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February 2023, Volume 73, Issue 2

SHORT COMMUNICATION

Role of stem cells in arteriovenous access: perspective from Lower Middle Income Countries

Authors: Nadeem Ahmed Siddiqui  ( Department of Vascular Surgery, Aga Khan University Hospital )
Aden Javed  ( 3rd Year MBBS Student, Medical College, Aga Khan University, Karachi, Pakistan )
Ahsan Raza Raja  ( 3rd Year MBBS Student, Medical College, Aga Khan University, Karachi, Pakistan )

Abstract

Adequately created well functional haemodialysis access is an important part for the physical and mental wellbeing of renal failure patients. Every effort should be made to enhance the patency of these accesses. Recently, stem cell treatment modalities have opened new avenues in the better patency of arteriovenous fistula. Use of mesenchymal stromal cells (MSC) to prevent venous neointimal hyperplasia have been studied with good success rates. Adopting such costly treatment modalities in low middle income class country like Pakistan is associated with significant challenges. This short report discusses the current role of stem cells in arteriovenous access and how this exciting modality can be utilized in our country.

 

Keywords: Dialysis access, arteriovenous fistula, Stem cell, Mesenchymal stromal cell.

 

DOI: 10.47391/JPMA.AKUS-26

 

Introduction

 

Globally there are more than 850 million individuals who are living with chronic kidney disease (CKD), acute kidney injury (AKI), and renal replacement therapy (RRT), of these more than 4 million people have end stage kidney disease (ESKD) in which chronic dialysis is required for survival.1 For vascular access in these individuals The National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative (NKF-KDOQI) recommends using arteriovenous fistulas (AVF) rather than arteriovenous graft (AVG) or central venous catheter (CVC), as these two have been associated with a higher rate of complications and risk of mortality when compared to AVFs.2,3 Kenneth Appell successfully made the first subcutaneous anastomosis between the radial artery and the cephalic vein in 1965, following its ideation by James E. Cimino and Michael J. Brescia as shown in figure 1.

 

 

This pioneering surgery was named arteriovenous fistula which got published in 1966.4 The anastomosing of an artery to a nearby vein enables blood to skip the capillary network and directly move from the artery into the vein, this high pressure and flow of arterial blood causes arterialization of the vein over time (Figure1).5

In the recent years there has been a large shift to upper arm AVFs due to NKF-KDOQI’s clinical practice guidelines.7 However 60 % of AVFs are unable to mature owing to the formation of VS, following venous neointimal hyperplasia (VNH), in the venous outflow tract.8 It is suggested that aberrant shear force, hypoxic damage, inflammatory cytokines, matrix deposition, and other variables all contribute to the pathogenesis of VNH/VS.8 In the United States, the yearly cost of placing and maintaining dialysis VA surpasses a billion dollars.9 Targeting vascular remodelling and healing surrounding the arteriovenous anastomosis after AVF construction is critical to reducing stenosis development since juxta anastomotic is the most frequent site for AVF stenosis to develop.10 Numerous researches have focussed on creating local therapeutics to prevent VNH development, these include gene therapies, recombinant elastase, biologic small molecule inhibitors, and stem cells.11-15 In this short report, we aim to discuss the evolving role of stem cells for better patency of AVF, implementation challenges pertaining to low-middle class income countries like Pakistan and future prospects for this treatment modality in resource constraint countries.

 

Role of stem cell in dialysis access

 

Stem cell treatment has emerged as a very promising and sophisticated scientific research topic in the past decade or so. The advancements in medical treatment options have sparked high hopes.16 Stem cells are often categorized according to their differentiation potentials, which include totipotent, pluripotent, multipotent, and unipotent.17 According to recent studies multipotent mesenchymal stromal cells (MSCs), often referred to as mesenchymal stem cells, are able to differentiate into different cell types from their original tissue under certain circumstances, unlike the previous belief that they are only able to develop into cell types within a single lineage, for this reason they have numerous benefits and applications.18 MSCs can be isolated from bone marrow or adipose tissue thus are autologous and have a limited risk of tissue rejection and ethical problems as compared to fatal pluripotent stem cells which are acquired from fatal tissues or aborted embryos.19,20 MSCs also possess anti-inflammatory, anti-apoptotic, and immunomodulatory properties, furthermore they are able to migrate to sites of injuries and inflammation and are able to play an important role in tissue development, repair, and protection.21,22 In context to the role of MSC in dialysis access surgery, MSCs at the anastomosis may alter late remodelling occurring because of changes in vessel wall shear stress.23 A study involving an immunodeficient male mice model demonstrated that topical application of 250,000 allogenic adipose tissue-derived MSCs to the adventitial surface of the outflow vein (periadventitial xenotransplantation) during carotid artery to jugular vein AVF construction reduces the formation of VNH/VS, hence increasing patency of AVF by suppressing Mcp-1 gene expression.24  This gene is responsible for monocyte recruitment and the reduction of CD68 (+) cell infiltration into the vessel wall.24 At present there is a scarcity of literature on cell transplantation in human AVFs. However, Conte et al. have previously done multi-centre phase 1 and 2 clinical trials that evaluated the safety of human (allogenic) endothelial cell implants (Vascugel) following the formation of arteriovenous access for dialysis purposes. In the second phase, 57 individuals (27 AVF and 30 AVG) were recruited and were randomly selected for Vascugel or placebo (control matrices) during operation. Since no significant difference was found in early complication rates among the Vascugel and placebo groups at four weeks, this trial met its primary objective of safety. Later on, the complications reported were mainly vascular access-related issues or ESKD-related comorbidities. At 24 weeks, there was no statistically significant difference in patency amidst the control and treatment group (AVFs and AVGs); nevertheless, the study might not be sufficiently powered to establish a statistically significant difference. The results suggest that, as compared to alternative cell therapies, MSCs likely have a substantial role in extending dialysis AVF longevity.25 Recent  studies like the one done by Piryani et al. has examined the efficacy of human adipose-derived MSCs in averting AVF failure by limiting VNH.26

Past studies have reported the use of stem cells and progenitor cells for aiding in vascular remodelling and endothelial regeneration.14,24 In a bovine model, autologous late outgrowth endothelial cells administration to the anastomosis site following insertion of polytetrafluoroethylene grafts for dialysis reduces venous stenosis (VS).13 Another study demonstrated coculturing endothelial progenitor cells and fibroblasts decreased fibroblasts conversion to myofibroblasts during hypoxic damage in cell culture.27 Forte et al. documented MSCs to have decreased carotid artery stenosis following arteriotomy in a rat model as the luminal area was 36% larger in carotid arteries treated with MSC compared to arteries of individuals in the control group.28 Although many studies have assessed the role of stem cell on different aspects of arteriovenous access, Table 1 summarize some of the important studies done in this area.

 

 

Barriers for stem cell research and therapy

 

Stem cell therapy implementation faces a lot of barriers in a developing country like Pakistan, these include socioeconomic, religious and infrastructural challenges.29 Pakistan's healthcare system facilities are inadequate to fulfil the demands of its people. On average, one hospital bed exists for more than 1,680 individuals.30 Considering 40% of the country lives under the poverty line, gross enrolment numbers in secondary schools is below 23%; neonatal mortality rates of 40.4 per 1000 live births and an unemployment rate of 6.3%, so a great majority of households are unable to fund stem cell therapies due to insufficient earnings and financial constraints.31 Other challenges concerning stem cell therapies and its expansion include low levels of education, a shortage of qualified human resources, struggle to stay up-to-date with technological advances, a dearth of information, an absence of civic infrastructure, an absence of medical insurance, exorbitant private healthcare and pharmaceutical costs, challenges in following up, an absence of social workers, rehabilitative help, inadequate freshwater availability, and poor sanitation and cleanliness.32 There is currently no official Islamic stance on stem cell studies. However, a few Muslim leaders support stem cell research on the rationale that an embryo in the early stages of gestation lacks a soul, whereas others say that aborting a foetus at any point of gestation is ethically wrong.33 More importantly in Pakistan there is  spread of misinformation and extremism which have contributed to by social inequality, narcotics trafficking, religious oppression, as well as psychological factors.34 All the above mentioned limitations gets even more complicated by the fact that available literature on the role of stem cell in dialysis access procedures is scarce and do not conclusively support the long term beneficial role of stem cell therapy.

 

Conclusion

 

Despite all these challenges, prospect of stem cell treatment in dialysis access surgeries are very bright and every effort should be made to address the above-mentioned issues by creating adequate social awareness, proper networking and collaboration at national and international level, seeking funding opportunities for such projects, acquiring human and infrastructural resources like state-of-the-art labs with trained personnel and aiming to develop policies which support such endeavours.

There seems to be great possibilities for therapeutic intervention with MSCs, with no notable side effects. Nevertheless, it will take a good amount of time before MSCs can actually come in common use in inpatient beds or physician practices globally let alone in Pakistan. There are presently more than 1,130 registered Clinical Trails (CTs) mentioned on clinicaltrials.gov for MSCs of these 35 have been completed and are published, with favourable outcomes and no major complications. This figure is set to increase in the near future. The growing number of CTs, especially MSCs, will aid in assessing the clinical efficacy and potential of these intriguing biological reservoirs.

 

Disclaimer: None to declare.

 

Conflict of Interest: None to declare.

 

Funding Disclosure: None to declare.

 

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