coil domain. Nature Genetics, 16:179-183, 1997.
13. Ibraghimov-Beskrovnaya O, Dackowski WR, Foggensteiner L, Coleman N, Thiru S, Petrey LR, Burn TC, Connors TD, Van Raay T, Bradley J, Qian F, Onuchic LF, Watnick TJ, Piontek K, Hakim RM, Germino GG, Landes GM, Sandford R, Klinger KW. Polycystin: in vitro synthesis, in vivo tissue expression and subcellular localization identifies a large membrane-associated protein. Proc Natl Acad Sci, USA, 94:6397-6402, 1997
14. Watnick TJ, Piontek KB, Cordal TM, Weber H, Gandolph MA, Qian F, Lens XM, Neumann HPH, Germino GG. An unusual pattern of mutation in the replicated portion of PKD1 is revealed by use of a novel strategy for mutation detection. Hum Molec Genet, 6:1473-1481, 1997.
15. Watnick T, Germino GG. Genetic Mechanisms of Kidney Disease. Chapter in Diseases of the Kidney, Sixth Edition; Schrier RW, Gottschalk CW, editors; Little, Brown and Company, Boston; pp. 465-497, 1997.
16. Germino GG. Autosomal Dominant Polycystic Kidney Disease: A Two-Hit Model. Hospital Practice, 32:81-102, 1997.
17. Qian F, Germino GG. 'Mistakes Happen': Somatic mutation and disease. Am J Hum Genet, 61:1000-1005, 1997.
18. Mücher G, Becker J, Knapp M, Büttner R, Moser M, Rudnik-Schöneborn S, Somlo S, Germino GG, Onuchic L, Avner E, Guay-Woodford L, Zerres K. Fine mapping of the autosomal recessive polycystic kidney disease locus (PKHD1) and the genes MCM, RDS, CKII-?, GSTA1 at 6p21.1-p12. Genomics, 48:40-45, 1998.
19. Zerres K, Mücher G, Becker J, Seinkamm C, Rudnik-Schöneborn S, Heikkilä P, Rapola J, Salonen R, Germino GG, Onuchic L, Somlo S, Avner ED, Harman LA, Stockwin JM, Guay-Woodford LM. Prenatal diagnosis of autosomal recessive polycystic kidney disease (ARPKD): Molecular genetics, clinical experience and fetal morphology. Am J Med Genet, 76:137-144, 1998.
20. 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, type I. Molec Cell, 2:247-251, 1998.
21. Watnick TJ, Torres VE, Gandolph MA, Weber H, Neumann HPH, Germino GG. Gene conversion may be an important cause of mutation in PKD1. Hum Molec Genet, 7:1239-1243, 1998.
22. Germino GG, Onuchic LF. Polycystic Kidney Disease. Chapter in Textbook of Molecular Medicine, Jameson JL, editor; Blackwell Scientific Publications, Cambridge, pp. 675-683, 1998.
23. Piontek KB, Germino GG. Murine PKD1 Introns 21 and 22 lack the extreme polypyrimidine bias present in human PKD1. Mammalian Genome, 10:194-196, 1999.
24. Park JH, Dixit MP, Onuchic LF, Wu G, Gonchanuk AN, Kneitz S, Santarina LB, HayashT, Avner ED, Guay-Woodford L, Zerres K, Germino GG, Somlo S. A 1 Mb BAC/PAC-based physical map of the autosomal recessive polycystic kidney disease gene (PKHD1) region on chromosome 6. Genomics, 57:249-255, 1999.
25. Pei Y, Watnick T, He N, Wang K, Liang Y, Parfrey P, Germino G, St. George-Hyslop P. Somatic PKD2 mutations in individual kidney and liver cysts support a "two-hit" model of cystogenesis in type 2 autosomal dominant polycystic kidney disease. J Am Soc Nephrol, 10:1524-1529, 1999.
26. Reynolds DM, Hayashi T, Cai Y, Veldhuisen B, Watnick TJ, Lens XM, Mochizuki T, Qian F, Fossdal R, Coto E, Wu G, Breuning MH, Germino GG, Peters DJM, Somlo S. Abberant splicing in the PKD2 gene as a cause of polycystic kidney disease. J Am Soc Nephrol, 10:2342-2351, 1999.
27. Watnick T, Phakdeekitcharoen B, Johnson A, Gandolph M, Wang M, Briefel G, Klinger KW, Kimberling W, Gabow P, Germino GG. Mutation detection of PKD1 identifies a novel mutation common to three families with severe disease. Am J Hum Genet, 65:1561-1571, 1999.
28. Onuchic LF, Mrug M, Lakings AL, Muecher G, Becker J, Zerres K, Avner ED, Dixit M, Somlo S, Germino GG, Guay-Woodford, LM. Genomic organization of the KIAA0057 gene that encodes a TRAM-like protein and its exclusion as a polycystic kidney and hepatic disease 1 (PKHD1) candidate gene. Mammalian Genome, 10:1175-1178, 1999.
29. Watnick TJ, Germino GG. The molecular basis of autosomal dominant polycystic kidney disease. Semin Nephrol, 19:327-343, 1999
30. Hofmann Y, Becker J, Wright F, Avner E, Mrug M, Guay-Woodford L, Somlo S, Zerres K, Germino GG, Onuchic LF. Genomic structure of the gene for the human P1-protein (MCM3) and its exclusion as a candidate for autosomal recessive polycystic kidney disease. Euro J Hum Genet, 8:163-166, 2000.
31. Watnick T, He N, Wang K, Liang Y, Parfrey P, Hefferton D, St. George-Hyslop P, *Germino G, *Pei Y. Somatic mutations of PKD1 in ADPKD2 cystic tissue suggests a possible pathogenic effect of trans-heterozygous mutations. Nat Genet, 25:143-144, 2000. (* = Co-correspondents)
32. Phakdeekitcharoen B, Watnick TJ, Ahn C, Whang D-Y, Burkhard B, Germino GG. Thirteen novel mutations of the replicated region of PKD1 in an Asian population. Kid Inter, 58:1400-1412, 2000.
33. Boletta A, Qian F, Onuchic LF, Bhunia AK, Phakdeekitcharoen B, Hanaoka K, Guggino W, Monaco L, Germino GG. Polycystin-1, the gene product of PKD1, induces resistance to apoptosis and spontaneous tubulogenesis in MDCK cells. Molec Cell, 6:1267-1273, 2000.
34. Hanaoka K, Qian F, Boletta A, Bhunia A, Piontek K, Tsiokas L, Sukhatme VP, Germino GG, Guggino WB. Co-assembly of polycystin 1 and 2 produces unique cation permeable currents. Nature, 408:990-994, 2000.
35. Germino GG, Chapman A. Autosomal Dominant Polycystic Kidney Disease, in The Metabolic and Molecular Bases of Inherited Disease (8th edition), by Scriver CR, Beaudet AL, Sly WS, and Valle D, eds; McGraw Hill, 2000
36. Pei Y, Paterson AD, Wang KR, Ne N, Hefferton D, Watnick T, Germino G, Parfrey P, Somlo S, St. George-Hyslop P. Bilineal disease and trans-heterozygotes in autosomal dominant polycystic kidney disease. Am J Human Genet, 68:355-363, 2001.
37. Phakdeekitcharoen B, Watnick TJ, Germino GG. Mutation detection of entire duplicated part of PKD1 in genomic DNA sample. J Am Soc Nephrol, 12:955-963, 2001.
38. Kawaguchi M, Onuchic LF, Li X-D, Essayan DM, Schroeder J, Ziao H-Q, Liu MC, Germino G, Huang S-K. Identification of a novel ctokine, ML-1, and its expression in subjects with asthma. J Immunology, 167:4430, 2001.
39. Boletta A, Qian F, Onuchic LF, Bragonzi A, Cortese M, Courtoy PJ, Deen PM, Soria MR, Devuyst O, Monaco L, Germino GG. Biochemical characterization of bona fide polycystin-1 in vitro and in vivo. Am J Kid Dis, 38:1421-1429, 2001.
40. Watnick TJ, Germino GG. Introduction to Genetic Renal Disease, in Diseases of the Kidney (7th edition), by Schrier RW and Gottschalk CW, eds; Lippincott, Williams and Wilkins, 2001.
41. Chauvet V, Qian F, Boute N, Cai Y, Phakdeekitcharoen B, Onuchic LF, Attie-Bitach T, Guicharnaud L, Devuyst O, Germino GG, Gubler MC. Expression of PKD1 and PKD2 transcripts and proteins in human embryo and during normal kidney development. Am J Pathol, 160:973-983, 2002.
42. Bhunia AK, Piontek K, Boletta A, Liu L, Qian F, Xu P-N, Germino FJ, Germino GG. PKD1 induces p21waf1 and regulation of the cell cycle via direct activation of the JAK-STAT signaling pathway in a process requiring PKD2. Cell, 109:157-168, 2002.
43. Onuchic LF, Furu L, Nagasawa Y, Hou X, Eggermann T, Ren Z, Bergmann C, Senderck J, Esquivel E, Zeltner R, Rudnik-Schoneborn S, Mrug M, Sweeney W, Avner ED, Zerres K, Guay-Woodford LM, Somlo S, Germino GG. PKHD1, the polycystic kidney and hepatic disease 1 gene, encodes a novel large protein containing multiple immunoglobulin-like plexin-transcription-factor domains and parallel beta-helix 1 repeats. Am J Hum Genet, 70:1305-1317, 2002.
44. Onuchic LF, Mrug M, Hou X, Eggermann T, Bergmann C, Zerres K, Ellis D. Avner, Laszlo F, Somlo S, Nagasawa Y, Germino G, Guay-Woodford LM. Refinement of the autosomal recessive polycystic kidney disease (pkhd1) interval and exclusion of an ef hand-containing gene as pkhd1 candidate gene . Am J Genet, 110:346-352, 2002.
45. Nagasawa Y, Matthiesen S, Onuchic LF, Hou X, Bergmann C, Esquivel E, Senderek J, Ren Z, Zeltner R, Furu L, Avner E, Moser M, Somlo S, Guay-Woodford L, Büttner R, Zerres K, Germino GG. Identification and characterization of Pkhd1, the mouse orthologue of the human ARPKD gene. J Am Soc Nephrol, 13:2246-2258, 2002.
46. Qian F, Boletta A, Bhunia AK, Xu H, Liu L, Ahrabi AM, Watnick TJ, Zhou F, Germino GG. Cleavage of polycystin-1 requires the REJ domain and is disrupted by human ADPKD1-associated mutations. Proc Natl Acad Sci, USA, 99:16981-16986, 2002.
47. Bergmann C., Senderek J, Sedlacek B, Pegiazoglou I, Puglia P, Eggermann T, Rudnick-Schoneborn S, Furu L, Onuchic LF, de Baca M, Germino GG, Guay-Woodford L, Somlo S, Moser M, Buttner R, Zerres K. Spectrum of mutations in the gene for autosomal recessive polycystic kidney disease (ARPKD/PKHD1). J Am Soc Nephrol, 14:76-89, 2003.
48. Furu L, Onuchic LF, Gharavi A, Hou X, Esquivel E, Nagasawa Y, Bergmann C, Senderek J, Avner E, Zerres K, Germino GG, Guay-Woodford LM, Somlo S. Milder presentation of recessive polycystic kidney disease requires presence of amino acid substitution mutations. J Am Soc Nephrol, 14:2004-3014, 2003
49. Sutters M, Germino G. Autosomal dominant polycystic kidney disease: molecular genetics and pathophysiology. J Lab Clin Med, 141:91-101, 2003.
50. Watnick T, Germino GG. From cilia to cyst. Nature Genet 34:355-356, 2003.
51. Boletta A, Germino GG. Role of polycystins in renal tubulogenesis. Trends Cell Biol. 13:484-92, 2003.