- Email: [email protected]
Cysts and Swellings: A Systematic Review of the Association Between Polycystic Kidney Disease and Abdominal Aortic Aneurysm
Cysts and Swellings: A Systematic Review of the Association Between Polycystic Kidney Disease and Abdominal Aortic Aneurysm Marc A. Bailey,1,2 Kathryn J. Griffin,1,2 Adam L. Windle,1 Simon W. Lines,1,3 and D. Julian A. Scott,1,2 Leeds, United Kingdom
Background: Whether abdominal aortic aneurysm (AAA) forms part of the extrarenal manifestations of autosomal-dominant polycystic kidney disease (ADPKD) is unclear. We set out to review the evidence for an association. Materials and Methods: PubMed, Medline, Embase, and Web of Science databases 1960e2011 were searched [abdominal aortic aneurysm OR AAA OR triple A] AND [polycystic kidney disease OR PKD OR ADPKD OR Renal Cysts]. No limitations were placed on article type or language. Reference lists were recursively searched as were pertinent journal contents. Results: Eighteen papers were included. Since the first documented case of ADPKD and AAA in 1980, there have been 23 case reports. The voluminous kidneys make AAA diagnosis challenging and surgical exposure difficult. Two studies have assessed aortic diameter in patients with ADPKD and controls, one finding increased aortic diameter in ADPKD (2.7 cm vs. 2.3 cm, P < 0.02) and the other finding no difference. A further study identified a higher incidence of renal cysts in patients with AAA compared to controls (54% vs. 30%, P ¼ 0.0006). Conclusion: There is not enough clinical evidence to determine if ADPKD and AAA share a common pathology. Larger multicenter trials are required to determine if a link exists.
INTRODUCTION Isolated, renal cysts occur in 24e50% of the population over 50 years of age and are thought to be of little clinical importance; they are more common
Disclaimer: The authors confirm there has been no prior or duplicate publication of this work. No specific funding was received for this work but Marc A. Bailey and Kathryn J. Griffin are National Institute for Health Research (UK)-funded academic trainees. No authors have a conflict of interest to report. 1
The Division of Cardiovascular & Diabetes Research, The Leeds Institute of Genetics, Health & Therapeutics, Multidisciplinary Cardiovascular Research Centre, University of Leeds, Leeds LS2 9JT, UK. 2 The Leeds Vascular Institute, The General Infirmary at Leeds, Great George Street, Leeds LS1 3EX, UK. 3 Department of Renal Medicine, St. James’s University Hospital, Beckett Street, Leeds LS9 7TF, UK.
Correspondence to: Marc A. Bailey, MBChB, BSc, MRCS, NIHR Academic Clinical Fellow in Vascular Surgery, The Leeds Vascular Institute, The General Infirmary at Leeds, Great George Street, Leeds LS1 3EX, UK; E-mail: [email protected] Ann Vasc Surg 2013; 27: 123–128 http://dx.doi.org/10.1016/j.avsg.2012.05.013 Ó Annals of Vascular Surgery Inc. Manuscript received: February 13, 2012; manuscript accepted: May 14, 2012; published online: October 22, 2012.
with advancing age.1,2 In contrast, polycystic kidney disease (PKD) has significant morbidity. Autosomal dominant polycystic kidney disease (ADPKD) is the most common form of PKD and effects 1 in 1,000 of the population.3 It is characterized by the formation and enlargement of multiple cysts, primarily in the kidneys but also in the liver, pancreas, and spleen. The cysts cause progressive renal parenchymal destruction, glomerular dysfunction, and progressive chronic kidney disease, often resulting in renal replacement therapy or transplantation.4 ADPKD has well-documented associations with potentially life-threatening cardiovascular complications including intracranial berry aneurysms (which may rupture, causing subarachnoid hemorrhage), hypertension, and mitral or aortic valvular dysfunction.3,5 Whether abdominal aortic aneurysms (AAA) form part of the extrarenal, vascular manifestations of ADPKD has been debated for the last 30 years. The aim of this systematic literature review is to summarize the documented evidence of an association between PKD and AAA and link these clinical findings to recent advances in our understanding of the underlying molecular biology. 123
124 Bailey et al.
Annals of Vascular Surgery
Potentially relevant studies identified and screened for retrieval n = 56 Studies excluded n = 37 Irrelevant content by title review (n = 37) Studies retrieved for more detailed evaluation n = 19
Potentially appropriate studies to be included in the systematic review n = 15
Studies not meeting inclusion criteria n = 4 Dissecting thoracic aneurysm (n = 2) Coronary artery aneurysm (n = 1) Aortic root dilatation (n = 1)
Studies excluded from review n = 1 Letter containing no new data (n = 1) Studies included in systematic review n = 14
Studies included in systematic review n = 18
Articles identified from recursive searching of included papers, other reviews and hand searching of pertinent journals n = 4
Fig. 1. PRISMA flow diagram depicting the search strategy for the study.
METHODS PubMed, Medline, Embase, and Web of Science databases (1960e2011) were searched using the Boolean operators: [abdominal aortic aneurysm OR AAA OR triple A] AND [polycystic kidney disease OR PKD OR ADPKD OR Renal Cysts] in December 2011. Returned citations were interrogated by title, abstract, and key words for relevance. Papers were included if they considered an association between renal cystic disease and AAA. We placed no limitations on year of publication, language, or type of article. Full-text versions of all articles were obtained. At this stage, any articles that did not present any novel data (e.g., reviews or comments) were excluded. Reference lists of all returned articles were recursively searched for other relevant citations. Additionally, the contents of pertinent journals were hand searched (Journal of Vascular Surgery, European Journal of Vascular & Endovascular Surgery, Annals of Vascular Surgery, Nephron, Journal of the American Society of Nephrology, and Nephrology Dialysis & Transplantation). A full search strategy and PRISMA diagram is presented in Figure 1. Included articles were reviewed by two independent reviewers (MB, KG) and any disagreements resolved by open discussion.
RESULTS Our search strategy identified 18 papers for inclusion in the review. The majority were individual
case reports or case series of patients with ADPKD and AAA (with or without other vascular anomalies). The first documented report of the association was by Chapman and Hilson in the Lancet in 19806 in which they described AAA in 3 out of 31 patients (10%) with ADPKD in their dialysis program in Guy’s Hospital, London. This sparked 3 response letters over the following 3 months: Montoleiu et al.7 wrote in support of Chapman and Hilson, also presenting a single case of ADPKD and AAA, as did Roodvoets,8 reporting 1 patient with AAA out of 20 patients (5%) on dialysis for ADPKD. However, Aubia et al.9 in the same edition disputed the interpretation that the association was not by chance and themselves reported 4 cases of AAA in 71 patients in their hemodialysis program in the Hospital de L’Esperanc¸a, Barcelona, none of whom had ADPKD. In total in the literature there have been 23 reported cases of ADPKD and AAA.6e8,10e19 Of these, 19 had attempted repair (3 after aneurysm rupture) with reported success in 16 patients; there were 3 deaths (2 after aneurysm rupture). A recurring theme in these cases was the difficulty in diagnosing AAA. The large polycystic kidneys prevented easy palpation of the aneurysm and can themselves present with pain, mimicking that of a leaking aneurysm, causing delayed or missed diagnosis. The voluminous kidneys also posed a challenge when accessing the aneurysm surgically and is has been suggested that left nephrectomy should be considered to aid aortic exposure and cross clamping
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Cysts and swellings 125
Table I. A Comparison of the two published case-control studies on aortic diameter in patients with ADPKD Aortic diameter (cm, mean ± standard deviation) Study
Country
Age (yrs)
ADPKDb (n ¼ 40)
Controlb normal family members (n ¼ 41)
Torra et al. 1996d
Spain
60
2.2 ± 0.45 _ 1.9 ± 0.27 \
2.1 ± 0.31 _ 2.0 ± 0.34 \ Controlc
Kato et al. 2001
Japan
60 ± 1
ADPKDc (n ¼ 14)
GN (n ¼ 201)
DM (n ¼ 46)
2.7 ± 0.14a
2.3 ± 0.03
2.3 ± 0.05
_, men; \, women; ADPKD, autosomal dominant polycystic kidney disease; GN, chronic glomerulonephritis; DM, diabetes. Aortic size based on: b, aortic ultrasound, c, aortic computed tomographic angiography, d, data from patients over 60 years only. a P < 0.02 vs. CGN and DM.
or in more recent years an endovascular approach to repair.18 The first study to investigate the association between ADPKD and AAA in more depth was Torra et al. (Barcelona, Spain) in 1996.20 The authors recruited 139 ADPKD patients from 59 families, 30 of whom were on hemodialysis, and used 149 healthy family members (without evidence of renal cysts on ultrasound and normal haplotype) as the control group. They compared maximal aortic diameter in ADPKD and control groups (stratified by age and sex) and found no statistically significant difference in aortic diameter between groups. They identified two patients meeting diagnostic criteria for AAA in both ADPKD and control groups. Although the authors do not present an overall average age for the study population, it is clear from the presented results that only 27% of patients in the study were over the age of 60 years, with the rest too young to reasonably expect significant aortic dilatation. Notwithstanding this limitation of the study, there was no statistically significant difference in aortic diameter when the over 60 age group (n ¼ 81) were analyzed separately (Table I). In 2001, Kato and coworkers (Hamamatsu, Japan)21 also investigated aortic diameter in a cohort of 261 patients with renal disease. They compared maximal aortic diameter by computed tomography (CT) based on cause of renal dysfunction: primary chronic glomerulonephritis (GN, n ¼ 201), diabetes (DM, n ¼ 46), and ADPKD (n ¼ 14). Aortic diameter was increased in patients on hemodialysis. ADPKD patients had a significantly increased aortic diameter compared to those with CGN and DM (P < 0.02, Table I) when controlling for hemodialysis use; however, the incidence of AAA (maximal aortic diameter 3 cm) was not statistically significantly different across the three groups: 6.5% in the GN
group, 2.2% in the DM group, and 7.1% in the ADPKD group. Although this study contained 261 patients, only 14 (5.4%) had ADPKD. In a more recent study, Yaghoubain et al.22 investigated the relationship between AAA and incidental renal cysts. They retrospectively reviewed the CT scans of 100 patients with AAA and 100 age and sex matched controls from their institution in Los Angeles, USA. They reported that 54% of AAA patients had renal cysts compared to 30% in control group (P ¼ 0.0006, relative risk ¼ 2.73). Multivariate analysis confirmed independent predictors of renal cysts were age, COPD, and the presence of AAA.
DISCUSSION There is a clear relationship between ADPKD and vascular anomalies but a link to AAA has been controversial. Twenty-three cases of concomitant ADPKD and AAA have been previously published and two studies have investigated the aortic diameter of patients with ADPKD compared to various control groups with contradictory findings. More recently, the presence of AAA has been linked to incidental renal cysts, although this is of uncertain clinical significance. The numbers of patients in all of these studies has been relatively small. Interestingly, a similar pattern of increased incidence of incidental renal cysts has been demonstrated in a large study of 1,884 patients with aortic dissection (n ¼ 518) compared to healthy controls (n ¼ 1,366)23 perhaps suggesting common underlying etiological factors. Although reports of incidental renal cysts and aneurysm or aortic dissection are of interest to this topic, it is important to recognize that the pathology driving simple renal cysts and
126 Bailey et al.
PKD is different. A case report on aortic dissection and PKD revealed myxoid medial degeneration in the aortic tissue on histology24 and an earlier report of 11 ADPKD patients with cardiovascular anomalies revealed 7 (64%) with aortic root dilatation, which on histological analysis also demonstrated widespread myxomatous degeneration.25 What remains unclear is if ADPKD and aortic degeneration manifesting as AAA or aortic dissection really do share a common pathogenic mechanism or if patients with ADPKD are more likely to have hypertension and atherosclerosis driving the development of aortic pathology in later life. It is well established that matrix metalloproteinases (MMPs), specifically MMP-2 and MMP-9, play a key role in the breakdown of the aortic wall and drive the development and progression of AAA.26e29 Cultured kidney tubules from a hereditary mouse model of PKD contain high levels of MMP-2 and MMP-9,30 and kidney protein extracts from the murine PKD model confirmed increased expression and activity of MMP-2 and MMP-9 (although this was far more apparent for MMP2).31 Further, MMP-2 and MMP-9 are detectable in the fluid from human renal cysts32 and elevated serum levels of MMP-9 have been demonstrated in humans with ADPKD compared to healthy controls.33 Taken together, these studies suggest MMP-2 and MMP-9 are critical to matrix degradation in the formation of both renal cysts and aneurysmal disease. This shared pathophysiology prompted Takagi and Umemoto34 to publish a hypothesis suggesting that the diseased kidney tubules in ADPKD produce higher than normal levels of MMPs that drive the development of concurrent AAA. While this is an interesting theory, it is also important to consider the upstream genetics driving the process (Fig. 2). Although there is a strong familial susceptibility to AAA, as yet definitive evidence of a single genetic culprit is lacking.35 ADPKD has strong heritability linked to two genetic mutations: PKD1 on chromosome 16 and PKD2 on chromosome 4, which code for polycystin 1 and polycystin 2, respectively.3,4 These polycystins are, however, not limited to the nephron, but are abundantly present in the vasculature, including the aorta36,37 and mutations in these genes lead to the development of a vascular phenotype.38,39 Gene disruption in the mouse results in PKD and aortic thinning that can lead to dissecting aneurysms, vascular fragility, and abnormal calcium signaling.40e42 It has been established that these polycystins form multimeric transient receptor potential (TRP) channels, which appear to be primarily
Annals of Vascular Surgery
Genetic Mutation
Polycystin Dysfunction
Kidneys
Vascular Tree
MMP 2&9 Overproduction
MMP 2&9 Overproduction
Matrix Degeneration
Matrix Degeneration
Renal Cysts
Aortic Dissection
AAA
Fig. 2. Flow chart demonstrating the proposed relationship between inherited or acquired polycystin protein dysfunction leading to matrix metalloproteinase overproduction locally in the kidneys and vasculature leading to the concurrent development of renal cysts and abdominal aortic aneurysm.
involved in calcium and sodium entry into the cell and are present throughout the vascular tree.43 This is a particularly interesting finding as these TRP channels are prime targets for pharmacological modulation. The work published to date suggests a possible link between renal cystic disease and AAA. Further work reporting the aortic diameter of patients with ADPKD and controls and investigating the relationship between AAA and renal cysts is required. It is likely that multi-center studies will be required in order to generate significant numbers to draw definitive conclusions. There is sufficient basic science literature to postulate a common pathophysiology in ADPKD and AAA and the advances in our understanding of the function of polycystins and the implications of their dysfunction suggests an interesting area for future investigation.
Vol. 27, No. 1, January 2013
CONCLUSIONS In summary, the last 30 years have seen 23 cases of ADPKD and AAA reported in the literature, but relatively few studies further investigating the potential association between these conditions. Those reporting aortic diameter in patients with ADPKD have had small sample sizes and produced contradictory results, but a recent study reported an increased incidence of renal cysts in patients with AAA compared to healthy controls. There is currently not enough evidence to draw definitive conclusions and further high-quality primary studies are required. Notwithstanding, there is evidence that the genetic defects in ADPKD lead to changes in the vascular tree and overexpression of MMPs. These molecular events also require further investigation to enhance our understanding of the pathology driving AAA.
No specific funding was received for this work. Marc A. Bailey and Kathryn J. Griffin are NIHR-funded academic clinical fellows in vascular surgery. REFERENCES 1. Kissane JM. The morphology of renal cystic disease. In: Gardner KD ed. Cystic Diseases of the Kidney. New York: John Wiley & Sons, 1976. p 31. 2. Laucks SP, McLachlan SF. Ageing and simple cysts of the kidney. Br J Radiol 1981;54:12e4. 3. Torres VE, Harris PC, Pirson Y. Autosomal dominant polycystic kidney disease. Lancet 2007;369:1287e301. 4. Wilson PD. Polycystic kidney disease. N Engl J Med 2004;350:151e64. 5. Ecder T, Schrier RW. Cardiovascular abnormalities in autosomal dominant polycystic kidney disease. Nephrology 2009;5:221e8. 6. Chapman JR, Hilson AJ. Polycystic kidneys and abdominal aortic aneurysms. Lancet 1980;1:646e7. 7. Montoliu J, Torras A, Revert L. Polycystic kidneys and abdominal aortic aneurysms. Lancet 1980;1:1133e4. 8. Roodvoets AP. Aortic aneurysms in presence of kidney disease. Lancet 1980;1:1413e4. 9. Aubia J, Lloveras J, Masramon J, et al. Aortic aneurysms in presence of kidney disease. Lancet 1980;1:1414. 10. Okamoto Y, Awazu A, Ono K, et al. Surgical treatment of abdominal aneurysm in hemodialysis patient with polycystic kidney. Nihon Geka Hokan 1983;52:718e24. 11. Goeau-Brissonniere O, Renier JF, Bacourt F. Abdominal aortic aneurysm associated with aortic hypoplasia and polycystic kidneys. J Vasc Surg 1990;12:504e5. 12. Vanmaele R, Witbreuk M, De Broe M, et al. Abdominal aortic aneurysm and polycystic kidneys. Nephron 1995;69: 107e8. 13. Stiasny B, Schulze BD, Graf S, et al. Vessel malformation in a patient with ADPKD: megadolichobasilar artery, abdominal aortic and iliac aneurysms. Contrib Nephrol 1995;115: 182e4.
Cysts and swellings 127
14. Hadimeri H, Norden G, Friman S, et al. Autosomal dominant polycystic kidney disease in a kidney transplant population. Nephrol Dial Transplant 1997;12:1431e6. 15. Ahmad M, Rasul FM. Atypical presentation of ruptured abdominal aortic aneurysm. Am J Emerg Med 1998;16: 438. 16. Lacombe M. Abdominal aortic aneurysm and autosomal dominant polycystic kidney disease. Annales de Chirurgie 2000;125:648e53. 17. Todorov V, Jankova M, Bogdanova N, et al. Abdominal aortic aneurysm and autosomal dominant polycystic kidney disease. Nephrol Dial Transplant 2004;10:63e6. 18. Inoguchi H, Komori K, Maehara Y. Surgical management of abdominal aortic aneurysm associated with polycystic kidney disease: report of two cases. Surg Today 2008;38: 253e7. 19. Das Neves MA Jr, Melo RC, Goes AMDO Jr, et al. Association between infrarenal abdominal aortic aneurysm and autosomal dominant polycystic kidney disease: A case report. J Vascular Brasileiro 2009;8:186e8. 20. Torra R, Nicolau C, Badenas C, et al. Abdominal aortic aneurysms and autosomal dominant polycystic kidney disease. J Am Soc Nephrol 1996;7:2483e6. 21. Kato A, Takita T, Furuhashi M, et al. Abdominal aortic aneurysms in hemodialysis patients with autosomal dominant polycystic kidney disease. Nephron 2001;88: 185e6. 22. Yaghoubian A, de Virgilio C, White RA, et al. Increased incidence of renal cysts in patients with abdominal aortic aneurysms: a common pathogenesis? Ann Vasc Surg 2006;20: 787e91. 23. Kim EK, Choi ER, Song BG, et al. Presence of simple renal cysts is associated with increased risk of aortic dissection: a common manifestation of connective tissue degeneration? Heart 2011;97:55e9. 24. Lee CC, Chang WT, Fang CC, et al. Sudden death caused by dissecting thoracic aortic aneurysm in a patient with autosomal dominant polycystic kidney disease. Resuscitation 2004;63:93e6. 25. Leier CV, Baker BP, Kilman JW, et al. Cardiovascular abnormalities associated with adult polycystic kidney disease. Ann Intern Med 1984;100:683e8. 26. Sakalihasan N, Delvenne P, Nusgens BV, et al. Activated forms of MMP2 and MMP9 in abdominal aortic aneurysms. J Vasc Surg 1996;24:127e33. 27. Davis V, Persidskaia R, Baca-Regen L, et al. Matrix metalloproteinase-2 production and its binding to the matrix are increased in abdominal aortic aneurysms. Arterioscler Thromb Vasc Biol 1998;18:1625e33. 28. Longo GM, Xiong W, Greiner TC, et al. Matrix metalloproteinases 2 and 9 work in concert to produce aortic aneurysms. J Clin Invest 2002;110:625e32. 29. Wilson WR, Anderton M, Choke EC, et al. Elevated plasma MMP1 and MMP9 are associated with abdominal aortic aneurysm rupture. Eur J Vasc Endovasc Surg 2008;35: 580e4. 30. Rankin CA, Suzuki K, Itoh Y, et al. Matrix metalloproteinases and TIMPS in cultured C57BL/6J-cpk kidney tubules. Kidney Int 1996;50:835e44. 31. Rankin CA, Itoh Y, Tian C, et al. Matrix metalloproteinase-2 in a murine model of infantile-type polycystic kidney disease. J Am Soc Nephrol 1999;10:210e7. 32. Harada H, Furuya M, Ishikura H, et al. Expression of matrix metalloproteinase in the fluids of renal cystic lesions. J Urol 2002;168:19e22.
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33. Nakamura T, Ushiyama C, Suzuki S, et al. Elevation of serum levels of metalloproteinase-1, tissue inhibitor of metalloproteinase-1 and type IV collagen, and plasma levels of metalloproteinase-9 in polycystic kidney disease. Am J Nephrol 2000;20:32e6. 34. Takagi H, Umemoto T. Matrix metalloproteinases synthesized in autosomal dominant polycystic kidney disease play a role in development of a concurrent abdominal aortic aneurysm. Med Hypotheses 2005;64:778e81. 35. Bown MJ, Jones GT, Harrison SC, et al. Abdominal aortic aneurysm is associated with a variant in low-density lipoprotein receptor-related protein 1. Am J Hum Genet 2011;89:619e27. 36. Griffin MD, Torres VE, Grande JP, et al. Vascular expression of polycystin. J Am Soc Nephrol 1997;8:616e26. 37. Torres VE, Cai Y, Chen X, et al. Vascular expression of polycystin-2. J Am Soc Nephrol 2001;12:1e9. 38. Qian Q, Li M, Cai Y, et al. Analysis of the polycystins in aortic vascular smooth muscle cells. J Am Soc Nephrol 2003;14:2280e7.
Annals of Vascular Surgery
39. Rossetti S, Chauveau D, Kubly V, et al. Association of mutation position in polycystic kidney disease 1 (PKD1) gene and development of a vascular phenotype. Lancet 2003;361: 2196e201. 40. Kim K, Drummond I, Ibraghimov-Beskrovnaya O, et al. Polycystin 1 is required for the structural integrity of blood vessels. Proc Natl Acad Sci 2000;97:1731e6. 41. Hassane S, Claij N, Lantinga-van Leeuwen IS, et al. Pathogenic sequence for dissecting aneurysm formation in a hypomorphic polycystic kidney disease 1 mouse model. Arterioscler Thromb Vasc Biol 2007;27: 2177e83. 42. Morel N, Vandenberg G, Ahrabi AK, et al. PKD1 haploinsufficiency is associated with altered vascular reactivity and abnormal calcium signaling in the mouse aorta. Pflugers Arch 2009;457:845e56. 43. Beech DJ, Bahnasi YM, Dedman AM, et al. TRPC channel lipid specificity and mechanisms of lipid regulation. Cell Calcium 2009;45:583e8.
Background: Whether abdominal aortic aneurysm (AAA) forms part of the extrarenal manifestations of autosomal-dominant polycystic kidney disease (ADPKD) is unclear. We set out to review the evidence for an association. Materials and Methods: PubMed, Medline, Embase, and Web of Science databases 1960e2011 were searched [abdominal aortic aneurysm OR AAA OR triple A] AND [polycystic kidney disease OR PKD OR ADPKD OR Renal Cysts]. No limitations were placed on article type or language. Reference lists were recursively searched as were pertinent journal contents. Results: Eighteen papers were included. Since the first documented case of ADPKD and AAA in 1980, there have been 23 case reports. The voluminous kidneys make AAA diagnosis challenging and surgical exposure difficult. Two studies have assessed aortic diameter in patients with ADPKD and controls, one finding increased aortic diameter in ADPKD (2.7 cm vs. 2.3 cm, P < 0.02) and the other finding no difference. A further study identified a higher incidence of renal cysts in patients with AAA compared to controls (54% vs. 30%, P ¼ 0.0006). Conclusion: There is not enough clinical evidence to determine if ADPKD and AAA share a common pathology. Larger multicenter trials are required to determine if a link exists.
INTRODUCTION Isolated, renal cysts occur in 24e50% of the population over 50 years of age and are thought to be of little clinical importance; they are more common
Disclaimer: The authors confirm there has been no prior or duplicate publication of this work. No specific funding was received for this work but Marc A. Bailey and Kathryn J. Griffin are National Institute for Health Research (UK)-funded academic trainees. No authors have a conflict of interest to report. 1
The Division of Cardiovascular & Diabetes Research, The Leeds Institute of Genetics, Health & Therapeutics, Multidisciplinary Cardiovascular Research Centre, University of Leeds, Leeds LS2 9JT, UK. 2 The Leeds Vascular Institute, The General Infirmary at Leeds, Great George Street, Leeds LS1 3EX, UK. 3 Department of Renal Medicine, St. James’s University Hospital, Beckett Street, Leeds LS9 7TF, UK.
Correspondence to: Marc A. Bailey, MBChB, BSc, MRCS, NIHR Academic Clinical Fellow in Vascular Surgery, The Leeds Vascular Institute, The General Infirmary at Leeds, Great George Street, Leeds LS1 3EX, UK; E-mail: [email protected] Ann Vasc Surg 2013; 27: 123–128 http://dx.doi.org/10.1016/j.avsg.2012.05.013 Ó Annals of Vascular Surgery Inc. Manuscript received: February 13, 2012; manuscript accepted: May 14, 2012; published online: October 22, 2012.
with advancing age.1,2 In contrast, polycystic kidney disease (PKD) has significant morbidity. Autosomal dominant polycystic kidney disease (ADPKD) is the most common form of PKD and effects 1 in 1,000 of the population.3 It is characterized by the formation and enlargement of multiple cysts, primarily in the kidneys but also in the liver, pancreas, and spleen. The cysts cause progressive renal parenchymal destruction, glomerular dysfunction, and progressive chronic kidney disease, often resulting in renal replacement therapy or transplantation.4 ADPKD has well-documented associations with potentially life-threatening cardiovascular complications including intracranial berry aneurysms (which may rupture, causing subarachnoid hemorrhage), hypertension, and mitral or aortic valvular dysfunction.3,5 Whether abdominal aortic aneurysms (AAA) form part of the extrarenal, vascular manifestations of ADPKD has been debated for the last 30 years. The aim of this systematic literature review is to summarize the documented evidence of an association between PKD and AAA and link these clinical findings to recent advances in our understanding of the underlying molecular biology. 123
124 Bailey et al.
Annals of Vascular Surgery
Potentially relevant studies identified and screened for retrieval n = 56 Studies excluded n = 37 Irrelevant content by title review (n = 37) Studies retrieved for more detailed evaluation n = 19
Potentially appropriate studies to be included in the systematic review n = 15
Studies not meeting inclusion criteria n = 4 Dissecting thoracic aneurysm (n = 2) Coronary artery aneurysm (n = 1) Aortic root dilatation (n = 1)
Studies excluded from review n = 1 Letter containing no new data (n = 1) Studies included in systematic review n = 14
Studies included in systematic review n = 18
Articles identified from recursive searching of included papers, other reviews and hand searching of pertinent journals n = 4
Fig. 1. PRISMA flow diagram depicting the search strategy for the study.
METHODS PubMed, Medline, Embase, and Web of Science databases (1960e2011) were searched using the Boolean operators: [abdominal aortic aneurysm OR AAA OR triple A] AND [polycystic kidney disease OR PKD OR ADPKD OR Renal Cysts] in December 2011. Returned citations were interrogated by title, abstract, and key words for relevance. Papers were included if they considered an association between renal cystic disease and AAA. We placed no limitations on year of publication, language, or type of article. Full-text versions of all articles were obtained. At this stage, any articles that did not present any novel data (e.g., reviews or comments) were excluded. Reference lists of all returned articles were recursively searched for other relevant citations. Additionally, the contents of pertinent journals were hand searched (Journal of Vascular Surgery, European Journal of Vascular & Endovascular Surgery, Annals of Vascular Surgery, Nephron, Journal of the American Society of Nephrology, and Nephrology Dialysis & Transplantation). A full search strategy and PRISMA diagram is presented in Figure 1. Included articles were reviewed by two independent reviewers (MB, KG) and any disagreements resolved by open discussion.
RESULTS Our search strategy identified 18 papers for inclusion in the review. The majority were individual
case reports or case series of patients with ADPKD and AAA (with or without other vascular anomalies). The first documented report of the association was by Chapman and Hilson in the Lancet in 19806 in which they described AAA in 3 out of 31 patients (10%) with ADPKD in their dialysis program in Guy’s Hospital, London. This sparked 3 response letters over the following 3 months: Montoleiu et al.7 wrote in support of Chapman and Hilson, also presenting a single case of ADPKD and AAA, as did Roodvoets,8 reporting 1 patient with AAA out of 20 patients (5%) on dialysis for ADPKD. However, Aubia et al.9 in the same edition disputed the interpretation that the association was not by chance and themselves reported 4 cases of AAA in 71 patients in their hemodialysis program in the Hospital de L’Esperanc¸a, Barcelona, none of whom had ADPKD. In total in the literature there have been 23 reported cases of ADPKD and AAA.6e8,10e19 Of these, 19 had attempted repair (3 after aneurysm rupture) with reported success in 16 patients; there were 3 deaths (2 after aneurysm rupture). A recurring theme in these cases was the difficulty in diagnosing AAA. The large polycystic kidneys prevented easy palpation of the aneurysm and can themselves present with pain, mimicking that of a leaking aneurysm, causing delayed or missed diagnosis. The voluminous kidneys also posed a challenge when accessing the aneurysm surgically and is has been suggested that left nephrectomy should be considered to aid aortic exposure and cross clamping
Vol. 27, No. 1, January 2013
Cysts and swellings 125
Table I. A Comparison of the two published case-control studies on aortic diameter in patients with ADPKD Aortic diameter (cm, mean ± standard deviation) Study
Country
Age (yrs)
ADPKDb (n ¼ 40)
Controlb normal family members (n ¼ 41)
Torra et al. 1996d
Spain
60
2.2 ± 0.45 _ 1.9 ± 0.27 \
2.1 ± 0.31 _ 2.0 ± 0.34 \ Controlc
Kato et al. 2001
Japan
60 ± 1
ADPKDc (n ¼ 14)
GN (n ¼ 201)
DM (n ¼ 46)
2.7 ± 0.14a
2.3 ± 0.03
2.3 ± 0.05
_, men; \, women; ADPKD, autosomal dominant polycystic kidney disease; GN, chronic glomerulonephritis; DM, diabetes. Aortic size based on: b, aortic ultrasound, c, aortic computed tomographic angiography, d, data from patients over 60 years only. a P < 0.02 vs. CGN and DM.
or in more recent years an endovascular approach to repair.18 The first study to investigate the association between ADPKD and AAA in more depth was Torra et al. (Barcelona, Spain) in 1996.20 The authors recruited 139 ADPKD patients from 59 families, 30 of whom were on hemodialysis, and used 149 healthy family members (without evidence of renal cysts on ultrasound and normal haplotype) as the control group. They compared maximal aortic diameter in ADPKD and control groups (stratified by age and sex) and found no statistically significant difference in aortic diameter between groups. They identified two patients meeting diagnostic criteria for AAA in both ADPKD and control groups. Although the authors do not present an overall average age for the study population, it is clear from the presented results that only 27% of patients in the study were over the age of 60 years, with the rest too young to reasonably expect significant aortic dilatation. Notwithstanding this limitation of the study, there was no statistically significant difference in aortic diameter when the over 60 age group (n ¼ 81) were analyzed separately (Table I). In 2001, Kato and coworkers (Hamamatsu, Japan)21 also investigated aortic diameter in a cohort of 261 patients with renal disease. They compared maximal aortic diameter by computed tomography (CT) based on cause of renal dysfunction: primary chronic glomerulonephritis (GN, n ¼ 201), diabetes (DM, n ¼ 46), and ADPKD (n ¼ 14). Aortic diameter was increased in patients on hemodialysis. ADPKD patients had a significantly increased aortic diameter compared to those with CGN and DM (P < 0.02, Table I) when controlling for hemodialysis use; however, the incidence of AAA (maximal aortic diameter 3 cm) was not statistically significantly different across the three groups: 6.5% in the GN
group, 2.2% in the DM group, and 7.1% in the ADPKD group. Although this study contained 261 patients, only 14 (5.4%) had ADPKD. In a more recent study, Yaghoubain et al.22 investigated the relationship between AAA and incidental renal cysts. They retrospectively reviewed the CT scans of 100 patients with AAA and 100 age and sex matched controls from their institution in Los Angeles, USA. They reported that 54% of AAA patients had renal cysts compared to 30% in control group (P ¼ 0.0006, relative risk ¼ 2.73). Multivariate analysis confirmed independent predictors of renal cysts were age, COPD, and the presence of AAA.
DISCUSSION There is a clear relationship between ADPKD and vascular anomalies but a link to AAA has been controversial. Twenty-three cases of concomitant ADPKD and AAA have been previously published and two studies have investigated the aortic diameter of patients with ADPKD compared to various control groups with contradictory findings. More recently, the presence of AAA has been linked to incidental renal cysts, although this is of uncertain clinical significance. The numbers of patients in all of these studies has been relatively small. Interestingly, a similar pattern of increased incidence of incidental renal cysts has been demonstrated in a large study of 1,884 patients with aortic dissection (n ¼ 518) compared to healthy controls (n ¼ 1,366)23 perhaps suggesting common underlying etiological factors. Although reports of incidental renal cysts and aneurysm or aortic dissection are of interest to this topic, it is important to recognize that the pathology driving simple renal cysts and
126 Bailey et al.
PKD is different. A case report on aortic dissection and PKD revealed myxoid medial degeneration in the aortic tissue on histology24 and an earlier report of 11 ADPKD patients with cardiovascular anomalies revealed 7 (64%) with aortic root dilatation, which on histological analysis also demonstrated widespread myxomatous degeneration.25 What remains unclear is if ADPKD and aortic degeneration manifesting as AAA or aortic dissection really do share a common pathogenic mechanism or if patients with ADPKD are more likely to have hypertension and atherosclerosis driving the development of aortic pathology in later life. It is well established that matrix metalloproteinases (MMPs), specifically MMP-2 and MMP-9, play a key role in the breakdown of the aortic wall and drive the development and progression of AAA.26e29 Cultured kidney tubules from a hereditary mouse model of PKD contain high levels of MMP-2 and MMP-9,30 and kidney protein extracts from the murine PKD model confirmed increased expression and activity of MMP-2 and MMP-9 (although this was far more apparent for MMP2).31 Further, MMP-2 and MMP-9 are detectable in the fluid from human renal cysts32 and elevated serum levels of MMP-9 have been demonstrated in humans with ADPKD compared to healthy controls.33 Taken together, these studies suggest MMP-2 and MMP-9 are critical to matrix degradation in the formation of both renal cysts and aneurysmal disease. This shared pathophysiology prompted Takagi and Umemoto34 to publish a hypothesis suggesting that the diseased kidney tubules in ADPKD produce higher than normal levels of MMPs that drive the development of concurrent AAA. While this is an interesting theory, it is also important to consider the upstream genetics driving the process (Fig. 2). Although there is a strong familial susceptibility to AAA, as yet definitive evidence of a single genetic culprit is lacking.35 ADPKD has strong heritability linked to two genetic mutations: PKD1 on chromosome 16 and PKD2 on chromosome 4, which code for polycystin 1 and polycystin 2, respectively.3,4 These polycystins are, however, not limited to the nephron, but are abundantly present in the vasculature, including the aorta36,37 and mutations in these genes lead to the development of a vascular phenotype.38,39 Gene disruption in the mouse results in PKD and aortic thinning that can lead to dissecting aneurysms, vascular fragility, and abnormal calcium signaling.40e42 It has been established that these polycystins form multimeric transient receptor potential (TRP) channels, which appear to be primarily
Annals of Vascular Surgery
Genetic Mutation
Polycystin Dysfunction
Kidneys
Vascular Tree
MMP 2&9 Overproduction
MMP 2&9 Overproduction
Matrix Degeneration
Matrix Degeneration
Renal Cysts
Aortic Dissection
AAA
Fig. 2. Flow chart demonstrating the proposed relationship between inherited or acquired polycystin protein dysfunction leading to matrix metalloproteinase overproduction locally in the kidneys and vasculature leading to the concurrent development of renal cysts and abdominal aortic aneurysm.
involved in calcium and sodium entry into the cell and are present throughout the vascular tree.43 This is a particularly interesting finding as these TRP channels are prime targets for pharmacological modulation. The work published to date suggests a possible link between renal cystic disease and AAA. Further work reporting the aortic diameter of patients with ADPKD and controls and investigating the relationship between AAA and renal cysts is required. It is likely that multi-center studies will be required in order to generate significant numbers to draw definitive conclusions. There is sufficient basic science literature to postulate a common pathophysiology in ADPKD and AAA and the advances in our understanding of the function of polycystins and the implications of their dysfunction suggests an interesting area for future investigation.
Vol. 27, No. 1, January 2013
CONCLUSIONS In summary, the last 30 years have seen 23 cases of ADPKD and AAA reported in the literature, but relatively few studies further investigating the potential association between these conditions. Those reporting aortic diameter in patients with ADPKD have had small sample sizes and produced contradictory results, but a recent study reported an increased incidence of renal cysts in patients with AAA compared to healthy controls. There is currently not enough evidence to draw definitive conclusions and further high-quality primary studies are required. Notwithstanding, there is evidence that the genetic defects in ADPKD lead to changes in the vascular tree and overexpression of MMPs. These molecular events also require further investigation to enhance our understanding of the pathology driving AAA.
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