Nephrology Hypertension

Hereditary Renal Cystic Diseases: Autosomal Dominant Polycystic Kidney Disease

Does this patient have autosomal dominant polycystic disease?

Autosomal dominant polycystic kidney disease (ADPKD) is a systemic disease characterized by cyst formation in the kidneys and liver, resulting in progressive renal enlargement, progressive renal insufficiency and ultimately renal failure usually in the 6th decade of life. ADPKD is relatively common occurring in 1:700-1:1000 individuals.

ADPKD is a dominantly inherited disorder that does not skip a generation (Figure 1) and every offspring of an affected individual has a 50% chance of inheriting the gene.

Figure 1.

Pedigree of a family affected with autosomal dominant polycystic kidney disease.

PKD1, one of the genes responsible for ADPKD, was identified in 1994 on the short arm of chromosome 16 next to the TSC2 gene in a Portuguese family with both autosomal dominant polycystic kidney disease (ADPKD) and tuberous sclerosis complex (TSC). A second ADPKD gene, PKD2, was subsequently identified in the long arm of chromosome 4 in 1996. A third or possibly more gene loci may cause ADPKD but have not been identified.

The resulting disease phenotypes are very similar in PKD1 and PKD2 patients, except that patients with PKD2 mutations have milder symptoms (age of onset of hypertension is 10 years later, mean age of onset of end-stage renal disease (ESRD) is 74 vs. 55, and life expectancy is greater in PKD2 individuals by approximately 10 years).

Patients with ADPKD may live asymptomatically for many years. The most common renal symptoms that occur in ADPKD patients include pain, hypertension, gross hematuria, kidney stones and urinary tract infections. Patients describe thirst, urinary frequency, nocturia and abdominal pain as their most significant concerns.

Patients may also experience symptoms due to extra-renal involvement that include the liver and pancreas, cardiac valvular disease, intracranial aneurysms and diverticulosis as well as infertility related to seminal vesical cysts. ADPKD patients who progress to ESRD require kidney transplant or either peritoneal or hemodialysis.

ADPKD is generally a clinically late-onset hereditary systemic disorder characterized by significant renal and liver enlargement due to cyst growth and expansion. Physical findings include increased blood pressure on average by 30 years of age, including 20% of affected children, increased abdominal girth, and ventral and inguinal hernias and auscultory abnormalities related to cardiac valve diseases such as mitral valve prolapse and aortic insufficiency.

Multiple cysts found in the kidney may due to inherited or acquired circumstances. Among the inherited renal cystic diseases, ADPKD, tuberous sclerosis complex (TSC), medullary cystic kidney disease (MCKD) and Von Hippel-Lindau disease (VHL) are passed down in autosomal dominant manner; autosomal recessive diseases, including autosomal recessive polycystic kidney disease (ARPKD) and familial juvenile nephronopthisis (FJN), are less common and present in a single generation of affected individuals. Acquired cystic kidney disease (ACKD) is the most common non-hereditary cystic disease, usually occurring in patients (either adults or children) with long term renal insufficiency, especially dialysis patients.

Renal cysts are a manifestation of many systemic diseases. For example, the coexistence of renal cysts and angiomyolipomas is characteristic for tuberous sclerosis complex (TSC). VHL is a retinal and/or central nervous system disease. Its renal cysts are usually associated with multiple solid tumors. However, when those tumors are absent, the VHL kidney may appear similar to mild or early ADPKD.

Approximately 15% of ADPKD patients do not have a positive family history for the disorder. In these individuals, ultrasonographic screening of the parents if possible is recommended. In some individuals, this could be a mild disease where the affected parent is asymptomatic. For those where parents have been screened and are negative, ADPKD most likely resulted from a spontaneous mutation.

Isolated polycystic liver disease (PCLD) is an inherited autosomal dominant liver disease, in the absence of renal cysts. In cases of PCLD without renal involvement, the disease presents liver enlargement due to fluid-filled cysts derived from the biliary system. Mutations in the gene PRKCSH on chromosome 19 or the gene SEC63 on chromosome 6 have been identified as two genetic causes of ADPLD.

What tests to perform?

Urinalysis

ADPKD urine sample is usually bland, not significant for proteinuria or hematuria. Very low amounts of protein may be present on urine dipstick. Only 25% of adults and 32% of children have dipstick detectable proteinuria. Hematuria is atypical in ADPKD and when present it suggests hemorrhagic cyst, infection, uroepithelial lesion, or possible kidney stone. Further investigation, including imaging utilizing ultrasound or computed tomography (CT) may be necessary.

Twenty-four hour urine collections provides helpful information regarding protein intake by measuring urea excretion. Quantification of urinary protein excretion can also be established. Dietary constituents including sodium and potassium can be assessed.

Plasma or serum analyses

Complete blood count (CBC) diff platelets and comprehensive chemistry panels with phosphorus provide all biochemical information, such as electrolytes, creatinine, phosphate, and parathyroid hormone levels. Vit D 25 and Vit D 1,25 are also indicated for those with advanced renal insufficiency (chronic kidney disease [CKD] Stage 3 or 4). All patients with underlying renal disease will need a lipid panel since they are at higher risk for cardiovascular disease.

Ultrasound

The diagnosis of ADPKD is established primarily with ultrasound images of the kidneys. The presence of different numbers of renal cysts based on the age of the patient, along with the presence of enlarged kidneys is unique to ADPKD. Both magnetic resonance imaging (MRI) (Figure 2) and CT (Figure 3) images can be used in ADPKD in the case of complications, such as pain, bleeding and infection. However, they are not used for diagnostic purposes

Figure 2.

Coronal T2-weighted, single-shot fast spin echo magnetic resonance images from patients with ADPKD. (From Harris et al, JASN 17:3013-3019, 2006, with permission.)

Figure 3.

Kidney with simple and complex cyst. Contrast material-enhanced-CT scan shows a poorly enhancing solid lesion (arrowhead) on the posterior aspect of the right kidney and a small simple cyst (long arrow) anteriorly. The large cystic mass (thick arrow) on the posterolateral surface of the left kidney has a thick wall and numberous septa and is therefore considered indeterminate. Fluid in the cystic compartment of the lesion remained at water density.n (From Marotti et al, Radiology 162:679-684, 1987, with permission.)

Mutation screening

Mutation screening using direct sequencing of the PKD1 or PKD2 genes is commercially available. Direct sequencing is the most accurate and reliable method but is expensive. Since the mutations are often unique to each family, less expensive exon-specific sequencing is available after one family member’s mutations are identified. Current mutation detection rate is 85% for the PKD1 gene and 95% for the PKD2 gene. Genetic testing remains as an essential tool for pre-symptomatic screening for young individuals or potential kidney donors.

Molecular testing

Molecular testing for prenatal diagnosis or pre-implantation diagnosis is also available for families whose members have an established mutation. From most mutation screening programs, the mutations described are scattered and are unique. Most mutations in either gene are single base changes or insertions or deletions of a small number of base pairs, resulting in truncated proteins and loss of protein function. Patients with mutations in the 5’ region have slightly more severe and more vascular disease than the 3’ region.

ADPKD has large phenotypic variability among affected individuals, attributable to PKD genetic and allelic variability and, possibly, modifier gene effects. Genetic effects are attributed to the PKD gene involved. As noted, PKD1 mutations are associated with more severe disease and earlier onset. PKD1 patient also have an earlier incidence of hypertension. Gender differences have been observed in PKD2 patients: men with PKD2 mutations progress to ESRD faster than women. No such difference is demonstrable for PKD1 patients.

The impact of allelic heterogeneity on the severity of ADPKD is less known. No clear correlation has been demonstrated between severity of disease phenotype and the position of the mutation in PKD2, or within the mutation type in either PKD gene. High levels of allelic heterogeneity exists for PKD 1 and 2 genes, mutations are usually highly variable and spread throughout the entire gene. Analysis of the phenotypic variability in renal function between monozygotic twins and sibs supports a role for both environmental and genetic modifiers.

The ADPKD Mutation Database at Mayo Clinic (http://www.pkdb.mayo.edu), the most complete mutation database for the disease, currently classifies ADPKD genetic variations into 12 categories: frameshift, nonsense, splice-site substitutions, IVS (intervening sequence) variations, silent changes, silent 3’ untranslated changes, synonymous changes, and rearrangements (deletions and duplications). PKD1 gene is significantly more polymorphic compared to PKD2.

Over all, an ADPKD diagnosis is mainly based on a family history and abdominal ultrasound screening. Genetic testing remains an essential tool for presymptomatic diagnosis in young individuals or potential kidney donors but its accuracy is approximately 88% by sequence analysis for both PKD1 and PKD2 mutations. Molecular testing for prenatal diagnosis or preimplantation diagnosis is also available for families whose members are on risk of severe, early-onset mutations.

How should patients with ADPKD be managed?

Despite significant advances in the understanding of the genetics of ADPKD and the mechanism of cyst growth, no treatment specifically directed toward the disease is yet available. Current treatments focus on slowing the disease progression and reducing symptoms.

For example, poorly controlled hypertension accelerates the decline in renal function. Activation of the renin-angiotensin-aldosterone system (RAAS) in ADPKD has been confirmed by elevated plasma rennin activity and aldosterone in patients. Administration of an angiotensin converting enzyme (ACE) inhibitor to ADPKD patients resulted in a significantly greater decrease in renal vascular resistance and increase in renal plasma flow than in control group. Current recommendations for target blood pressure level and the initial drug of choice for ADPKD are based on the Seventh Joint National Committee (JNC7) recommendations for all patients with chronic kidney disease, targeting blood pressure below 130/80 mm Hg using ACE inhibitors or angiotensin receptor blockers (ARBs).

Studies of Vasopressin V2 receptor antagonists in a rat/murine model and human subjects show that they successfully slows renal cyst growth by inhibition of the V2 receptor, potentially reducing intracellular cAMP levels, resulting in decreased water reabsorption and urinary osmolality. A large quantity of fluid intake mimics the inhibition condition and may be eventually beneficial.

The best way to address sodium and phosphate is control dietary sodium and protein intake. Sometimes patients need dietary counseling. Closer lipid monitoring with regard to cholesterol level is also beneficial. Acidosis can be corrected by giving bicarbonate. Parathyroid hormone needs to be brought under control, otherwise the patient will have fragile bone and calcium deposits in their vessels.

Significant extrarenal manifestations, such as polycystic liver and intracranial aneurysm, may present in some ADPKD patients. Most polycystic liver patients are asymptomatic and require no treatment. In symptomatic individuals, therapy is directed toward reducing cyst volume and hepatic size. Options include percutaneous cyst aspiration and sclerosis, laparoscopic fenestration, or open surgical fenestration.

Procedures used to deal with intracranial aneurysms vary by the size. Intracranial aneurysm (ICA) cluster in ADPKD families and occur in 10% of individuals with a family history of an non-ruptured ICA and 20% of individuals with a family history of a ruptured ICA. Screening for the presence of ICA is recommended for those with an affected family member.

Asymptomatic aneurysms measuring less than 5mm in diameter can be observed and followed at regular intervals (typically every 3 years). Any unruptured intracranial aneurysms larger than 10mm are at high risk for rupture and should be subject to surgical clipping at its neck or coiling if possible.

What happens to patients with ADPKD?

Kidney enlargement is a universal feature of ADPKD. Significant progression of cyst growth and kidney enlargement precedes the loss of kidney function in ADPKD. The multicenter study using magnetic resonance imaging (MRI) following ADPKD progression--the Consortium for Radiological Imaging in the study of Polycystic Kidney Disease (CRISP)--reported total kidney volume is a strong predictor of future decline in GFR to CKD Stage 3. PKD1 patients demonstrated significantly larger kidney volumes, but with a similar rate of kidney growth between PKD1 and PKD2 (PKD1 5.68%/yr; PKD2 4.82%/yr). More cysts were detected in age matched PKD1 kidneys vs PKD2 kidneys, accounting for the differences seen in total kidney volumes seen.

The overall prevalence of hepatic cysts In the CRISP population was 83% (85% female and 79% males). Hepatic cysts increased in size and frequency with age; for instance, over 94% of patients 35 years and older demonstrating involvement. Importantly, hepatic cyst volume was significantly greater in women vs. men.

ESRD occurs in 50% of ADPKD patients between the ages of 57-73, depending on the clinical series. Risk factors for progression to renal failure include total kidney volume, PKD1 genotype, male gender, diagnosis of ADPKD before age 30, hematuria episodes before age 30, and hypertension onset before age 35. Hyperlipidemia, low renal blood flow, low HDL and increased sodium intake are associated with increased total kidney volume that may result in progressive renal insufficiency.

Fertility rates in ADPKD patients not on dialysis are similar to the general population. Hypertensive ADPKD women have a higher incidence of worsening hypertension and preeclampsia during pregnancy and higher rate of premature delivery; while the normotensive woman’s outcome is similar to the general population.

The protein products of the PKD1 and PKD2 genes are called polycystin-1 and polycystin-2. Polycystin-1 is a membrane-associated glycoprotein with 11 transmembrane domains. The protein is believed to function as a signal receptor. Polycystin-2 is an integral membrane glycoprotein with six transmembrane domains. Polycystin-2 belongs to the family of voltage-activated calcium channels and is involved in intracellular calcium regulation. The intracellular tail of polycystin-1 interacts with the C-terminal cytoplasmic tail of polycystin-2 and they work as a functional unit.

Mutations in polycystin-1&2 result in changes in intracellular calcium levels as well as increases in the level of cAMP. A change in the balance of these two critical intracellular components lead to alterations in the RAS (Ras subfamily of small GTPases) pathway, the mTOR (mammalian target of rapamycin) pathway, cell turnover, apoptosis, and fluid secretion through the CFTR (cystic fibrosis transmembrane conductance regulator) channel.

A randomized, controlled trial involving at least 142 hypertensive patients with ADPKD showed that ACE inhibitors were associated with slowing in the rate of decline in renal function and urinary protein reduction in those with proteinuria. A prospective, randomized, 3 year study demonstrated a significantly greater decline in creatinine clearance and increase in proteinuria in the amlodipine (calcium channel blocker) group compared with the candesartan (angiotensin II receptor antagonists) group.

Blocking the vasopressin V2 receptor would reduce intracellular cAMP accumulation. Animal models demonstrated V2-specific vasopressin receptor antagonists delay disease progression. Several phases II and III clinic trials testing tolvaptan on ADPKD patients with intact kidney function have been completed. The trials are designed to evaluate the long-term effectiveness and safety of tolvaptan by monitoring total kidney volume and cyst volumes by MRI and measuring a composite of clinical markers in ADPKD patients. Importantly, reduction in rate of cyst growth by more than 50% was found in the tolvaptan treated group with a slower rate of decline in kidney function. Side effects related to increased urine output including polyuria and polydipsia were found in the tolvaptan treated participants and a slight increase in prevalence of increased liver transaminases were found.

How to utilize team care?

Specialty consultations

Genetic counseling: During the diagnosis procedure, a geneticist should explain to the family: linkage analysis of the disease which would require participation of other family members with and without the disease.

Direct sequencing and mutation analysis is more accurate in PKD2 families than families with PKD1 mutations.

If ADPKD is diagnosed, the patient should receive counseling on family planning, understand the genetic risk for inheritance of an autosomal dominant disorder, and start to receive treatment if necessary. The patient should be told that each child of an affected person has a 50% chance of inheriting the disease gene. Each at-risk family member should be informed of the methods of diagnosis and of the availability of prenatal diagnosis. However, before a diagnostic test is performed, every subject also needs to be informed about the consequences of diagnostic screening, particularly regarding insurability, to permit informed judgment.

Nurses

Nurses should help with performing blood pressure checking, remind patient to take the right dose of medication, and assist physician-patient communication. Home blood pressure monitoring is an important feature of management/administration of required subcutaneous and intravenous medications such as erythropoietin will be supported by nurses.

Pharmacists

Conservative therapies known to slow the progression of kidney disease and those appropriate to treat the attendant manifestations of reduced kidney function (including hypertension, anemia, acidosis, and hyperparathyroidism) remain the standard of care. In case of growth retardation, appropriate methods should be employed.

Dietitians

Dietitians should help individuals with ADPKD understand the role of renal diet in helping to preserve kidney function, reducing the amount of phosphate, protein, sodium and acid in the diet.

Therapists (physical, occupational, speech, other)

Patients whose condition progresses to ESRD require renal replacement therapy and will need their nephrologists and transplant team to cooperates well for a successful transplant.

A physical therapist may be involved in post-surgery care.

Other considerations

  • MIM codes:#173900-POLYCYSTIC KIDNEY DISEASE 1; PKD1: #613095-POLYCYSTIC KIDNEYDISEASE 2; PKD2

ADPKD usually doesn’t require hospitalization, unless emergency dialysis.

Additional:

Athena Diagnostics, Inc. (APDKD1&2 gene direct sequencing available)

http://www.athenadiagnostics.com/content/index.jsp

Polycystic Kidney Disease Foundation

Internet: www.pkdcure.org

American Association of Kidney Patients

Internet: www.aakp.org

National Kidney Foundation

Internet: www.kidney.org

What is the evidence?

"The polycystic kidney disease 1 gene encodes a 14 kb transcript and lies within a duplicated region on chromosome 16". Cell. vol. 77. 1994. pp. 881-894.

(Authors presented the process (history) of search for PKD1 gene, and emphasized the importance to search PKD1 protein (later polycystin1) and the pathophysiology of ADPKD.)

Kandt, RS, Haines, JL, Smith, M, Northrup, H, Gardner, RJM, Short, MP, Dumars, K, Roach, ES, Steingold, S, Wall, S, Blanton, SH, Flodman, P, Kwiatkowski, DJ, Jewell, A, Weber, JL, Roses, A D, Pericak-Vance, M A. "Linkage of an important gene locus for tuberous sclerosis to a chromosome 16 marker for polycystic kidney disease". Nature Genetics. vol. 2. pp. 37-41.

(An earlier linkage study revealed PKD1 and TSC2 gene locus.)

Iglesias, CG, Torres, VE, Offord, KP, Holley, KE, Beard, CM, Kurland, LT. "Epidemiology of adult polycystic kidney disease, Olmsted County, Minnesota: 1935-1980". Am J Kidney Dis. vol. 2. 1983. pp. 630-639.

(A retrospective area Cohort on ADPKD.)

Harris, PC, Torres, VE. "Polycystic kidney disease". Annu Rev Med. vol. 60. 2009. pp. 321-337.

(The Mayo review on both major polycystic kidney diseases)

Gabow, PA, Gardner, KD. "Autosomal dominant polycystic kidney disease". The Cystic Kidney. Kluwer. 1990. pp. 295-326.

(A early description on ADPKD before locate both PKD genes.)

Ecder, T, Fick-Brosnahan, GM, Schrier, RW, Schrier, RW. "Polycystic Kidney disease". Diseases of the kidney & urinary tract. Wolters Kluwer Health/Lippincott Williams & Wilkins. 2007. pp. 502-540.

(A textbook chapter covering polycystic kidney diseases.)

O’Sullivan, DA, Torres, B, Johnson, RJ, Feehally, J. "Autosomal dominant polycystic kidney disease". Comprehensive Clinical Nephrology. Harcourt. 2000. pp. 9.49.1-9.49.12.

(A chapter specific on ADPKD in a textbook.)

Li, A, Davila, S, Furu, L, Qian, Q, Tian, X, Kamath, P, King, B, Torres, V, Somlo, S. "Mutations in PRKCSH Cause Isolated Autosomal Dominant Polycystic Liver Disease". Am J Hum Genet. vol. 72. 2003. pp. 691-703.

(Authors analyzed and concluded mutations in PRKCSH lead to ADPLD, and hypothesize on the possible mechanism.)

Reynolds, DM, Falk, CT, Li, A, King, BF, Kamath, PS, Huston, J, Shub, C, Iglesias, DM, Martin, RS, Pirson, Y, Torres, VE, Somlo, S. "Identification of a locus for autosomal dominant polycystic liver disease, on chromosome 19p13.2-13.1". Am J Hum Genet. vol. 67. 2000. pp. 1598-1604.

(Authors ascertained two large families with polycystic liver disease without renal involvement (cysts) and reported a genomewide scan for genetic linkage.)

Davila, S, Furu, L, Gharavi, A, Tian, X, Onoe, T, Qian, Q, Li, A, Cai, Y, Kamath, PS, King, BF, Azurmendi, PJ, Tahvanainen, P, Kääriäinen, H, Höckerstedt, K, Devuyst, O, Pirson, Y, Martin, RS, Lifton, RP, Tahvanainen, E, Torres, VE, Somlo, S. "Mutations in SEC63 Cause Autosomal Dominant Polycystic Liver Disease". Nature Genetics. vol. 36. 2004. pp. 575-577.

(In addition to identified genes, evidence suggests co-translational protein-processing pathways play a role in maintaining epithelial luminal structure and implicate non-cilial ER proteins in human polycystic disease.)

Pei, Y, Obaji, J, Dupuis, A, Paterson, AD, Magistroni, R, Dicks, E, Parfrey, P, Cramer, B, Coto, E, Torra, R, San Millan, JL, Gibson, R, Breuning, M, Peters, D, Ravine, D. "Unified criteria for ultrasonographic diagnosis of ADPKD". J Am Soc Nephrol. vol. 20. 2009. pp. 205-12.

(After the initial Ravine criteria published in 1994, authors unify the ultrasound criteria for PKD1 and PKD2 subtypes)

Vicente, E, Torres, M.D., Arlene, B, Chapman, M.D., Olivier Devuyst, M.D., Ron, T, Gansevoort, M.D., Jared, J, Grantham, M.D., Eiji Higashihara, M.D., Ronald, D, Perrone, M.D., Holly, B, Krasa, M.S., John Ouyang, Frank, S, Czerwiec, M.D.. "Tolvaptan in Patients with Autosomal Dominant Polycystic Kidney Disease". New England Journal of Medicine. vol. 367. Dec 2012. pp. 2407-2418.

(The latest report on Tolvaptan research in patients with sutosomal dominant polycystic kidney disease.)

Wolyniec, W, Jankowska, MM, Krol, E, Czarniak, P, Rutkowski, B. "Current diagnostic evaluation of autosomal dominant polycystic kidney disease". Polskie Archiwum Medycyny Wewnetrznej. vol. 118. 2003. pp. 767-773.

(A Polish review of diagnosis and monitoring of ADPKD at early and later stage of the disease.)

Chapman, AB, Greenberg, A. "Polycystic and other cystic kidney disease". Primer on Kidney Disease. Saunders. 2009. pp. 345-353.

(A textbook chapter introducing cystic kidney disease.)

Sweeney, WE, Avner, ED. "Diagnosis and management in childhood polycystic kidney disease". Pediatr Nephrol. vol. 26. 2011. pp. 675-692.

(A review of ADPKD and ARPKD diagnosis and developing therapies in childhood polycystic kidney disease care.)

Marotti, M, Hricak, H, Fritzsche, P, Crooks, LE, Hedgcock, MW, Tanagho, EA. "Complex and simple renal cysts: Comparative evaluation with MR imaging". Radiology. vol. 162. 1987. pp. 679-684.

(An early publication on distinguishing simple and complex renal cysts by using MRI.)

Harris, PC, Bae, KT, Rossetti, S, Torres, VE, Grantham, JJ, Chapman, AB, Guay-Woodford, LM, King, BF, Wetzel, LH, Baumgarten, DA, Kenney, PJ, Consugar, M, Klahr, S, Bennett, WM, Meyers, CM, Zhang, Q, Thompson, PA, Zhu, F, Miller, JP. "Cyst number but not the rate of cystic growth is associated with the mutated gene in autosomal dominant polycystic kidney disease". JASN. vol. 17. 2006. pp. 3013-3019.

(The source of MRI image)

Nicolau, C, Torra, R, Badenas, C, Vilana, R, Bianchi, L, Gilabert, R, Darnell, A, Bru, C. "Autosomal dominant polycystic kidney disease types 1 and 2: assessment of US sensitivity for diagnosis". Radiology. vol. 213. 1999. pp. 273-276.

(Authors recommend ultrasound as the first-line imaging technique to diagnose ADPKD.)

Tan, YC, Blumenfeld, J, Rennert, H. "Autosomal dominant polycystic kidney disease: Genetics, mutations and microRNAs". Biochimica et Biophysica Acta. vol. 1812. 2011. pp. 1202-1212.

(Up-to-date review of genetic and molecular information on ADPKD.)

Igarashi, P, Somlo, S. "Genetics and pathogenesis of polycystic kidney disease". J Am Soc Nephrol. vol. 2. 2002. pp. 2384.

(A comprehensive review of genetic and pathological aspects of PKD and related mouse models.)

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. vol. 13. 2002. pp. 1230-1237.

(A study of the correlation between the position of the PKD1 mutation and the early onset of ESRD.)

Rossetti, S, Chauveau, D, Kubly, V, Slezak, JM, aggar-Malik, AK, Pei, Y, Ong, AC, Stewart, F, Watson, ML, Bergstralh, EJ, Winearls, CG, Torres, VE, Harris, PC. "Association of mutation position in polycystic kidney disease 1 (PKD1) gene and development of a vascular phenotype". Lancet. vol. 361. 2003. pp. 2196-2201.

(A study of the correlation between PKD genes and its extrarenal vascular phenotype)

Harris, PC, Bae, KT, Rossetti, S, Torres, VE, Grantham, JJ, Chapman, AB, Guay-Woodford, LM, King, BF, Wetzel, LH, Baumgarten, DA, Kenney, PJ, Consugar, M, Klahr, S, Bennett, WM, Meyers, CM, Zhang, Q, Thompson, PA, Zhu, F, Miller, JP. "Cyst number but not the rate of cystic growth is associated with the mutated gene in autosomal dominant polycystic kidney disease". JASN. vol. 17. 2006. pp. 3013-3019.

(A profound finding of CRISP study: PKD1 is more severe because more cysts develop earlier, not because they grow faster in comparison with PKD2.)

Hateboer, N, v 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. European PKD1-PKD2 Study Group". Lancet. vol. 353. 1999. pp. 103-107.

(The first publication defining the clinic expression and survival rate in PKD1 and PKD2 diseases.)

Peral, B, Gamble, V, San Millan, JL, Strong, C, Sloane-Stanley, J, Moreno, F, Harris, PC. "Splicing mutations of the polycystic kidney disease 1 (PKD1) gene induced by intronic deletion". Hum Mol Genet. vol. 4. 1995. pp. 569-574.

(Authors presented deletion in intro result in aberrant splicing in PKD1 gene.)

Persu, A, Duyme, M, Pirson, Y, Lens, XM, Messiaen, T, Breuning, MH, Chauveau, D, Levy, M, Grunfeld, JP, Devuyst, O. "Comparison between siblings and twins supports a role for modifier genes in ADPKD". vol. 66. 2004. pp. 2132-2136.

(Authors examined variations among PKD affected siblings vs. monozygotic twins and suggest that modifier genes account for the variability.)

Chapman, AB, Johnson, A, Gabow, PA, Schrier, RW. "The renin-angiotensin-aldosterone system and autosomal dominant polycystic kidney disease". N Engl J Med. vol. 323. 1990. pp. 1091.

(Authors presented renin-angiotensin-aldosterone system is stimulated significantly more in hypertensive patients with PKD and hypothesized that the increased renin release may contribute to the early development of hypertension in PKD.)

Torres, VE, Wilson, DM, Burnett, JC, Johnson, CM, Offord, KP. "Effect of inhibition of converting enzyme on renal hemodynamics and sodium management in polycystic kidney disease". Mayo Clin Proc. vol. 66. 1991. pp. 1010.

(Author studied renal hemodynamics and concluded the renal renin-angiotensin system plays a central role in the alterations in renal hemodynamics and sodium management associated with the development of hypertension in ADPKD.)

Watson, ML, Macnicol, AM, Allan, PL, Wright, AF. "Effects of angiotensin converting enzyme inhibition in adult polycystic kidney disease". Kidney Int. vol. 41. 1992. pp. 206.

(A study of renal and systemic hemodynamic response to lisinopril: an ACE inhibitor.)

Zeier, M, Fehrenbach, P, Geberth, S, Möhring, K, Waldherr, R, Ritz, E. "Renal histology in polycystic kidney disease with incipient and advanced renal failure". Kidney Int. vol. 42. 1992. pp. 1259-1265.

(A series of pathological comparisons of earlier and later stages of ADPKD)

Gabow, PA, Watson, ML, Torres, VE. "Definition and natural history of autosomal dominant polycystic kidney Disease". Polycystic kidney disease. Oxford University Press. 1996. pp. 333-355.

(A comprehensive chapter on ADPKD.)

Higashihara, E, Torres, VE, Chapman, AB, Grantham, JJ, Bae, K, Watnick, TJ, Horie, S, Nutahara, K, Ouyang, J, Krasa, HB, Czerwiec, FS. "Tolvaptan in Autosomal Dominant Polycystic Kidney Disease: Three Years’ Experience". Clin J Am Soc Nephrol. vol. 6. 2011. pp. 2499-2507.

(Total kidney volume and eGFR analysis for the three year tolvaptan study in ADPKD.)

Golin, CO, Johnson, AM, Fick, G, Gabow, PA. "Insurance for autosomal dominant polycystic kidney disease patients prior to end-stage renal disease". Am J Kidney Dis. vol. 27. 1996. pp. 220-223.

(Authors investigate the health insurance and life insurance issue facing ADPKD patients.)
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