- Email: [email protected]
Myofibroblasts: the ideal target to prevent arteriovenous fistula failure?
commentary
2.
3.
4.
5.
6.
Cummins EP, Berra E, Comerford KM et al. Prolyl hydroxylase-1 negatively regulates IkappaB kinase-beta, giving insight into hypoxia-induced NFkappaB activity. Proc Natl Acad Sci USA 2006; 103: 18154–18159. Peyssonnaux C, Datta V, Cramer T et al. HIF-1a expression regulates the bactericidal capacity of phagocytes. J Clin Invest 2005; 115: 1806–1815. Heemann U, Szabo A, Hamar P et al. Lipopolysaccharide pretreatment protects from renal ischemia/reperfusion injury: possible connection to an interleukin-6dependent pathway. Am J Pathol 2000; 156: 287–293. Zager RA, Johnson AC, Lund S. ‘Endotoxin tolerance’: TNF-alpha hyper-reactivity and tubular cytoresistance in a renal cholesterol loading state. Kidney Int 2007; 71: 496–503. He K, Chen X, Han C et al. Lipopolysaccharideinduced cross-tolerance against renal ischemia–reperfusion injury is mediated
7.
8.
9.
10.
by hypoxia-inducible factor-2a-regulated nitric oxide production. Kidney Int 2014; 85: 276–288. Kojima I, Tanaka T, Inagi R et al. Protective role of hypoxia-inducible factor-2a against ischemic damage and oxidative stress in the kidney. J Am Soc Nephrol 2007; 18: 1218–1226. Schley G, Klanke B, Schodel J et al. Selective stabilization of HIF-1a in renal tubular cells by 2-oxoglutarate analogues. Am J Pathol 2012; 181: 1595–1606. Wang Z, Schley G, Turkoglu G et al. The protective effect of prolyl-hydroxylase inhibition against renal ischaemia requires application prior to ischaemia but is superior to EPO treatment. Nephrol Dial Transplant 2012; 27: 929–936. Zager RA, Johnson AC, Hanson SY et al. Ischemic proximal tubular injury primes mice to endotoxin-induced TNF-alpha generation and systemic release. Am J Physiol Renal Physiol 2005; 289: F289–F297.
see basic research on page 289
Myofibroblasts: the ideal target to prevent arteriovenous fistula failure? Juan Camilo Duque1 and Roberto I. Vazquez-Padron1 The arteriovenous fistula (AVF) failure is a major cause of morbidity in the hemodialysis population. Most AVFs fail due to neointimal hyperplasia (NIH). In this issue, Yang et al. delineated a mechanism responsible for transforming the fistula adventitia into a fertile soil for neointimal precursors. These authors pondered the role of hypoxia-regulated hypoxia-inducible factor-1 (HIF-1a), vascular endothelial growth factor A (VEGF-A), and matrix metalloproteinases (MMPs) in the activation of those adventitial myofibroblasts that may significantly contribute to the formation of the fistula neointima. Kidney International (2014) 85, 234–236. doi:10.1038/ki.2013.384
According to the US Renal Data System, 546,000 Americans rely on a vascular access to receive life-saving hemodialysis.1 The arteriovenous fistula (AVF) is the preferred vascular access 1 DeWitt Daughtry Family Department of Surgery, Leonard M. Miller School of Medicine, University of Miami, Miami, Florida, USA Correspondence: Roberto I. Vazquez-Padron, Department of Surgery, Leonard M. Miller School of Medicine, University of Miami, 1600 NW 10th Avenue, RMSB 1009D, Miami, Florida 33136, USA. E-mail: [email protected]
234
since the United States implemented the Fistula First Breakthrough Initiative in 2003, given its improved performance and lower complication rates compared with prosthetic grafts or central venous catheters. However, the rate of AVF failure (40–60%) is still unacceptable and profoundly impacts morbidity in the hemodialysis population. In general, AVF fails mostly because of complications secondary to obstructive neointimal hyperplasia (NIH). Despite the wide recognition of this problem, no
substantial efforts have been made so far to identify the underlying mechanisms that lead to the formation of occlusive neointima in AVF. The article by Yang et al.2 (this issue) contributes to the delineation of the cellular and molecular mechanisms responsible for transforming the fistula adventitia into a fertile soil for neointimal precursors. This and previous work from Dr. Misra’s group3 have highlighted the importance of hypoxiainducible factor-1 (HIF-1a), vascular endothelial growth factor A (VEGF-A), and matrix metalloproteinases (MMPs) in the activation of adventitial myofibroblasts that could potentially contribute to neointimal formation (Figure 1). Consequently, this study provides rationale for using anti-VEGF-A therapies at the time of fistula creation to avoid NIH and thus reduce the rate of primary failure in vascular accesses. Targeting myofibroblastic activity in the fistula adventitia at the time of creation to improve its maturation is an emerging idea that requires attention and further innovation. The myofibroblast is friend and foe during vein adaptation to arterial flow and is primordial to maintain venous hemostasis after AVF establishment.4 Myofibroblast precursors residing in the venous adventitia sense the abrupt mechanical forces produced by arterial flow to rapidly adjust its genomic expression program to help increase vascular resistance. This adaptive response includes the formation of bundles of contractile microfilaments and extensive cell-tomatrix attachment sites as well as the secretion of MMPs, collagen, and extracellular matrix proteins to re-enforce the fistula wall. However, the excessive myofibroblastic healing response typically observed after implementation of AVF contributes not only to neointimal formation but also to the thickening of the tunica media and adventitial fibrosis, which compromise the proper function of the fistula. As proposed by Yang et al.,2 an ideal therapy to reduce venous stenosis formation should be not only locally but also timely delivered to the adventitia of the vessel wall to prevent myofibroblast expansion while allowing Kidney International (2014) 85, 232–247
commentary
Surgical trauma
Myofibroblast activation
HIF-1α
Hypoxia
Myofibroblast precursors Adventitia
Myofibroblast
VEGF-A MMP-2 and -9
Proliferation Migration
Media
Intima Neointima cells
Figure 1 | Hypothetical mechanism leading to myofibroblast activation in the fistula adventitia. HIF-1a, hypoxia-inducible factor-1; MMP, matrix metalloproteinase; VEGF-A, vascular endothelial growth factor A.
the proper adaptation process within the outflow vein. This strategy is expected to prevent aneurysms and other complications associated with insufficient remodeling of the fistula wall. The article by Yang et al.2 also reminds us of a number of fundamental questions regarding the pathobiology of AVF that still remain unsolved. One of those current challenges concentrates on the anatomical source or sources of neointimal cells in the failed AVF. The remodeling of the outflow vein requires the expansion and mobilization of myofibroblasts from local precursors, given that recent studies have ruled out any contribution of circulating progenitors and fibrocytes (bone marrowderived) to this process.5 The venous cells that can transform into myofibroblasts are (1) adventitial fibroblasts, (2) pericytes, (3) endothelial cells (endothelial–mesenchymal transition), and (4) smooth muscle cells.6 The rate by which each of these cell types contributes to the pool of myofibroblasts in the neointima is unknown. The complete identification of the nature of the proliferating and migrating cells in the neointima is important because it could influence the choice of the antiproliferative drug and its dosing. Cell type-specific interventions mediated Kidney International (2014) 85, 232–247
by drugs might be an important part of the ideal approach to ameliorate stenosis and prolong access patency. Another major observation described by Yang et al.2 is the noxious effect of surgical trauma to the vasa vasorum of the outflow vein and its possible relationship with the development of NIH. In their murine fistula model, surgical trauma triggers the expression of HIF-1a and subsequent upregulation of VEGF-A and MMPs in adventitial myofibroblasts. Currently, the impact of ischemia/reperfusion injury on the outflow vein is considered a minor downstream factor determining fistula adequacy. The creation of the fistula in the mouse (by connection of the right carotid artery to the ipsilateral jugular vein) could be more traumatic than that in humans; so more studies with preclinical animal models and patients are warranted to determine whether surgical trauma is truly an independent predictor of fistula outcomes. Conversely, a recent retrospective study has shown a better overall functional patency in brachiobasilic AVFs implemented with a two-stage process that includes a complex surgical dissection (stage 1,
creation, and stage 2, transposition) than in those created in a single operation.7 The importance of developing novel periadventitial delivery systems to target early development of NIH in AVF is also recognized by Yang et al.2 The periadventitial delivery of drugs, genes, or cells over the anastomotic region of a newly created fistula can allow higher local treatment concentrations with lower systemic toxicity.8 This type of delivery has been demonstrated to be less problematic, as the vein and the anastomotic area are accessible for therapies during a surgical procedure. Paulson et al.9 have recently demonstrated the technical success and safety of perivascular delivery using sirolimuseluting wraps (COLL-R) around grafts in 12 patients. The individuals who received a sirolimus-eluting wrap around the graft venous anastomosis had excellent primary unassisted rates; however, this finding should be carefully considered, given that the study lacked a control group. Nevertheless, the results described by Paulson et al.9 demonstrate for the first time that periadventitial delivery of drugs can safely and effectively suppress NIH in dialysis accesses. Larger randomized trials are needed to determine whether COLL-R can prolong AVF patency. The fundamental question of whether a single application of a therapeutic agent is sufficient to control a chronic process will require careful studies. In conclusion, we should remain cautious in interpreting and extrapolating from the new study by Yang et al.,2 mostly because of the inherent limitations of its animal model. Mice are useful in gaining insight into the mechanisms leading to NIH, but the hemodynamics, vascular anatomy, and pathology of rodents do not necessarily mimic those of humans. This skepticism is further amplified by the failure of presumed therapies that were effective in animals to prevent NIH in patients.10 Therefore, the efficacy of local delivery of anti-VEGF monoclonal antibody (bevacizumab) or small hairpin RNAs in preventing AVF stenosis should be tested in large animals whose physiology, function, and anatomy are closer to those 235
commentary
of humans as part of the complex journey from the bench to the beside.
5.
DISCLOSURE
The authors declared no competing interests.
6.
REFERENCES
7.
1.
2.
3.
4.
US Renal Data System. USRDS 2012 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States. National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health: Bethesda, MD, USA, 2012; www.usrds.org. accessed 12 July 2013. Yang B, Janardhanan R, Vohra P et al. Adventitial transduction of lentivirus-shRNAVEGF-A in arteriovenous fistula reduces venous stenosis formation. Kidney Int 2014; 85: 289–306. Janardhanan R, Yang B, Vohra P et al. Simvastatin reduces venous stenosis formation in a murine hemodialysis vascular access model. Kidney Int 2013; 84: 338–352. Coen M, Gabbiani G, Bochaton-Piallat M-L. Myofibroblast-mediated adventitial
8.
9.
10.
remodeling. Arterioscler Thromb Vasc Biol 2011; 31: 2391–2396. Skartsis N, Manning E, Wei Y et al. Origin of neointimal cells in arteriovenous fistulae: bone marrow, artery, or the vein itself? Semin Dial 2011; 24: 242–248. Hinz B, Phan SH, Thannickal VJ et al. The myofibroblast: one function, multiple origins. Am J Pathol 2007; 170: 1807–1816. Vrakas G, Defigueiredo F, Turner S et al. A comparison of the outcomes of one-stage and two-stage brachiobasilic arteriovenous fistulas. J Vasc Surg 2013; 53: 1632–1638. Cheung AK, Terry C, Li L. Pathogenesis and local drug delivery for prevention of vascular access stenosis. J Ren Nutr 2008; 18: 140–145. Paulson WD, Kipshidze N, Kipiani K et al. Safety and efficacy of local periadventitial delivery of sirolimus for improving hemodialysis graft patency: first human experience with a sirolimus-eluting collagen membrane (Coll-R). Nephrol Dial Transplant 2012; 27: 1219–1224. Conte MS, Bandyk DF, Clowes AW et al. Results of PREVENT III: a multicenter, randomized trial of edifoligide for the prevention of vein graft failure in lower extremity bypass surgery. J Vasc Surg 2006; 43: 742–751.
see clinical investigation on page 383
The importance of quantifying genetic heterogeneity in ADPKD Arlene B. Chapman1 Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary renal disease. New data from Paul et al. suggest that mutations in the PKD1 and PKD2 genes may account for all cases of ADPKD. Further improvements in mutation detection methodologies are needed to determine the true relative frequency of PKD1 versus PKD2 as well as to establish the value of mutation type and location to predict disease severity in this disorder. Kidney International (2014) 85, 236–237. doi:10.1038/ki.2013.371
In this issue of Kidney International, Paul et al.1 painstakingly review five independent families with autosomal dominant polycystic kidney disease (ADPKD) reported not to be linked to mutations in either the PKD1 or the PKD2 gene. The initial assignment of 1
Emory University School of Medicine, Atlanta, Georgia, USA Correspondence: Arlene B. Chapman, Emory University School of Medicine, Clinical Interaction Network, 1364 Clifton Road, Suite GG23, Atlanta, Georgia 30322, USA. E-mail: [email protected] 236
non-PKD1 and non-PKD2 status creates the potential for at least a third gene responsible for ADPKD. By reviewing the original pedigrees and phenotypes, analyzing original and recollected DNA, and directly sequencing the PKD1 and PKD2 genes in cases where this methodology was not available at the time of the original publication, Paul et al. have identified mutations in the PKD1 or the PKD2 gene with no evidence for a third unidentified locus. They clarify that the five ADPKD families previously
reported as unlinked to PKD1 or PKD2 mutations are not actually unlinked but were either misdiagnosed with ADPKD, with a presentation inconsistent with this disease, or reported as unlinked because of mixups regarding biological samples or pedigree. All are now identified as PKD1 or PKD2 affected families. This work strengthens the view of many that there are only two genes responsible for the development of ADPKD. Consistent with our understanding of the natural history of PKD1 and of PKD2, those described by Paul et al.1 with PKD2 mutations appear to have a milder phenotype.2 Despite these findings, concern regarding other genetic loci that might cause ADPKD continues. Although direct gene sequencing is the current gold standard for a molecular diagnosis of ADPKD, a significant proportion of ADPKD individuals (approximately 10–13% in the best of hands) fail to demonstrate a mutation in either the PKD1 or the PKD2 gene. Large direct sequencing studies, including by the Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP), have an approximately 86% rate of mutation detection.3 Those with no mutations detected in this well-characterized cohort have a range of disease severity, but a significant proportion have a mild phenotype, similar to PKD2 CRISP individuals, and similar to other PKD families previously reported as unlinked. The absence of mutation identification in these individuals has been ascribed to the difficulty of completely sequencing the PKD1 gene; potential disease-causing sequence changes in non-coding regions in both PKD1 and PKD2; mosaicism; or combined hypomorphic alleles. Even considering these possibilities, genes other than PKD1 or PKD2 may cause ADPKD, and clarification of this issue is needed. A full understanding of the genetic epidemiology of ADPKD is necessary to develop an accurate natural history of ADPKD, provide accurate prognostic information to patients, develop novel targets for Kidney International (2014) 85, 232–247
2.
3.
4.
5.
6.
Cummins EP, Berra E, Comerford KM et al. Prolyl hydroxylase-1 negatively regulates IkappaB kinase-beta, giving insight into hypoxia-induced NFkappaB activity. Proc Natl Acad Sci USA 2006; 103: 18154–18159. Peyssonnaux C, Datta V, Cramer T et al. HIF-1a expression regulates the bactericidal capacity of phagocytes. J Clin Invest 2005; 115: 1806–1815. Heemann U, Szabo A, Hamar P et al. Lipopolysaccharide pretreatment protects from renal ischemia/reperfusion injury: possible connection to an interleukin-6dependent pathway. Am J Pathol 2000; 156: 287–293. Zager RA, Johnson AC, Lund S. ‘Endotoxin tolerance’: TNF-alpha hyper-reactivity and tubular cytoresistance in a renal cholesterol loading state. Kidney Int 2007; 71: 496–503. He K, Chen X, Han C et al. Lipopolysaccharideinduced cross-tolerance against renal ischemia–reperfusion injury is mediated
7.
8.
9.
10.
by hypoxia-inducible factor-2a-regulated nitric oxide production. Kidney Int 2014; 85: 276–288. Kojima I, Tanaka T, Inagi R et al. Protective role of hypoxia-inducible factor-2a against ischemic damage and oxidative stress in the kidney. J Am Soc Nephrol 2007; 18: 1218–1226. Schley G, Klanke B, Schodel J et al. Selective stabilization of HIF-1a in renal tubular cells by 2-oxoglutarate analogues. Am J Pathol 2012; 181: 1595–1606. Wang Z, Schley G, Turkoglu G et al. The protective effect of prolyl-hydroxylase inhibition against renal ischaemia requires application prior to ischaemia but is superior to EPO treatment. Nephrol Dial Transplant 2012; 27: 929–936. Zager RA, Johnson AC, Hanson SY et al. Ischemic proximal tubular injury primes mice to endotoxin-induced TNF-alpha generation and systemic release. Am J Physiol Renal Physiol 2005; 289: F289–F297.
see basic research on page 289
Myofibroblasts: the ideal target to prevent arteriovenous fistula failure? Juan Camilo Duque1 and Roberto I. Vazquez-Padron1 The arteriovenous fistula (AVF) failure is a major cause of morbidity in the hemodialysis population. Most AVFs fail due to neointimal hyperplasia (NIH). In this issue, Yang et al. delineated a mechanism responsible for transforming the fistula adventitia into a fertile soil for neointimal precursors. These authors pondered the role of hypoxia-regulated hypoxia-inducible factor-1 (HIF-1a), vascular endothelial growth factor A (VEGF-A), and matrix metalloproteinases (MMPs) in the activation of those adventitial myofibroblasts that may significantly contribute to the formation of the fistula neointima. Kidney International (2014) 85, 234–236. doi:10.1038/ki.2013.384
According to the US Renal Data System, 546,000 Americans rely on a vascular access to receive life-saving hemodialysis.1 The arteriovenous fistula (AVF) is the preferred vascular access 1 DeWitt Daughtry Family Department of Surgery, Leonard M. Miller School of Medicine, University of Miami, Miami, Florida, USA Correspondence: Roberto I. Vazquez-Padron, Department of Surgery, Leonard M. Miller School of Medicine, University of Miami, 1600 NW 10th Avenue, RMSB 1009D, Miami, Florida 33136, USA. E-mail: [email protected]
234
since the United States implemented the Fistula First Breakthrough Initiative in 2003, given its improved performance and lower complication rates compared with prosthetic grafts or central venous catheters. However, the rate of AVF failure (40–60%) is still unacceptable and profoundly impacts morbidity in the hemodialysis population. In general, AVF fails mostly because of complications secondary to obstructive neointimal hyperplasia (NIH). Despite the wide recognition of this problem, no
substantial efforts have been made so far to identify the underlying mechanisms that lead to the formation of occlusive neointima in AVF. The article by Yang et al.2 (this issue) contributes to the delineation of the cellular and molecular mechanisms responsible for transforming the fistula adventitia into a fertile soil for neointimal precursors. This and previous work from Dr. Misra’s group3 have highlighted the importance of hypoxiainducible factor-1 (HIF-1a), vascular endothelial growth factor A (VEGF-A), and matrix metalloproteinases (MMPs) in the activation of adventitial myofibroblasts that could potentially contribute to neointimal formation (Figure 1). Consequently, this study provides rationale for using anti-VEGF-A therapies at the time of fistula creation to avoid NIH and thus reduce the rate of primary failure in vascular accesses. Targeting myofibroblastic activity in the fistula adventitia at the time of creation to improve its maturation is an emerging idea that requires attention and further innovation. The myofibroblast is friend and foe during vein adaptation to arterial flow and is primordial to maintain venous hemostasis after AVF establishment.4 Myofibroblast precursors residing in the venous adventitia sense the abrupt mechanical forces produced by arterial flow to rapidly adjust its genomic expression program to help increase vascular resistance. This adaptive response includes the formation of bundles of contractile microfilaments and extensive cell-tomatrix attachment sites as well as the secretion of MMPs, collagen, and extracellular matrix proteins to re-enforce the fistula wall. However, the excessive myofibroblastic healing response typically observed after implementation of AVF contributes not only to neointimal formation but also to the thickening of the tunica media and adventitial fibrosis, which compromise the proper function of the fistula. As proposed by Yang et al.,2 an ideal therapy to reduce venous stenosis formation should be not only locally but also timely delivered to the adventitia of the vessel wall to prevent myofibroblast expansion while allowing Kidney International (2014) 85, 232–247
commentary
Surgical trauma
Myofibroblast activation
HIF-1α
Hypoxia
Myofibroblast precursors Adventitia
Myofibroblast
VEGF-A MMP-2 and -9
Proliferation Migration
Media
Intima Neointima cells
Figure 1 | Hypothetical mechanism leading to myofibroblast activation in the fistula adventitia. HIF-1a, hypoxia-inducible factor-1; MMP, matrix metalloproteinase; VEGF-A, vascular endothelial growth factor A.
the proper adaptation process within the outflow vein. This strategy is expected to prevent aneurysms and other complications associated with insufficient remodeling of the fistula wall. The article by Yang et al.2 also reminds us of a number of fundamental questions regarding the pathobiology of AVF that still remain unsolved. One of those current challenges concentrates on the anatomical source or sources of neointimal cells in the failed AVF. The remodeling of the outflow vein requires the expansion and mobilization of myofibroblasts from local precursors, given that recent studies have ruled out any contribution of circulating progenitors and fibrocytes (bone marrowderived) to this process.5 The venous cells that can transform into myofibroblasts are (1) adventitial fibroblasts, (2) pericytes, (3) endothelial cells (endothelial–mesenchymal transition), and (4) smooth muscle cells.6 The rate by which each of these cell types contributes to the pool of myofibroblasts in the neointima is unknown. The complete identification of the nature of the proliferating and migrating cells in the neointima is important because it could influence the choice of the antiproliferative drug and its dosing. Cell type-specific interventions mediated Kidney International (2014) 85, 232–247
by drugs might be an important part of the ideal approach to ameliorate stenosis and prolong access patency. Another major observation described by Yang et al.2 is the noxious effect of surgical trauma to the vasa vasorum of the outflow vein and its possible relationship with the development of NIH. In their murine fistula model, surgical trauma triggers the expression of HIF-1a and subsequent upregulation of VEGF-A and MMPs in adventitial myofibroblasts. Currently, the impact of ischemia/reperfusion injury on the outflow vein is considered a minor downstream factor determining fistula adequacy. The creation of the fistula in the mouse (by connection of the right carotid artery to the ipsilateral jugular vein) could be more traumatic than that in humans; so more studies with preclinical animal models and patients are warranted to determine whether surgical trauma is truly an independent predictor of fistula outcomes. Conversely, a recent retrospective study has shown a better overall functional patency in brachiobasilic AVFs implemented with a two-stage process that includes a complex surgical dissection (stage 1,
creation, and stage 2, transposition) than in those created in a single operation.7 The importance of developing novel periadventitial delivery systems to target early development of NIH in AVF is also recognized by Yang et al.2 The periadventitial delivery of drugs, genes, or cells over the anastomotic region of a newly created fistula can allow higher local treatment concentrations with lower systemic toxicity.8 This type of delivery has been demonstrated to be less problematic, as the vein and the anastomotic area are accessible for therapies during a surgical procedure. Paulson et al.9 have recently demonstrated the technical success and safety of perivascular delivery using sirolimuseluting wraps (COLL-R) around grafts in 12 patients. The individuals who received a sirolimus-eluting wrap around the graft venous anastomosis had excellent primary unassisted rates; however, this finding should be carefully considered, given that the study lacked a control group. Nevertheless, the results described by Paulson et al.9 demonstrate for the first time that periadventitial delivery of drugs can safely and effectively suppress NIH in dialysis accesses. Larger randomized trials are needed to determine whether COLL-R can prolong AVF patency. The fundamental question of whether a single application of a therapeutic agent is sufficient to control a chronic process will require careful studies. In conclusion, we should remain cautious in interpreting and extrapolating from the new study by Yang et al.,2 mostly because of the inherent limitations of its animal model. Mice are useful in gaining insight into the mechanisms leading to NIH, but the hemodynamics, vascular anatomy, and pathology of rodents do not necessarily mimic those of humans. This skepticism is further amplified by the failure of presumed therapies that were effective in animals to prevent NIH in patients.10 Therefore, the efficacy of local delivery of anti-VEGF monoclonal antibody (bevacizumab) or small hairpin RNAs in preventing AVF stenosis should be tested in large animals whose physiology, function, and anatomy are closer to those 235
commentary
of humans as part of the complex journey from the bench to the beside.
5.
DISCLOSURE
The authors declared no competing interests.
6.
REFERENCES
7.
1.
2.
3.
4.
US Renal Data System. USRDS 2012 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States. National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health: Bethesda, MD, USA, 2012; www.usrds.org. accessed 12 July 2013. Yang B, Janardhanan R, Vohra P et al. Adventitial transduction of lentivirus-shRNAVEGF-A in arteriovenous fistula reduces venous stenosis formation. Kidney Int 2014; 85: 289–306. Janardhanan R, Yang B, Vohra P et al. Simvastatin reduces venous stenosis formation in a murine hemodialysis vascular access model. Kidney Int 2013; 84: 338–352. Coen M, Gabbiani G, Bochaton-Piallat M-L. Myofibroblast-mediated adventitial
8.
9.
10.
remodeling. Arterioscler Thromb Vasc Biol 2011; 31: 2391–2396. Skartsis N, Manning E, Wei Y et al. Origin of neointimal cells in arteriovenous fistulae: bone marrow, artery, or the vein itself? Semin Dial 2011; 24: 242–248. Hinz B, Phan SH, Thannickal VJ et al. The myofibroblast: one function, multiple origins. Am J Pathol 2007; 170: 1807–1816. Vrakas G, Defigueiredo F, Turner S et al. A comparison of the outcomes of one-stage and two-stage brachiobasilic arteriovenous fistulas. J Vasc Surg 2013; 53: 1632–1638. Cheung AK, Terry C, Li L. Pathogenesis and local drug delivery for prevention of vascular access stenosis. J Ren Nutr 2008; 18: 140–145. Paulson WD, Kipshidze N, Kipiani K et al. Safety and efficacy of local periadventitial delivery of sirolimus for improving hemodialysis graft patency: first human experience with a sirolimus-eluting collagen membrane (Coll-R). Nephrol Dial Transplant 2012; 27: 1219–1224. Conte MS, Bandyk DF, Clowes AW et al. Results of PREVENT III: a multicenter, randomized trial of edifoligide for the prevention of vein graft failure in lower extremity bypass surgery. J Vasc Surg 2006; 43: 742–751.
see clinical investigation on page 383
The importance of quantifying genetic heterogeneity in ADPKD Arlene B. Chapman1 Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary renal disease. New data from Paul et al. suggest that mutations in the PKD1 and PKD2 genes may account for all cases of ADPKD. Further improvements in mutation detection methodologies are needed to determine the true relative frequency of PKD1 versus PKD2 as well as to establish the value of mutation type and location to predict disease severity in this disorder. Kidney International (2014) 85, 236–237. doi:10.1038/ki.2013.371
In this issue of Kidney International, Paul et al.1 painstakingly review five independent families with autosomal dominant polycystic kidney disease (ADPKD) reported not to be linked to mutations in either the PKD1 or the PKD2 gene. The initial assignment of 1
Emory University School of Medicine, Atlanta, Georgia, USA Correspondence: Arlene B. Chapman, Emory University School of Medicine, Clinical Interaction Network, 1364 Clifton Road, Suite GG23, Atlanta, Georgia 30322, USA. E-mail: [email protected] 236
non-PKD1 and non-PKD2 status creates the potential for at least a third gene responsible for ADPKD. By reviewing the original pedigrees and phenotypes, analyzing original and recollected DNA, and directly sequencing the PKD1 and PKD2 genes in cases where this methodology was not available at the time of the original publication, Paul et al. have identified mutations in the PKD1 or the PKD2 gene with no evidence for a third unidentified locus. They clarify that the five ADPKD families previously
reported as unlinked to PKD1 or PKD2 mutations are not actually unlinked but were either misdiagnosed with ADPKD, with a presentation inconsistent with this disease, or reported as unlinked because of mixups regarding biological samples or pedigree. All are now identified as PKD1 or PKD2 affected families. This work strengthens the view of many that there are only two genes responsible for the development of ADPKD. Consistent with our understanding of the natural history of PKD1 and of PKD2, those described by Paul et al.1 with PKD2 mutations appear to have a milder phenotype.2 Despite these findings, concern regarding other genetic loci that might cause ADPKD continues. Although direct gene sequencing is the current gold standard for a molecular diagnosis of ADPKD, a significant proportion of ADPKD individuals (approximately 10–13% in the best of hands) fail to demonstrate a mutation in either the PKD1 or the PKD2 gene. Large direct sequencing studies, including by the Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP), have an approximately 86% rate of mutation detection.3 Those with no mutations detected in this well-characterized cohort have a range of disease severity, but a significant proportion have a mild phenotype, similar to PKD2 CRISP individuals, and similar to other PKD families previously reported as unlinked. The absence of mutation identification in these individuals has been ascribed to the difficulty of completely sequencing the PKD1 gene; potential disease-causing sequence changes in non-coding regions in both PKD1 and PKD2; mosaicism; or combined hypomorphic alleles. Even considering these possibilities, genes other than PKD1 or PKD2 may cause ADPKD, and clarification of this issue is needed. A full understanding of the genetic epidemiology of ADPKD is necessary to develop an accurate natural history of ADPKD, provide accurate prognostic information to patients, develop novel targets for Kidney International (2014) 85, 232–247