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 a spectrum of extrarenal manifestations with variable penetrance. Cyst growth and expansion occurs throughout the patient’s lifetime, resulting in progressive renal enlargement, renal insufficiency and ultimately renal failure usually in the 6th decade of life. ADPKD is one of the most common genetic diseases in humans, 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. Mutations in PKD1 and PKD2 are causative in about 85% and 15% of cases of ADPKD, respectively. In very few cases, no mutation can be found on the PKD1 or PKD2 locus. A third gene locus causing autosomal dominant polycystic kidney (and liver) disease was recently identified, and involves the GANAB gene, encoding the ER-resident glucosidase II, subunit α. Other loci remain unknown, but contribute very little to the global prevalence of ADPKD.

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

Small renal cysts exist from early stages of fetal development on, but continue to grow throughout a lifetime. Small cysts are unlikely to cause symptoms, and patients with ADPKD may live asymptomatically for many years. The most common renal symptoms that occur in ADPKD patients include hypertension, pain, gross hematuria, kidney stones and urinary tract infections. Pain can be acute, from cyst rupture, hemorrhage or infection, or chronic, from the mass effect of very large cystic kidneys. Patients describe increased abdominal girth, abdominal fullness, early satiety, nausea and back pain. In later stages, thirst, urinary frequency, nocturia and abdominal pain are the most significant concerns.

Patients may also experience symptoms from extrarenal manifestations that include intracranial aneurysms, cystic disease of liver and pancreas, cardiac valvular disease (most commonly mitral valve prolapse), colonic diverticulosis, as well as infertility, related to seminal vesical cysts. ADPKD patients who progress to ESRD require kidney transplant or either peritoneal or hemodialysis.

On physical exam, characteristic findings include increased blood pressure on average by 30 years of age, including 20% of affected children, palpable kidneys, increased abdominal girth, ventral and inguinal hernias, and auscultatory abnormalities related to cardiac valve diseases such as mitral valve prolapse or aortic insufficiency.

Multiple cysts found in the kidney may due to inherited or acquired circumstances. Among the inherited renal cystic diseases, ADPKD, HNF-1β related kidney disease, 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 syndromatic diseases. For example, the coexistence of renal cysts and angiomyolipomas is characteristic for tuberous sclerosis complex (TSC). VHL is primarily a tumor syndrome involving retina, cerebellum, adrenal glands, kidneys and other organs. Its renal cysts are not necessarily associated with coexisting clear cell carcinomas. When other tumors are absent, the VHL kidney may appear similar to mild or early ADPKD. Mutations in the HNF-1β gene manifest in a multitude of different phenotypes, that may or may not involve maturity-onset diabetes of the young (MODY-5), hepatic and pancreatic abnormalities, autism, CAKUT-spectrum abnormalities and polycystic kidneys, sometimes identical with PKD1/2 mutations.

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 may have resulted from parental mosaicism, spontaneous de-novo mutation or uncertain biological paternity.

Isolated polycystic liver disease (PCLD) is an inherited autosomal dominant liver disease. 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 genes PRKCSH, SEC63 and LRP5 have been identified as genetic causes of ADPLD. Mutations in the recently identified GANAB gene that are causative in rare PKD1-negative, PKD2-negative ADPKD, give rise to polycystic liver phenotypes as well, emphasizing that ADPKD and PCLD represent one spectrum of diseases with significant genotypic and phenotypic overlap. Interestingly, PRKCSH and GANAB encode for two different (α-, β-) subunits of the same enzyme, glucosidase-II. Along with the SEC63 gene product, they play a biological role along the same ER-secretory pathway.

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 provide 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), platelets and comprehensive chemistry panels with phosphorus provide all biochemical information, such as electrolytes, creatinine, phosphate, and parathyroid hormone levels. 25(OH)-Vitamin D and 1,25(OH)2-Vitamin D 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. MRI-based determination of total kidney volume (TKV) is becoming a more and more important biomarker for the stage of ADPKD and the rate of progression. Although prognostic estimations can be made very reliably based on TKV, this is not (yet) the standard of care, and is mostly used as a research biomarker in clinical trials.

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. (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 a large phenotypic variability among affected individuals, attributable to PKD genetic and allelic variability, modifier gene effects and environmental effects. Genetic effects are attributed to the PKD gene involved. As noted, PKD1 mutations are associated with more severe disease and earlier onset. PKD1 patients 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 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.

Overall, an ADPKD diagnosis is mainly based on a family history and renal ultrasound screening. Genetic testing remains an essential tool for presymptomatic diagnosis in young individuals or potential kidney donors.

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.

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).

Results of the HALT-PKD trials suggest that rigorous blood pressure control with ACEI or ACEI/ARB combinations in early ADPKD may favourably alter the rate of renal function decline. Rigorous versus standard blood pressure targets were defined as 95/60-110/75 mm Hg versus 120/70-130/80 mm Hg, respectively. The measured positive renal outcomes of rigorous blood pressure control included a slower progression of total kidney volume and urinary albumin excretion, while a statistically significant change in eGFR was not observed in the study follow-up timeframe of 8 years. In addition, rigorous blood pressure control led to a greater decline in LV mass index than standard blood pressure control, which serves as a surrogate determinant of cardiovascular morbidity and mortality.

Studies of Vasopressin V2 receptor antagonists in a rat/murine model and human subjects show that they successfully slow renal cyst growth by inhibition of the V2 receptor, potentially reducing intracellular cAMP levels, resulting in decreased water reabsorption and urinary osmolality. The V2-receptor antagonist Tolvaptan, as compared with placebo, was shown to decrease the progression of total kidney volume and the worsening of renal function in a 3-year study timeframe, but adverse events from liver function test abnormalities, as well as aquaresis-related poor tolerability led to a higher rate of therapy discontinuation. As of now, Tolvaptan is not recommended for the therapy of ADPKD in the United States. A large quantity of fluid intake mimics the pharmacological inhibition of vasopressin mediated intracellular cAMP increase, and may be eventually beneficial.

Three major trials investigating mTOR inhibition in ADPKD with Sirolimus or Everolimus did not result in significant outcomes that could be clinically meaningful at this point. Future therapeutic studies are at various stages of clinical investigation, involving the substances bosutinib, tesevatinib, targeting various receptor and non-receptor-tyrosine kinases, as well as derivatives of the glucosylceramide synthetase inhibitor Genz-123346.

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 therapy with somatostatin analogues, percutaneous cyst aspiration and sclerosis, laparoscopic fenestration, open surgical fenestration or even partial hepatectomy.

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. While screening for the presence of ICA is not recommended solely on the basis of an ADPKD diagnosis, it is clearly recommended for those with a family member with an ICA, and also for those with uncertain family history or high-risk professions.

Asymptomatic aneurysms measuring less than 5 mm in diameter can be observed and followed at regular intervals (typically every 3 years). Any unruptured intracranial aneurysms larger than 10 mm are at high risk for rupture and should be subject to surgical or neuro-radiological intervention.

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 that 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 versus 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 mutation, 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.

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.

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), as well as metabolic and cardiovascular health (therapy of diabetes, hyperuricemia, dyslipidemia etc.) 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

  • ICD-9 codes: 753.13 Polycystic kidney, autosomal dominant·

  • 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. 1992. pp. 37-41.

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

Mochizuki, T, Wu, G, Hayashi, T, Xenophontos, SL, Veldhuisen, B, Saris, JJ, Reynolds, DM, Cai, Y, Gabow, PA, Pierides, A, Kimberling, WJ, Breuning, MH, Deltas, CC, Peters, DJ, Somlo, S. "PKD2, a gene for polycystic kidney disease that encodes an integral membrane protein.". Science.. vol. 272. 1996. pp. 1339-42.

(Discovery of the PKD2 gene.)

Porath, B, Gainullin, VG, Cornec-Le Gall, E, Dillinger, EK, Heyer, CM, Hopp, K, Edwards, ME, Madsen, CD. "Genkyst Study Group, HALT Progression of Polycystic Kidney Disease Group; Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease, Harris PC. Mutations in GANAB, Encoding the Glucosidase IIα Subunit, Cause Autosomal-Dominant Polycystic Kidney and Liver Disease.". Am J Hum Genet.. vol. 98. 2016. pp. 1193-207.

(The third discovered ADPKD 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, Dordrecht, Kluwer. "Autosomal dominant polycystic kidney disease, In: The Cystic Kidney,". 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. In: Diseases of the kidney & urinary tract.". Philadelphia, 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. In: Comprehensive Clinical Nephrology,". 2000.

(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 genome-wide 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 a role of secretory pathway components in the pathogenesis of polycystic liver [and kidney] disease.)

Cnossen, WR, te Morsche, RH, Hoischen, A, Gilissen, C, Chrispijn, M, Venselaar, H, Mehdi, S, Bergmann, C, Veltman, JA, Drenth, JP. "Whole-exome sequencing reveals LRP5 mutations and canonical Wnt signaling associated with hepatic cystogenesis.". Proc Natl Acad Sci U S A.. vol. 111. 2014. pp. 5343-8.

(The chronologically third known locus of ADPLD not a ciliary, nor a secretory pathway gene, but a Wnt signalling mediator.)

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, Arlene, B, Chapman, Olivier Devuyst, Ron, T, Gansevoort, Jared, J, Grantham, Eiji Higashihara, Ronald, D, Perrone, Holly, B, Krasa, John Ouyang, Frank, S, Czerwiec. "TEMPO 3:4 Trial Investigators; Tolvaptan in Patients with Autosomal Dominant Polycystic Kidney Disease.". New England Journal of Medicine,. vol. 367. 2012. pp. 2407-2418.

(The TEMPO 3:4 trial investigating TKV and renal function in patients with autosomal dominant polycystic kidney disease, receiving Tolvaptan versus placebo.)

Caroli, A, Perico, N, Perna, A, Antiga, L, Brambilla, P, Pisani, A, Visciano, B, Imbriaco, M, Messa, P, Cerutti, R, Dugo, M, Cancian, L, Buongiorno, E, De Pascalis, A, Gaspari, F, Carrara, F, Rubis, N, Prandini, S, Remuzzi, A, Remuzzi, G, Ruggenenti, P. "ALADIN study group. Effect of longacting somatostatin analogue on kidney and cyst growth in autosomal dominant polycystic kidney disease (ALADIN): a randomised, placebo-controlled, multicentre trial.". Lancet.. vol. 382. 2013. pp. 1485-95.

(An initial trial of long acting octreotide suggests efficacy in TKV trajectory, but fails to demonstrate statistical significance.)

Pisani, A, Sabbatini, M, Imbriaco, M, Riccio, E, Rubis, N, Prinster, A, Perna, A, Liuzzi, R, Spinelli, L, Santangelo, M, Remuzzi, G, Ruggenenti, P. "ALADIN Study Group. Long-term Effects of Octreotide on Liver Volume in Patients With Polycystic Kidney and Liver Disease.". Clin Gastroenterol Hepatol.. vol. 14. 2016. pp. 1022-1030.

(Long-acting octreotide significantly reduces liver volume in patients with ADPKD and PLD, and the treatment effect is sustained after discontinuation.)

Torres, VE, Abebe, KZ, Chapman, AB, Schrier, RW, Braun, WE, Steinman, TI, Winklhofer, FT, Brosnahan, G, Czarnecki, PG, Hogan, MC, Miskulin, DC, Rahbari-Oskoui, FF, Grantham, JJ, Harris, PC, Flessner, MF, Moore, CG, Perrone, RD. "HALT-PKD Trial Investigators. Angiotensin blockade in late autosomal dominant polycystic kidney disease.". N Engl J Med.. vol. 371. 2014. pp. 2267-76.

Schrier, RW, Abebe, KZ, Perrone, RD, Torres, VE, Braun, WE, Steinman, TI, Winklhofer, FT, Brosnahan, G, Czarnecki, PG, Hogan, MC, Miskulin, DC, Rahbari-Oskoui, FF, Grantham, JJ, Harris, PC, Flessner, MF, Bae, KT, Moore, CG, Chapman, AB. "HALT-PKD Trial Investigators. Blood pressure in early autosomal dominant polycystic kidney disease.". N Engl J Med.. vol. 371. 2014. pp. 2255-66.

(The HALT-PKD A/B trials investigate single versus dual blood pressure control with ACEI or ACEI/ARB combination, in patients with ADPKD, including targeting standard versus rigorous blood pressure targets in patients with early stage ADPKD.)

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

(A textbook chapter introducing cystic kidney disease.)

Sweeney, WE, von Vigier, RO, Frost, P, Avner, ED. "Src inhibition ameliorates polycystic kidney disease.". J Am Soc Nephrol.. vol. 19. 2008. pp. 1331-41.

(Animal study motivating future therapeutic trials of Bosutinib in human ADPKD.)

Sweeney, WE, Frost, P, Avner, ED. "Tesevatinib ameliorates progression of polycystic kidney disease in rodent models of autosomal recessive polycystic kidney disease.". World J Nephrol.. vol. 6. 2017. pp. 188-200.

(Animal study motivating future therapeutic trials of Tesevatinib in human ADPKD.)

Bukanov, NO, Smith, LA, Klinger, KW, Ledbetter, SR, Ibraghimov-Beskrovnaya, O. "Long-lasting arrest of murine polycystic kidney disease with CDK inhibitor roscovitine.". Nature.. vol. 444. 2006. pp. 949-52.

(A remarkable study using Roscovitine in a murine model of polycystic kidney disease, giving rise to an emerging interest in proliferative/cell cycle and transcription regulation pathways as a therapeutic target in human ADPKD.)

Natoli, TA, Smith, LA, Rogers, KA, Wang, B, Komarnitsky, S, Budman, Y, Belenky, A, Bukanov, NO, Dackowski, WR, Husson, H, Russo, RJ, Shayman, JA, Ledbetter, SR, Leonard, JP, Ibraghimov-Beskrovnaya, O. "Inhibition of glucosylceramide accumulation results in effective blockade of polycystic kidney disease in mouse models.". Nat Med.. vol. 16. 2010. pp. 788-92.

(An animal study demonstrating efficacy of glucosylceramide synthetase inhibition as a therapeutic model in polycystic 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 and. "the CRISP Consortium 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. 2011. pp. 1202-1212.

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

Igarashi, P, Somlo, S and, feature editor. "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 and. "the CRISP Consortium. 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,". Kidney Int. 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 and, 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. In: 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. "TEMPO Formula and 156-05-002 study investigators. Tolvaptan in Autosomal Dominant Polycystic Kidney Disease: Three Years’ Experience.". Clin J Am Soc Nephrol Oct. 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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