J Artif Organs DOI 10.1007/s10047-014-0767-z

REVIEW

Artificial Kidney / Dialysis

Is regenerative medicine a new hope for kidney replacement? Maciej Nowacki • Tomasz Kloskowski • Marta Pokrywczyn´ska • Łukasz Nazarewski Arkadiusz Jundziłł • Katarzyna Pietkun • Dominik Tyloch • Marta Rasmus • Karolina Warda • Samy L. Habib • Tomasz Drewa

•

Received: 12 September 2013 / Accepted: 1 April 2014  The Japanese Society for Artificial Organs 2014

Abstract The availability of kidney and other organs from matching donors is not enough for many patients on demand for organ transplant. Unfortunately, this situation is not better despite the many of new interesting projects of promoting family, cross or domino transplants. These inexorable global statistics forced medical researchers to find a new potential therapeutic option that would guarantee safety and efficacy for the treatment of ESRD comparable to kidney transplantation. The aim of our review is to summarize the scientific literature that relating to the modern as well as innovative experimental methods and possibilities of kidney regeneration and, in addition, to find whether the regenerative medicine field will be a new hope for curing the patient with renal disease complications. The most important achievements in the field of regenerative medicine of kidney, which were mentioned and described here, are currently cumulated in 4 areas of interest: stem cell-based therapies, neo-kidneys with specially designed

M. Nowacki (&)
T. Kloskowski (&)
M. Pokrywczyn´ska
A. Jundziłł
K. Pietkun
D. Tyloch
M. Rasmus
K. Warda
T. Drewa Department of Tissue Engineering, Nicolaus Copernicus University in Torun´, Ludwik Rydygier Collegium Medicum, Ul. Karłowicza 24, 85-092 Bydgoszcz, Poland e-mail: [email protected] T. Kloskowski e-mail: [email protected] Ł. Nazarewski Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland A. Jundziłł Department of General and Endocrine Surgery, Nicolaus Copernicus University in Torun´, Ludwik Rydygier Collegium Medicum, Bydgoszcz, Poland

scaffolds or cell-seeded matrices, bioartificial kidneys and innovative nanotechnologically bioengineered solutions. Nowadays, we can add some remarks that the regenerative medicine is still insufficient to completely replace current therapy methods used in patients with chronic kidney disease especially with the end-stage renal disease where in many cases kidney transplantation is the only one chance. But we think that development of regenerative medicine especially in the last 20 years brings us more and more closer to solve many of today’s problems at the frontier of nephrology and transplantology. Keywords Kidney regeneration
Regenerative medicine
Tissue engineering

K. Pietkun Department and Clinic of Rehabilitation, Nicolaus Copernicus University in Torun´, Ludwik Rydygier Collegium Medicum, Bydgoszcz, Poland S. L. Habib Department of Geriatric, South Texas Veterans Health System, The University of Texas Health Science Center, San Antonio, TX, USA S. L. Habib Department of Cellular and Structural Biology, The University of Texas Health Science Center, San Antonio, TX, USA T. Drewa Urology Department, Nicolaus Copernicus Hospital in Torun´, Torun´, Poland

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Introduction The first successful solid organ transplantation was performed in kidney between identical twins in Boston, USA, 1954. The new era of kidney transplantation was considered with a major advance of modern medicine that provides high-quality life with more than 90% survival rate in patients with end-stage renal disease (ESRD) [1, 2]. However, the availability of kidney and other organs from matching donors is not enough for many patients on demand for organ transplant. These inexorable statistics forced medical researchers to find a new potential therapeutic option that would guarantee safety and efficacy for the treatment of ESRD comparable to kidney transplantation. Regenerative medicine and stem cell therapies seem to be very promising fields for many patients with chronic kidney disease (CKD) and acute kidney injury (AKI) [3–8].

Aim of the work The aim of review is to summarize the scientific literature that relating to the modern as well as innovative experimental methods and possibilities of kidney regeneration and, in addition, to find whether the regenerative medicine field will be a new hope for curing the patient with renal disease complications.

Most important clinical problems and needs in kidney failure treatment Current treatment of chronic kidney failure is based on early referral of patient with chronic kidney disease to nephrologists, to minimize the disease progression at the earlier stages, and kidney replacement therapy at the endstage of renal disease. The first indicators for referral to nephrologist are changes in glomerular filtration rate (\30 mL/min/1.73 m2), progressive decline of kidney function ratio of urine protein to creatinine[100 mg/mmol (about 900 mg/24 h) or urine albumin to creatinine ratio [60 mg/mmol (about 500 mg/24 h), inability to achieve treatment targets and rapid changes in kidney function [9– 11]. The majority of patients with early CKD do not establish renal failure, but they have increased risk of cardiovascular disease or other systemic complications. However, this group of patients has a relatively guaranteed treatment, care and the availability of modern medicines or precisely constructed guidelines and recommendations [12, 13]. There are many patients with CKD at stage 4 or 5 who are qualified for kidney replacement. Those patients have severe reduction of kidney function or end-stage renal

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failure (ESRF) defined by some authors as end-stage renal disease (ESRD). Those patients have significant problems with renal replacement therapy (RRT)—including longterm dialysis or current dilemmas of transplantology and high mortality rates [14–16]. Long-term dialysis can be correlated with many complications and systemic clinical problems including anemia, higher risk of cardiovascular disease, protein-calorie malnutrition, problems with infection, lower level of immunity, renal osteodystrophy, calciphylaxis, and other important pathological and pathophysiological negative changes [17–19]. In current kidney transplantation, there is a problem of increasing number of global organ needs and insufficient number of potential donors. Unfortunately, this situation is not better despite the many of new interesting projects of promoting family, cross or domino transplants. Moreover, it was estimated that waiting list for renal transplants in US increased four times in the last 10 years [20–22]. Another very important group of patients is the group with AKI especially in a large group of intensive care patients. AKI is described as a violent loss of kidney function. AKI can be caused by pre-renal volume depletion and reduced renal perfusion, filtration rate, intrinsic due to failure to the glomeruli, renal tubules or interstitium or postrenal caused by obstruction of urinary tract. In addition, AKI may be diagnosed on the basis of the rapid increase of creatinine and urea concentration in the serum or reduction of urine output. Moreover, loss of kidney function is characterized by disorders of electrolyte equilibrium especially hyperkalemia which may reveal arrhythmias. The precise diagnosis of the cause of AKI is based on accurate medical history, examination and supporting tests. Acute Dialysis Quality Initiative (ADQI) proposed the RIFLE criteria useful in the staging of patients with AKI, which determine the specific stage and clinical status of patient. Treatment of patients with AKI is still problematic issues despite a huge number of developed concepts and medical guidelines [23–28].

The place of tissue engineering and regenerative medicine in current medicine Tissue engineering is a multidisciplinary biomedical tool that applies the principles of engineering and life sciences toward the development and manufacture of biological substitutes that could restore, maintain and improve the function of damaged tissues [29, 30]. Regenerative medicine is a new branch of clinical medicine strictly directed to the development of new therapies for series of common diseases. In a comprehensive and expanded definition, we can recognize that the

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term ‘‘regenerative medicine’’ refers to the clinical application of procedures directly based on tissue engineering assumptions and achievement, serving onto the maximal restoring or replacing damaged tissues and organs. This definition also includes the therapeutic use of such methods in anti-aging or correlated with previous degeneration processes of the cells, as well as potential auxiliary element in systemic correction of congenital or developmental structural and morphological defects, for example associated with previous intraoperative extensive resection or trauma intervention [31–33]. Crucial in the development of these two overlapping strictly science branches, such as tissue engineering and regenerative medicine in recent years, seems to be the use of specific cell therapies and scaffolds obtained through modern technological methods, such as nanotechnology, bio and synthetic polymers chemistry, material technology, and other novel and innovative chemical, engineering and biophysical processes [34–36]. It was indicated that regenerative medicine may be an alternative method of treatment of certain diseases such as diabetes mellitus or vitiligo, and could be a scientific hope for many unsolved medical problems [37, 38]. This type of hope is constructed mainly on the basis of still increasingly growing number of clinical procedures based on regenerative medicine and tissue engineering used in medical practice. The most well-known and developed tissue engineering procedures are used nowadays in the reconstructive orthopedics, especially in the cartilage regeneration [39–41]. During the last few decades many alternatives of regenerative therapies have been proposed for bladder or ureter reconstruction [42–45]. However, these new therapies in many descriptions are perceived as complicated, insufficient or severe in application for solid and parenchymatous organ regenerations [46, 47]. The key question for many nephrologists, urologists, transplantologists, biomedical scientists and many patients with kidney diseases is to obtain more information on how the dynamic development of regenerative medicine may have a potential influence on the future treatment of selected kidney diseases.

Stem cell-based therapy for kidney diseases The mammalian kidney has a low cell turnover. However, in response to injury, the number of proliferating renal cells rapidly increases [48]. Several studies were applied to identify which cell type promotes kidney regeneration. Identification of cells expressing stem markers is the main priority in adult patient with kidney disease. Different stem cell populations isolated from the kidney are characterized in Table 1.

Table 1 Stem cells/progenitors isolated from postnatal kidney Stem cells

Stem cell marker

Localization

References

rKS56

GDNF, Pax2, WT1, Wnt4, Sca-1, c-kit

S3 segment of nephron

Kitamura et al. [49]

Multipotent adult resident stem cell

CD133, PAX-2

Interstitium and proximal tabuli

Bussolati et al. [50]

MSCs

CD34, Sca-1, CD29, CD44, CD49e, CD90.2

Glomeruli

da Silva Meirelles et al. [51]

CD117 MRPCs

Vimentin, CD90 Pax-2, Oct4

Proximal tubules

Gupta et al. [52]

PEC

CD24, CD133

Bowman’s capsule

Sagrinati et al. [53]

Multipotent mesenchymal stem cells

CD133-, CD146, CD24, PAX-2, CD29, CD34, CD166, CD73, CD90, CD105, CD146, vimentin, nestin

Glomeruli deprived of the Bowman’s capsule

Bruno et al. [54]

Kidney progenitors

CD133, nestin, SSEA4, Nanog, SOX2, OCT4/ POU5F1

Papilla loop of Henle

Ward et al. [55]

MRPC multipotent renal progenitor cells PEC parietal epithelial cells

There are evidences that bone marrow mesenchymal stem cells (BM-MSCs) and hematopoietic stem cells (HSCs) migrate to the kidney following injury and contribute regeneration [56, 57]. Based on this observation, the therapeutic effect of exogenous BM-MSCs and HSCs has been investigated in both animal models and patients with AKI [58, 59]. In addition, several studies indicated that administration of exogenous BM-MSCs or HSCs into patients with AKI improved functional and structural recovery of both glomerular and tubular compartments. Another study showed that bone marrow stem cells may replace tubular, mesangial, interstitial, podocytes and endothelial cells [60–65]. However, the contribution of bone marrow stem cells in renal regeneration is very low and it does not exceed a few percent of cells [66]. The role of HSCs in kidney regeneration following AKI was evaluated by either mobilizing HSCs using cytokines or by transfusing HSCs. The outcomes of these studies vary considerably. It was reported that bone marrow stem cells’ mobilization with G-CSF, combination of G-CSF and M-CSF or G-CSF and SCF may be renoprotective in cisplatin, gentamycin or folic acid-induced model of AKI [67–69]. In contrast, To¨egel et al. reported that HSCs’ mobilization with G-CSF has a deleterious effect on renal function in the

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ischemic AKI. In this study, HSCs’ mobilization was associated with increased severity of renal failure and mortality compared to the control. This may be explained by mobilization by G-CSF of other cells than HSCs such as granulocytes [70]. The therapeutic effect of HSCs transplantation is shown in recent study using rat model of ischemic AKI. HSCs were detected in the kidney at significant amounts only within the first 24 h after infusion. This study shows no differences in kidney function or histomorphologic changes of AKI after HSCs administration compared to control animals. This study provided evidence that HSCs do not significantly contribute to tubular repair or ameliorate renal damage in ischemic AKI [71, 72]. Small number of transplanted HSCs could be incorporated into post-ischemic renal tubules and express epithelial markers. In addition, HSCs do not integrate into renal tubules in the first week after injury when most renal repair occurs. Moreover, phenomenon of differentiation of bone marrow stem cells into the epithelial cells may be the results of cell fusion. It may consider that intrarenal cells are the main source of renal repair, and a single injection of bone morrow stem cells does not make a significant contribution to renal functional or structural recovery [59, 62, 66, 67]. Several preclinical experiments indicated that transplantation of in vitro expanded bone marrow MSCs may protect and reverse AKI. It is believed that BM-MSCs facilitate kidney regeneration not only by differentiation in renal cells but mainly also by secretion of trophic factors, which enhance regeneration [58, 62, 73]. Currently, there are two trails: the phase I clinical trial (NCT00733876) is to evaluate the safety of allogeneic bone marrow MSCs for treatment of AKI following cardiac surgery. The second trial (NCT01275612) is to test the feasibility and safety of systemic infusion of allogenic ex vivo expanded BM-MSCs to repair the kidney and improve function in patients with solid organ cancers who develop AKI after chemotherapy with cisplatin. The results of these trials will be fundamental for the future research to improve the transplantation process in patients with AKI.

Stem cells and kidney regeneration Because kidney has more complex construction and function than other parts of urinary tract like bladder, ureter or urethra, its regeneration using tissue engineering should be more difficult and will require use of several types of cells. Tissue engineering, the developing field of science, leads to isolation of new stem cells that can be used for organ regeneration. Different types of cells have been used in kidney regeneration, but these experiments were performed mainly in vitro or on small animal model (rodents). Lack of

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clinical data and studies on large animal models like pig shows complexity of kidney regeneration and indicates that it is too early to find promising treatment. One of the earliest conceptions in kidney tissue engineering was the use of embryonic stem cells (ESCs). These cells have totipotential properties and are able to differentiate to each type of cell. ESCs were successfully differentiated into renal cells using different types of factors. The embryonic stem cell lines can be differentiated into embryonic renal tubule epithelia when culture medium was supplemented with bone morphogenetic protein 4 (BMP4) [74]. Other studies showed that differentiation of ESCs into renal lineage was performed in three-step protocol using BMP4, activin A and lithium in first stage, retinoic acid in second and conditioned medium in last stage [75]. Similar factors for ESCs differentiation were showed in murine ESCs, with induced pluripotent stem cells (iPS) generated from mouse fibroblasts into tubular cells and podocytes [76–78]. Culture of these two cell types in medium supplemented with activin, glial-derived neurotrophic factor (GDNF) and bone morphogenetic protein 7 (BMP7) resulted in differentiation of mature renal cells. Interestingly, another study proposed regeneration of kidney-like tissue using renal progenitor cells without scaffold [79, 80]. In first stage, Wolffian ducts (WD) from timed pregnant rats at embryonic day 13 were isolated, cultured and allowed to bud creation. Next, each bud was separated and suspended in matrigel which induced branching to ureteric bud. Branched ureteric bud cells were next recombined with metanephric mesenchyme isolated from kidney in embryonic day 13, which allowed formation of tissue resembled latestage embryonic kidney. Such tissue implanted to rats developed branched collecting duct system, nephrons, glomeruli and apparent vasculature. Another study showed possibility of three-dimensional renal structure formation from a single primary renal cell in vitro. In addition, tubule- and glomerulus-like cells formation was observed in three-dimensional collagen-based culture system [81]. Highly expressed Sall1 (gene essential for kidney development), metanephric mesenchyme cell isolated from mouse embryos, was able to create colonies and form 3D kidney structure composed of glomeruli and renal tubules [82, 83]. In other, study kidney development was conducted using blastocyst complementation. Sall1-/- deficient blastocyst cells were complemented with pluripotent stem cells (PSC); as a result, deficient cells were replaced and the generated kidneys formed completely by injection of the PSC [84]. Another method is embryonic metanephrons transplantation. These structures after implantation were able to develop, enlarge and produce EPO and renin even to differentiate into functional nephrons [85–88]. Disadvantages of using the ESCs are ethical concerns and possibility of teratoma formation [89, 90].

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In recent years, scientists focused on more differentiated stem cells like bone marrow-derived MSCs, adiposederived stem cells (ADSCs), or amniotic fluid stem cells (AFSCs). Mesenchymal stem cells can be obtained from bone marrow. Despite invasive collection of tissue, this type of cells is easy to culture in vitro. Bone marrow MSCs have great potential to differentiate into many types of cells including renal epithelium [62], glomerular mesangial cells [65], tubular cells and glomerular podocytes [91], renal peritubular capillary when injected into host [64], or renal stem cells when implanted into mice with acute kidney ischemia/reperfusion [92]. Fat tissue is the excellent source of stem cells and can be obtained from minimal invasive liposuction, these cells are easy to isolate and culture and have great differentiative potential. ADSCs cultivation in conditioned medium derived from tubular epithelial cell culture promotes differentiation into epithelial cells, which was confirmed by expression of characteristic markers (cytokeratin 18, ZO-1, ZO-2) [93, 94]. Stem cells derived from amniotic fluid (AFSCs) also can be used for kidney regeneration. AFSC can integrate into existing renal tissues when injected into isolated murine embryonic kidney. Transfected with GFP stem cells derived from human amniotic fluid were able to integrate and proliferate during kidney organogenesis having potential to kidney regeneration [95]. Two years later another study showed that AFSCs cultured in medium containing FGF4 and hepatocyte GF triggered expression of ZO-1 (zona occludens-1, early kidney marker), CD2AP and NPHS2, which are markers of podocytes [96]. Chimeric culture of human AFSCs with mouse embryonic kidney cells resulted in AFSCs differentiation into renallike cells expressing renal cell markers: Pax-2, E-cadherin, calbindin, Wnt1 and laminin [97]. Similar to BM-MSCs, AFSCs can stimulate renal cell proliferation by paracrine effect when injected to immunodeficient mice with AKI. The effect between BM-MSCs and AFSCs was similar, and therefore BM-MSCs have advantage because of its greater availability [98, 99]. Taken together, it is hard to choose at this moment the most suitable stem cell type for kidney regeneration. Experiments with ESC showed the best results, but ethical concerns and possibility of teratoma formation limited their use. Alternative is use of autologous adult stem cells, which are not ethically controversial, do not induce immunological response and can be obtained during minimal invasive procedures. BM-MSC has been most frequently used for renal repair and regeneration, but stem cells from other sources like fat tissue or amniotic fluid have also promising properties. The experiments were performed only in vitro and on small animal models

indicating early stage of study. There is also small number of experiments with cells seeded on scaffold. More experiments about possibility of stem cells differentiation into renal cells and their growth on proper scaffold are necessary to expand study on large animals like pigs for example. The iPS are probably the future of the regenerative medicine of the kidney but unfortunately the method of secure and isolation is still not developed [100, 101].

Scaffolds and kidney regeneration Searching for the proper scaffold for cell growth is one of the most important issues in tissue and organ regeneration. Every year there is new materials created through development of biomaterial engineering (Table 2). The simplest Table 2 Scaffolds used in kidney regeneration Scaffold type

Application

Cells

References

Collagen vitrigel membrane

Renal glomerular tissue construction

Glomerular epithelial and mesangial

Wang and Takezawa [108]

Hyaluronic acid

UB branching

UB and MM

Rosines et al. [109]

Bovine pericardium (collagen and elastin)

CRF

Bone marrowderived cells (mesenchymal stem cells or mononuclear cells)

Caldas et al. [110]

Polyglycolic acid

Kidney-like structure construction Artificial renal unit construction

Cloned metanephroi

Lanza et al. [111]

Postnatal renal segments

Kim et al. [113]

Collagen/ Matrigel

Renal construct creation

Renal cells (epithelial cells, vascular endothelial cells, mesenchymal cells)

Lu¨ et al. [112]

Renal extra cellular matrix (ECM)

Wholekidney regeneration

Unseeded/ epithelial and endothelial cells/ embryonic stem cells

Sullivan et al. [102], Orlando et al. [103], Park et al. [104], Nakayama et al. [105], Song et al. [106], Bonandrini et al. [107]

Polyglycolic acid

UB ureteral bud, MM metanephric mesenchyme, CRF chronic renal failure

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method seems to be kidney decellularization, seeding such prepared scaffold with autologous cells and transplantation of created ‘‘neo-kidney’’ to the host. Sullivan and coworkers showed possibility of porcine kidney decellularization to create scaffold for whole-organ regeneration. They used SDS or Triton X for decellularization process in a high-throughput decellularization apparatus. These data conclude that prepared scaffold seeded with proper cells could be used in future for kidney regeneration [102]. The same group in earlier study have implanted decellularized porcine kidney to pig for 2 weeks. However, implantation of renal extra cellular matrix (ECM) led to thrombosis of vascular tree [103]. For proper function of such tissueengineered organ proceeding of blood vessels with endothelium is necessary. Similar studies on porcine or monkey kidney were conducted by other groups [104, 105]. Outstanding progress in this field was presented recently in the study of Song et al. In this work, regeneration of kidney tissues after kidney decellularization was performed by culture of epithelial and endothelial cells on scaffold surface in whole-organ bioreactor. As a result urine secretion was observed in vitro and in vivo through urinary conduit after orthotopic transplantation [106]. In work of Bonandrini et al., decellularization process of rat whole-kidney was reduced to 17 h preserving their structure of cortical extracellular matrix with architecture of vessels, glomeruli and tubuli preservation. Such prepared scaffold was next repopulated using murine ESCs. As a result recellularization of vascular structures, glomerular and peritubular capillaries was observed [107]. Scaffolds were also used for reconstruction of kidney components. Construction of renal glomerular tissue was performed using transparent collagen gel membrane called collagen vitrigel. Glomerular epithelial and mesangial cells were cocultured on both surfaces of this scaffold. Such approach resulted in three-dimensional reconstruction of glomerular organoid and was able to contribute to the polarity formation of epithelial cells [108]. In other study, hyaluronic acid in different concentration and molecular weight was able to modulate ureteric bud branching and promote mesenchymal-to-epithelial transformation, differentiation of metanephric mesenchyme, and ureteric bud and renal tubule development. Authors suggested that hyaluronic acid due to its properties can be used as a scaffold for kidney repair and tissue engineering [109]. Another experiment was performed on bovine pericardium scaffold seeded with bone marrow-derived cells (BM-MSC or mononuclear cells) in chronic renal failure (CRF) on rat model. Such prepared scaffolds were implanted into parenchyma of remnant kidneys which resulted in prevention of progressive deterioration of CRF [110]. Another approach is creation of structures resembling kidney properties. Lanza et al. used somatic cell nuclear

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transfer (therapeutic cloning) method for the construction of bioengineered kidney tissue. Unwoven polyglycolic acid sheets were used as a scaffold, which were seeded with cloned metanephroi (from adult cow fibroblasts) and transplanted into the subcutaneous space of the same cow for 6 and 12 weeks. As a result kidney-like structure, which produced urine-like fluid, built from organized glomeruluslike, tubular-like, and vascular elements was created [111]. Culture of renal cells (epithelial, vascular, endothelial and mesenchymal) on collagen/Matrigel scaffold was reported by Lu¨ et al. They observed construction of tubular- and glomerulus-like structures. Authors of this study suggested that such created renal construct can be used as a research model of drug detection or kidney development [112]. In other study, biodegradable polymer scaffold (Polyglycolic acid) seeded with postnatal renal segment (including nephron, epithelial, endothelial, vascular smooth muscle and stromal cells) was used for artificial renal unit creation. Such prepared constructs were next transplanted into subcutaneous dorsal space of 6 athymic mice. As a result, reconstitution of renal tissues (glomeruli and tubules) was observed [113].

Bioartificial kidney and nanotechnology The term bioartificial kidney (BAK) refers fully in the historical continuity to term ‘‘artificial kidney’’ and great assumptions of Dr. Kollf for an idea of a specifically designed system, which could support or replace natural filtrating process of the kidney [114]. Many of authors define BAK as a conventional hemofilter with bioreactor containing renal proximal tubule or another type of epithelial cells as an alternative for usually used dialysis machine [115–118]. In the scientific literature, the BAK term was used firstly as a defined description of specially constructed device with seeded previously in vitro cultivated cells in late ‘‘80s’’ of XX century in Aebischer [119– 121]. Many different BAK systems with innovative and different technical solutions were used in in vivo and in in vitro tests (Table 3), but in general the standard BAK device must be always constructed of clearly defined specific elements (Fig. 1). Different types of materials (scaffolds) were used in BAK construction. The most commonly used are hollow fibers from polyethersulfone (PES), polyvinylpyrrolidone (PVP), polysulfone (PSF) or their copolymers. Searching for new materials in recent years aims to find better solution in improving cell growth, their viability and proliferation on scaffold surface (Table 4). Such complicated construction and technical designs result from the very complex kidney function. The intention of the initiators of the BAK was not only a much better

J Artif Organs Table 3 Selected BAK systems: description depending on the applied solution Type of BAK

Construction model

References

Standard most popular BAK: Renal Tubule Assist Device (RAD)

This type of BAK is a hemofiltration cartridge containing 109 human renal tubule cells in a typical configuration of monolayer seeded in the hollow fibers.

Humes et al. [117]

RAD-Epo

A specially constructed erythropoietinexpressing bioartificial RAD device

Sun et al. [122]

BAK with embryonic stem cells

In this BAK concept, the device is based on the use of cultured human embryonic stem cells from isolated inner cell mass which could differentiate into the proximal tubular cells (Narayanan protocol).

Narayanan et al. [123], Pollock [124]

BAK with fibrin-based tissue-engineered renal proximal tubule.

BAK system based on use of a specially designed reabsorption hollow fiber membrane coated with fibrin for better support of renal cells. Potential BAK component or selfdevice prepared with lifespan-extended human renal proximal tubular epithelial cells.

Ng et al. [125]

Bioartificial renal Tubule Device (BTD)

Sanechika et al. [126], Saito et al. [127]

solution of filtration process versus standard dialysis machine and broadcasting of the smallest compact, portable device but also providing as close as possible by BAKs the natural processes and functions of kidney [128– 130]. This intention has been mainly related with the hormone and immuno-modulatory kidney functions, which are essential for normal homeostasis [116, 131]. The most well-known BAK system description is included in the patent publication (Cieslinski and Humes, 1993–1994), numbered EP 0746343 B1 with the title ‘‘BAK devices coated with cells suitable for use in vivo or ex vivo’’ which fully refers and present all standard features of ultrafiltration perfused device with renal cells which are seeded along a hollow fiber. Presented quote accurately characterized this type of construction: ‘‘…The hollow fibers must have high hydraulic conductivity, as measured in terms of the ultrafiltration coefficient. Suitably, the ultrafiltration coefficient is greater than 20 mL/h, Torr, preferably 20–100 mL/h, Torr. The hollow fibers

Fig. 1 Bioartificial kidney device. a The standard hemofilter with bioreactor containing renal proximal tubule cells. b The desired BAK internal structure. c Theoretical projection of the correct BAK internal implant (with marked iliac artery and vein)

suitably have a molecular weight cutoff, or pore size, which is B60,000 g/mol …’’ [132, 133]. The first clinical applications of BAK systems are still problematic which shows the deceleration of clinical test due to the inability to pass the 2nd phase of the clinical trial. But there are some reports which give a proverbial green light for the BAK system and its future challenge as,

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J Artif Organs Table 4 Scaffolds used in bioartificial kidneys (BAK) construction Scaffold type

Cells

References

PES/PVP hollow fibers alone or coated with fibrin

Proximal tubular cells derived from human, animal or cell lines

Tasnim et al. [115], Oo et al. [116], Ng et al. [125]

PSF hollow fibers alone or coated with pronectin-L or laminin

Proximal tubular cells derived from human, animal or cell lines

Tasnim et al. [115], Oo et al. [116], Aebischer et al. [120], Humes et al. [121], Sun et al. [122], Ceslinski et al. [132], Cieslinski et al. [133], Humes et al. [135]

PSF/PVP hollow fibers

Proximal tubular cells derived from human, animal or cell lines

Tasnim et al. [115]

Acrylic copolymer

Proximal tubular cells derived from human, animal or cell lines

Aebischer et al. [120]

EVAL hollow fibers alone or coated with attachin

Proximal tubular cells derived from human, animal or cell lines

Sanechika et al. [126], Saito et al. [127]

amPSF membranes

Proximal tubular cells derived from human, animal or cell lines

Teo et al. [138]

PCLdi(U-UPy) membranes

Proximal tubular cells derived from human, animal or cell lines Coculture of GEnC (glomerular endothelial cells) and podocytes

Dankers et al. [141]

Human cortical tubular cells

Ding et al. [143], Fissell et al. [144]

Micro-PEF nickel mesh electrospinning with collagen/PLC membranes SNM membranes

Resume and conclusions Slater et al. [142]

PES polyethersulfone, PVP polyvinylpyrrolidone, PSF polysulfone, EVAL ethylene vinyl alcohol, amPSF modified polysulfone using an acrylic monomer and polymerization with UV, PCLdi(U-UPy) ureido-pyrimidine modified bifunctional policaprolactone, SNM silicon nanopore membrane

for example, the study of James Tumlin et al. from 2008, where the RAD BAK was tested in the group of 58 patients with acute renal failure and the results shown, as could be cited, that RAD systems are associated with more rapid recovery of kidney function and better tolerance than conventional continuous renal replacement therapy (CRRT) [134]. In another study of Humes and Weitzel et al. [135], it has been shown in a small group of 10 patients that experimental treatment can be delivered safely for up to 24 h.

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The use of nanotechnological solutions in BAK projects is a relatively new concept. Many of such information are nowadays published in non-scientific journals often as news or popular short communications. The number of fully reviewed information is still limited and small, but the quantity and quality of work relating to the application of nanotechnology continues to grow like in the other medical specialties [136]. Another study suggests that use a specific material for a BAK construction like, for example specially produced hollow fibers, could have a significant impact onto exceeding the problematic second phase of clinical trial. These data may provide a positive and forward-looking approach to the subject of nanotechnology in use of BAK system and probably, a standard medical treatment [137]. Nowadays, in the most popular samples, use of nanotechnology in the BAK preparation and construction is expressed as improvement and modification of the membrane; or the use of specially produced due nanotechnology surfaces for bioreactor’s cell seeding. Some authors have used specially designed acrylic modified polysulfide membranes that improve renal proximal tubule cell adhesion and spreading; or a special 2D surface to inhibit the instance process of potential tubulogenesis. Another sample also used electrospun collagen nanofibres as a bioartificial composite basement membrane in in vitro model of the glomerular capillary wall [138–144].

In summary, we have summarized the current status and novel techniques of regenerative medicine and tissue engineering, which is the most interest for many research teams. The most important achievements in the field of regenerative medicine of kidney, which were mentioned and described here, are currently cumulated in 4 areas of interest: stem cell-based therapies, neo-kidney’s with specially designed scaffolds or cell-seeded matrices, BAK’s and innovative nanotechnologically bioengineered solutions. The clinical trials of general numbers of commonly used procedures are still small and insufficient. In many of described procedures, there are still a lot of technical problems and the main problem is not only the lack of a complete function restore but also the long-term endurance and poor capacity or a small level of biocompatibility of these solutions. Kidney is considered as one of most complicated organ and it is not easily to replace or regenerate like other tissues and organs. While tissues and organs of cartilage, bones, skin, muscles and urinary bladder are associated with a single biological, physiological or physical function and are much easier than kidney to replace.

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Nowadays, we can add some remarks that the regenerative medicine is still insufficient to completely replace current therapy methods used in patients with chronic kidney disease especially with the end-stage renal disease, where in many cases kidney transplantation is the only one chance. But, we cannot say that the regenerative medicine is a wrong way and does not give any hope for a future development of the science regarding the systemic treatment of patients with serious diseases and kidney dysfunction. In contrary, the development of regenerative medicine especially in the last 20 years with all achievements and all collected scientific information brings us more and more closer to solve many of today’s problems at the frontier of nephrology and transplantology in the field of kidney treatment, and this scientific way which sometimes seems to be a difficult and tortuous is appropriate and should be continued.

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Conflict of interest of interest.

The authors declare that they have no conflict

References

20.

21. 22.

1. Murray JE. Ronald Lee Herrick Memorial: June 15, 1931-December 27, 2010. Am J Transplant. 2011;11:419. 2. Tangri N, Stevens LA, Griffith J, Tighiouart H, Djurdjev O, Naimark D, et al. A predictive model for progression of chronic kidney disease to kidney failure. JAMA. 2011;305:1553–9. 3. Zoccali C, Kramer A, Jager KJ. Epidemiology of CKD in Europe: an uncertain scenario. Nephrol Dial Transplant. 2010;25:1731–3. 4. Nordio M, Limido A, Maggiore U, Nichelatti M, Postorino M, Quintaliani G. Italian dialysis and transplantation registry. Am J Kidney Dis. 2012;59:819–28. 5. Martı´nez-Mier G, Rayhilloye SC, Katz DA. Cadaveric kidney transplant using horseshoe kidney: report of two cases. Cir Cir. 2005;73:211–6. 6. Nowicki M, Zwiech R. Chronic renal failure in non-renal organ transplant recipients. Ann Transplant. 2005;10:54–7. 7. Czy_zewski Ł, Wyzgał J. The adequacy of transplantation education in the ESRD population in Poland. Ann Transplant. 2012;17:62–73. 8. Cheng K, Rai P, Plagov A, Lan X. Transplantation of bone marrow-derived MSCs improves cisplatinum-induced renal injury through paracrine mechanisms. Exp Mol Pathol. 2013;94:466–73. 9. Winkelmayer WC, Glynn RJ, Levin R, Owen WF Jr, Avorn J. Determinants of delayed nephrologist referral in patients with chronic kidney disease. Am J Kidney Dis. 2001;38:1178–84. 10. Demoulin N, Beguin C, Labriola L, Jadoul M. Preparing renal replacement therapy in stage 4 CKD patients referred to nephrologists: a difficult balance between futility and insufficiency. A cohort study of 386 patients followed in Brussels. Nephrol Dial Transplant. 2011;26:220–6. 11. Roderick P, Davies R, Jones C, Feest T, Smith S, Farrington K. Simulation model of renal replacement therapy: predicting future demand in England. Nephrol Dial Transplant. 2004;19:692–701. 12. Saweirs WW, Goddard J. What are the best treatments for early chronic kidney disease? A background paper prepared for the

23.

24.

25.

26.

27. 28. 29. 30.

31. 32.

33. 34. 35.

UK consensus conference on early chronic kidney disease. Nephrol Dial Transplant. 2007;22:ix31–8. Bauer C, Melamed ML, Hostetter TH. Staging of chronic kidney disease: time for a course correction. J Am Soc Nephrol. 2008;19:844–6. Bentata Y, Haddiya I, Latrech H, Serraj K, Abouqal R. Progression of diabetic nephropathy, risk of end-stage renal disease and mortality in patients with type-1 diabetes. Saudi J Kidney Dis Transpl. 2013;24:392–402. Chapman RJ, Templeton M, Ashworth S, Broomhead R, McLean A, Brett SJ. Long-term survival of chronic dialysis patients following survival from an episode of multiple-organ failure. Crit Care. 2009;13:R65. McLaughlin K, Jones B, Mactier R, Porteus C. Long-term vascular access for hemodialysis using silicon dual-lumen catheters with guidewire replacement of catheters for technique salvage. Am J Kidney Dis. 1997;29:553–9. Himmelfarb J, Ikizler TA. Hemodialysis. N Engl J Med. 2010;363:1833–45. Himmelfarb J. Hemodialysis complications. Am J Kidney Dis. 2005;45:1122–31. Hiesse C, Pessione F, Cohen S. Kidney grafts from elderly donors. Presse Med. 2003;32:942–51. de Klerk M, Zuidema WC, IJzermans JN, Weimar W. Alternatives for unsuccessful living donor kidney exchange pairs. Clin Transpl 2010;327–332. Silkensen JR. Long-term complications in renal transplantation. J Am Soc Nephrol. 2000;11:582–8. Lewandowska D, Pazik J, Gozdowska J, Wyzgał J, Szmidt J, Gała˛zka Z, et al. Medical problems with potential living kidney donors. Ann Transplant. 2009;14:69–69. Arulkumaran N, Annear NM, Singer M. Patients with end-stage renal disease admitted to the intensive care unit: systematic review. Br J Anaesth. 2013;110:13–20. Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P. Acute renal failure - definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care. 2004;8:R204–12. Kellum JA, Lameire N, For the KDIGO AKI Guideline Work Group. Diagnosis, evaluation, and management of acute kidney injury: a KDIGO summary (Part 1). Crit Care. 2013;17:204. Bla¨ser D, Weiler N. Acute kidney injury-prevention, risk stratification and biomarkers. Anasthesiologie Intensivmedizine Notfallmedizine Schmerztherapie. 2013;48:122–8. Endre ZH, Pickering JW. Acute kidney injury clinical trial design: old problems, new strategies. Pediatr Nephrol. 2013;28:207–17. Himmelfarb J. Acute kidney injury in the elderly: problems and prospects. Semin Nephrol. 2009;29:658–64. Mason C, Dunnill P. A brief definition of regenerative medicine. Regen Med. 2008;3:1–5. Khang D, Carpenter J, Chun YW, Pareta R, Webster TJ. Nanotechnology for regenerative medicine. Biomed Microdevices. 2010;12:575–87. Langer R, Vacanti JP. Tissue engineering. Science. 1993;260:920–6. Kaz´nica A, Joachimiak R, Drewa T, Drewa G. Application of tissue engineering in selected branches of regenerative medicine. Med Biol Sci. 2007;21:9–14. Egli RJ, Luginbuehl R. Tissue engineering-nanomaterials in the musculoskeletal system. Swiss Med Wkly. 2012;142:w13647. Gunatillake PA, Adhikari R. Biodegradable synthetic polymers for tissue engineering. Eur Cell Mater. 2003;20:1–16. Bajek A, Drewa T, Joachimiak R, Marszałek A, Gagat M, Grzanka A. Stem cells for urinary tract regeneration. Cen Eur J Urol. 2012;65:7–10.

123

J Artif Organs 36. Olson JL, Atala A, Yoo JJ. Tissue engineering: current strategies and future directions. Chonnam Med J. 2011;47:1–13. 37. Pokrywczynska M, Krzyzanowska S, Jundzill A, Adamowicz J, Drewa T. Differentiation of stem cells into insulin-producing cells: current status and challenges. Arch Immunol Ther Exp (Warsz). 2013;61:149–58. 38. Czajkowski R, Pokrywczynska M, Placek W, Zegarska B, Tadrowski T, Drewa T. Transplantation of cultured autologous melanocytes: hope or danger? Cell Transplant. 2010;19:639–43. 39. Reza HM, Ng BY, Gimeno FL, Phan TT, Ang LP. Umbilical cord lining stem cells as a novel and promising source for ocular surface regeneration. Stem Cell Rev. 2011;7:935–47. 40. Proffen B, von Keudell A, Vavken P. Evidence-based therapy for cartilage lesions in the knee—regenerative treatment options. Z Orthop Unfall. 2012;150:280–9. 41. Atala A, Kasper FK, Mikos AG. Engineering complex tissues. Sci Transl Med. 2012;4:160rv12. 42. Drewa T, Joachimiak R, Kaznica A, Sarafian V, Pokrywczynska M. Hair stem cells for bladder regeneration in rats: preliminary results. Transplant Proc. 2009;41:4345–51. 43. Pokrywczyn´ska M, Jundziłł A, Bodnar M, Adamowicz J, Tworkiewicz J, Szylberg L, et al. Do mesenchymal stem cells modulate the milieu of reconstructed bladder wall? Arch Ther Exp 2013;61:483–93. 44. Koziak A, Kania P, Marcheluk A, Dmowski T, Szczes´niewski R, Dorobek A. Reconstruction of long ureteral obstructions using xenogenic acellular collagen membranes. Ann Transplant. 2004;9:18–20. 45. Kloskowski T, Kowalczyk T, Nowacki M, Drewa T. Tissue engineering and ureter regeneration: is it possible. Int J Artif Organs. 2013;36:392–405. 46. Orlando G, Di Cocco P, D’Angelo M, Clemente K, Famulari A, Pisani F. Regenerative medicine applied to solid organ transplantation: where do we stand? Transplant Proc. 2010;42:1011–3. 47. Dubernard JM. The kidney. Bull Acad Natl Med. 2011;195:1661–7. 48. Witzgall R, Brown D, Schwarz C, Bonventre JV. Localization of proliferating cell nuclear antigen, vimentin, c-Fos, and clusterin in the postischemic kidney. Evidence for a heterogenous genetic response among nephron segments, and a large pool of mitotically active and dedifferentiated cells. J Clin Invest. 1994;93:2175–88. 49. Kitamura S, Yamasaki Y, Kinomura M, Sugaya T, Sugiyama H, Maeshima Y, et al. Establishment and characterization of renal progenitor like cells from S3 segment of nephron in rat adult kidney. FASEB J. 2005;19:1789–97. 50. Bussolati B, Bruno S, Grange C, Buttiglieri S, Deregibus MC, Cantino D, et al. Isolation of renal progenitor cells from adult human kidney. Am J Pathol. 2005;166:545–55. 51. da Silva Meirelles L, Chagastelles PC, Nardi NB. Mesenchymal stem cells reside in virtually all post-natal organs and tissues. J Cell Sci. 2006;119:2204–13. 52. Gupta S, Verfaillie C, Chmielewski D, Kren S, Eidman K, Connaire J, et al. Isolation and characterization of kidneyderived stem cells. J Am Soc Nephrol. 2006;17:3028–40. 53. Sagrinati C, Netti GS, Mazzinghi B, Lazzeri E, Liotta F, Frosali F, et al. Isolation and characterization of multipotent progenitor cells from the Bowman’s capsule of adult human kidneys. J Am Soc Nephrol. 2006;17:2443–56. 54. Bruno S, Bussolati B, Grange C, Collino F, di Cantogno LV, Herrera MB, et al. Isolation and characterization of resident mesenchymal stem cells in human glomeruli. Stem Cells Dev. 2009;18:867–80. 55. Ward HH, Romero E, Welford A, Pickett G, Bacallao R, Gattone VH 2nd, et al. Adult human CD133/1(?) kidney cells

123

56.

57.

58.

59.

60.

61.

62.

63.

64.

65.

66.

67.

68.

69.

70.

71.

72.

73.

isolated from papilla integrate into developing kidney tubules. Biochim Biophys Acta. 2011;1812:1344–57. De Broe ME. Tubular regeneration and the role of bone marrow cells: ‘stem cell therapy’-a panacea? Nephrol Dial Transplant. 2005;20:2318–20. To¨gel F, Hu Z, Weiss K, Isaac J, Lange C, Westenfelder C. Administered mesenchymal stem cells protect against ischemic acute renal failure through differentiation-independent mechanisms. Am J Physiol Renal Physiol. 2005;289:F31–42. Lin F, Cordes K, Li L, Hood L, Couser WG, Shankland SJ, et al. Hematopoietic stem cells contribute to the regeneration of renal tubules after renal ischemia-reperfusion injury in mice. J Am Soc Nephrol. 2003;14:1188–99. Stroo I, Stokman G, Teske GJ, Florquin S, Leemans JC. Haematopoietic stem cell migration to the ischemic damaged kidney is not altered by manipulating the SDF-1/CXCR4-axis. Nephrol Dial Transplant. 2009;24:2082–8. Gupta S, Verfaillie C, Chmielewski D, Kim Y, Rosenberg ME. A role for extrarenal cells in the regeneration following acute renal failure. Kidney Int. 2002;62:1285–90. Humphreys BD, Valerius MT, Kobayashi A, Mugford JW, Soeung S, Duffield JS, et al. Intrinsic epithelial cells repair the kidney after injury. Cell Stem Cell. 2008;2:284–91. Imasawa T, Utsunomiya Y, Kawamura T, Zhong Y, Nagasawa R, Okabe M, et al. The potential of bone marrow-derived cells to differentiate to glomerular mesangial cells. J Am Soc Nephrol. 2001;12:1401–9. Ito T, Suzuki A, Imai E, Okabe M, Hori M. Bone marrow is a reservoir of repopulating mesangial cells during glomerular remodeling. J Am Soc Nephrol. 2001;12:2625–35. Li J, Deane JA, Campanale NV, Bertram JF, Ricardo SD. The contribution of bone marrow-derived cells to the development of renal interstitial fibrosis. Stem Cells. 2007;25:697–706. Poulsom R, Forbes SJ, Hodivala-Dilke K, Ryan E, Wyles S, Navaratnarasah S, et al. Bone marrow contributes to renal parenchymal turnover and regeneration. J Pathol. 2001;195:229–35. Lin F, Moran A, Igarashi P. Intrarenal cells, not bone marrowderived cells, are the major source for regeneration in postischemic kidney. J Clin Invest. 2005;115:1756–64. Fang TC, Alison MR, Cook HT, Jeffery R, Wright NA, Poulsom R. Proliferation of bone marrow-derived cells contributes to regeneration after folic acid-induced acute tubular injury. J Am Soc Nephrol. 2005;16:1723–32. Iwasaki M, Adachi Y, Minamino K, Suzuki Y, Zhang Y, Okigaki M, et al. Mobilization of bone marrow cells by G-CSF rescues mice from cisplatin-induced renal failure, and M-CSF enhances the effects of G-CSF. J Am Soc Nephrol. 2005;16:658–66. Zhang H, Bai H, Yi Z, He X, Mo S. Effect of stem cell factor and granulocyte-macrophage colony-stimulating factor-induced bone marrow stem cell mobilization on recovery from acute tubular necrosis in rats. Ren Fail. 2012;34:350–7. To¨gel F, Isaac J, Hu Z, Weiss K, Westenfelder C. Renal SDF-1 signals mobilization and homing of CXCR4-positive cells to the kidney after ischemic injury. Kidney Int. 2005;67:1772–84. Burst V, Pu¨tsch F, Kubacki T, Vo¨lker LA, Bartram MP, Mu¨ller RU, et al. Survival and distribution of injected haematopoietic stem cells in acute kidney injury. Nephrol Dial Transplant. 2013;28:1131–9. Morigi M, Imberti B, Zoja C, Corna D, Tomasoni S, Abbate M, et al. Mesenchymal stem cells are renotropic, helping to repair the kidney and improve function in acute renal failure. J Am Soc Nephrol. 2004;15:1794–804. Herrera MB, Bussolati B, Bruno S, Fonsato V, Romanazzi GM, Camussi G. Mesenchymal stem cells contribute to the renal

J Artif Organs

74.

75.

76.

77.

78.

79.

80.

81. 82.

83.

84.

85. 86.

87. 88.

89.

90.

91.

repair of acute tubular epithelial injury. Int J Mol Med. 2004;14:1035–41. Bruce SJ, Rea RW, Steptoe AL, Busslinger M, Bertram JF, Perkins AC. In vitro differentiation of murine embryonic stem cells toward a renal lineage. Differentiation. 2007;75:337–49. Nishikawa M, Yanagawa N, Kojima N, Yuri S, Hauser PV, Jo OD, et al. Stepwise renal lineage differentiation of mouse embryonic stem cells tracing in vivo development. Biochem Biophys Res Commun. 2012;417:897–902. Ren X, Zhang J, Gong X, Niu X, Zhang X, Chen P, et al. Differentiation of murine embryonic stem cells toward renal lineages by conditioned medium from ureteric bud cells in vitro. Acta Biochim Biophys Sin (Shanghai). 2010;42:464–71. Kim D, Dressler GR. Nephrogenic factors promote differentiation of mouse embryonic stem cells into renal epithelia. J Am Soc Nephrol. 2005;16:3527–34. Morizane R, Monkawa T, Itoh H. Differentiation of murine embryonic stem and induced pluripotent stem cells to renal lineage in vitro. Biochem Biophys Res Commun. 2009;390:1334–9. Rosines E, Johkura K, Zhang X, Schmidt HJ, Decambre M, Bush KT, et al. Constructing kidney-like tissues from cells based on programs for organ development: toward a method of in vitro tissue engineering of the kidney. Tissue Eng Part A. 2010;16:2441–55. Rosines E, Sampogna RV, Johkura K, Vaughn DA, Choi Y, Sakurai H, et al. Staged in vitro reconstitution and implantation of engineered rat kidney tissue. Proc Natl Acad Sci USA. 2007;104:20938–43. Joraku A, Stern KA, Atala A, Yoo JJ. In vitro generation of three-dimensional renal structures. Methods. 2009;47:129–33. Osafune K, Takasato M, Kispert A, Asashima M, Nishinakamura R. Identification of multipotent progenitors in the embryonic mouse kidney by a novel colony-forming assay. Development. 2006;133:151–61. Mae S, Shono A, Shiota F, Yasuno T, Kajiwara M, GotodaNishimura N, Arai S, Sato-Otubo A, Toyoda T, Takahashi K, Nakayama N, Cowan CA, Aoi T, Ogawa S, McMahon AP, Yamanaka S, Osafune K. Monitoring and robust induction of nephrogenic intermediate mesoderm from human pluripotent stem cells. Nat Commun. 2013;4:1367. Usui JI, Kobayashi T, Yamaguchi T, Knisely AS, Nishinakamura R, Nakauchi H. Generation of kidney from pluripotent stem cells via blastocyst complementation. Am J Pathol. 2012;180:2417–26. Rogers SA, Talcott M, Hammerman MR. Transplantation of pig metanephroi. ASAIO J. 2003;49:48–52. Dekel B, Burakova T, Arditti FD, Reich-Zeliger S, Milstein O, Aviel-Ronen S, et al. Human and porcine early kidney precursors as a new source for transplantation. Nat Med. 2003;9:53–60. Hammerman MR. Renal organogenesis from transplanted metanephric primordial. J Am Soc Nephrol. 2004;15:1126–32. Matsumoto K, Yokoo T, Yokote S, Utsunomiya Y, Ohashi T, Hosoya T. Functional development of a transplanted embryonic kidney: effect of transplantation site. J Nephrol. 2012;25:50–5. Kooreman NG, Wu JC. Tumorigenicity of pluripotent stem cells: biological insights from molecular imaging. J R Soc Interface. 2010;7:S753–63. Tang C, Weissman IL, Drukker M. The safety of embryonic stem cell therapy relies on teratoma removal. Oncotarget. 2012;3:7–8. Singaravelu K, Padanilam BJ. In vitro differentiation of MSC into cells with a renal tubular epithelial-like phenotype. Ren Fail. 2009;31:492–502.

92. Jia X, Xie X, Feng G, L} u H, Zhao Q, Che Y, et al. Bone marrowderived cells can acquire renal stem cells properties and ameliorate ischemia-reperfusion induced acute renal injury. BMC Nephrol. 2012;13:105. 93. Baer PC, Bereiter-Hahn J, Missler C, Brzoska M, Schubert R, Gauer S, et al. Conditioned medium from renal tubular epithelial cells initiates differentiation of human mesenchymal stem cells. Cell Prolif. 2009;42:29–37. 94. Baer PC, Do¨ring C, Hansmann ML, Schubert R, Geiger H. New insights into epithelial differentiation of human adipose-derived stem cells. J Tissue Eng Regen Med. 2011;7:271–8. 95. Perin L, Giuliani S, Jin D, Sedrakyan S, Carraro G, Habibian R, et al. Renal differentiation of amniotic fluid stem cells. Cell Prolif. 2007;40:936–48. 96. Siegel N, Valli A, Fuchs C, Rosner M, Hengstschla¨ger M. Induction of mesenchymal/epithelial marker expression in human amniotic fluid stem cells. Reprod Biomed Online. 2009;19:838–46. 97. Siegel N, Rosner M, Unbekandt M, Fuchs C, Slabina N, Dolznig H, et al. Contribution of human amniotic fluid stem cells to renal tissue formation depends on mTOR. Hum Mol Genet. 2010;19:3320–31. 98. Hauser PV, De Fazio R, Bruno S, Sdei S, Grange C, Bussolati B, et al. Stem Cells derived from human amniotic fluid contribute to acute kidney injury recovery. Am J Pathol. 2010;177:2011–21. 99. Rosner M, Schipany K, Gundacker C, Shanmugasundaram B, Li K, Fuchs C, et al. Renal differentiation of amniotic fluid stem cells: perspectives for clinical application and for studies on specific human genetic diseases. Eur J Clin Invest. 2011;42:677–84. 100. Lensch MW, Rao M. Induced pluripotent stem cells: opportunities and challenges. Regen Med. 2010;5:483–4. 101. Okita K, Yamanaka S. Induced pluripotent stem cells: opportunities and challenges. Philos Trans R Soc Lond B Biol Sci. 2011;366:2198–207. 102. Sullivan DC, Mirmalek-Sani SH, Deegan DB, Baptista PM, Aboushwareb T, Atala A, et al. Decellularization methods of porcine kidneys for whole organ engineering using a highthroughput system. Biomaterials. 2012;33:7756–64. 103. Orlando G, Farney AC, Iskandar SS, Mirmalek-Sani SH, Sullivan DC, Moran E, et al. Production and implantation of renal extracellular matrix scaffolds from porcine kidneys as a platform for renal bioengineering investigations. Ann Surg. 2012;256:363–70. 104. Park KM, Woo HM. Porcine bioengineered scaffolds as new frontiers in regenerative medicine. Transplant Proc. 2012;44:1146–50. 105. Nakayama KH, Batchelder CA, Lee CI, Tarantal AF. Decellularized rhesus monkey kidney as three-dimensional scaffold for renal tissue engineering. Tissue Eng Part A. 2010;16:2207–16. 106. Song JJ, Guyette JP, Gilpin SE, Gonzalez G, Vacanti JP, Ott HC. Regeneration and experimental orthotopic transplantation of a bioengineered kidney. Nat Med. 2013;19:646–51. 107. Bonandrini B, Figliuzzi M, Papadimou E, Morigi M, Perico N, Casiraghi F et al. Recellularization of well preserved acellular kidney scaffold using embryonic stem cells. Tissue Eng Part A 2014. doi:10.1089/ten.tea.2013.0269. 108. Wang PC, Takezawa T. Reconstruction of renal glomerular tissue using collagen vitrigel scaffold. J Biosci Bioeng. 2005;99:529–40. 109. Rosines E, Schmidt HJ, Nigam SK. The effect hyaluronic acid size and concentration on branching morphogenesis and tubule differentiation in developing kidney culture systems: potential applications to engineering of renal tissue. Biomaterials. 2007;28:4806–17.

123

J Artif Organs 110. Caldas HC, Fernandes IM, Kawasaki-Oyama RS, Baptista MA, Plepis AM, Martins VA, et al. Effect of stem cells seeded onto biomaterial on the progression of experimental kidney disease. Exp Biol Med (Maywood). 2011;236:746–54. 111. Lanza RP, Chung HY, Yoo JJ, Wettstein PJ, Blackwell C, Borson N, et al. Generation of histocompatible tissues using nuclear transplantation. Nat Biotechnol. 2002;20:689–96. 112. Lu¨ SH, Lin Q, Liu YN, Gao Q, Hao T, Wang Y, et al. Selfassembly of renal cells into engineered renal tissue in collagen/ matrigel scaffold in vitro. J Tissue Eng Regen Med. 2012;10:786–92. 113. Kim SS, Park HJ, Han J, Choi CY, Kim BS. Renal tissue reconstruction by the implantation of renal segments on biodegradable polymer scaffold. Biotechnol Lett. 2003;25:1505–8. 114. Palmer RA, Price JDE, English ET, Newell T. Clinical trials with the Kolff Twin Coil artificial kidney. Can Med Assoc J. 1957;77:850–5. 115. Tasnim F, Deng R, Hu M, Liour S, Li Y, Ni M, et al. Achievements and challenges in bioartificial kidney development. Fibrogenesis Tissue Repair. 2010;3:14. 116. Oo ZY, Deng R, Hu M, Ni M, Kandasamy K, Ibrahim MSB. The performance of primary human renal cells in hollow fiber bioreactors for bioartificial kidneys. Biomaterials. 2011;32:8806–15. 117. Humes HD, MacKay SM, Funke AJ, Buffington DA. Tissue engineering of a bioartificial renal tubule assist device: in vitro transport and metabolic characteristics. Kidney Int. 1999;55:2502–14. 118. Wu¨stenberg PW, Bra¨unlich H, Hagemann I. Modern study methods in experimental nephrology. Z Urol Nephrol. 1986;79:411–28. 119. Chang TM. Applications of artificial cells in medicine and biotechnology. Biomater Artif Cells Artif Organs. 1987;15:1–20. 120. Aebischer P, Ip TK, Panol G, Galletti PM. The bioartificial kidney: progress towards an ultrafiltration device with renal epithelial cells processing. Life Support Syst. 1987;5:159–68. 121. Humes HD, Fissell WH, Weitzel WF, Buffington DA, Westover AJ, MacKay SM, et al. Metabolic replacement of renal function in uremic animals with a bioartificial kidney containing human cells. Am J Kidney Dis. 2002;39:1078–87. 122. Sun J, Wang C, Zhu B, Larsen S, Wu J, Zhao W. Construction of an erythropoietin-expressing bioartificial renal tubule assist device. Ren Fail. 2011;33:54–60. 123. Narayanan K, Schumacher KM, Tasnim F, Kandasamy K, Schumacher A, Ni M, et al. Human embryonic stem cells differentiate into functional renal proximal tubular-like cells. Kidney Int. 2013;83:593–603. 124. Pollock CA. Toward a bioartificial kidney: will embryonic stem cells be the answer? Kidney Int. 2013;83:543–5. 125. Ng CP, Zhuang Y, Lin AWH, Teo JCM. Fibrin-based tissueengineered renal proximal tubule for bioartificial kidney devices: development, characterization and in vitro transport study. Int J Tissue Eng. 2013;. doi:10.1155/2013/319476. 126. Sanechika N, Sawada K, Usui Y, Hanai K, Kakuta T, Suzuki H, et al. Development of bioartificial renal tubule devices with lifespan-extended human renal proximal tubular epithelial cells. Nephrol Dial Transplant. 2011;26:2761–9. 127. Saito A, Sawada K, Fujimura S, Suzuki H, Hirukawa T, Tatsumi R, et al. Evaluation of bioartificial renal tubule device prepared with lifespan-extended human renal proximal tubular epithelial cells. Nephrol Dial Transplant. 2012;27:3091–9.

123

128. Fujita Y, Terashima M, Kakuta T, Itoh J, Tokimasa T, Brown D, et al. Transcellular water transport and stability of expression in aquaporin 1-transfected LLC-PK1 cells in the development of a portable bioartificial renal tubule device. Tissue Eng. 2004;10:711–22. 129. Humes HD. Tissue engineering of a bioartificial kidney: a universal donor organ. Transplant Proc. 1996;28:2032–5. 130. de Francisco AL, Pin˜era C. Challenges and future of renal replacement therapy. Hemodial Int. 2006;10:S19–23. 131. Zhang H, Tasnim F, Ying JY, Zink D. The impact of extracellular matrix coatings on the performance of human renal cells applied in bioartificial kidneys. Biomaterials. 2009;30:2899–911. 132. Cieslinski DA, Humes DH. Bioartificial kidney devices coated with cells suitable for use in vivo or ex vivo. Patent number EP 0746343 B1. 2 Jan 2004. 133. Cieslinski DA, Humes DH. Tissue engineering of a bioartificial kidney. Biotechnol Bioeng. 1994;43:678–81. 134. Tumlin J, Wali R, Williams W, Murray P, Tolwani AJ, Vinnikova AK, et al. Efficacy and safety of renal tubule cell therapy for acute renal failure. J Am Soc Nephrol. 2008;19:1034–40. 135. Humes HD, Weitzel WF, Bartlett RH, Swaniker FC, Paganini EP, Luderer JR, et al. Initial clinical results of the bioartificial kidney containing human cells in ICU patients with acute renal failure. Kidney Int. 2004;66:1578–88. 136. Nowacki M, Jundziłł A, Bieniek M, Kowalczyk T, Kloskowski T, Drewa T. Modern biomaterials as hemostatic dressings in kidney nephron sparing surgery (NSS)-murine model. A preliminary report. Polim Med. 2012;42:35–43. 137. Oo ZY, Kandasamy K, Tasnim F, Zink D. A novel design of bioartificial kidneys with improved cell performance and haemocompatibility. J Cell Mol Med. 2013;17:497–507. 138. Teo JC, Ng RR, Ng CP, Lin AW. Surface characteristics of acrylic modified polysulfone membranes improves renal proximal tubule cell adhesion and spreading. Acta Biomater. 2011;7:2060–9. 139. Zhang H, Lau SF, Heng BF, Teo PY, Alahakoon PK, Ni M, et al. Generation of easily accessible human kidney tubules on two-dimensional surfaces in vitro. J Cell Mol Med. 2011;15:1287–98. 140. Rastogi A, Nissenson AR. Technological advances in renal replacement therapy: five years and beyond. Clin J Am Soc Nephrol. 2009;4:S132–6. 141. Dankers PY, Boomker JM, Huizinga-van der Vlag A, Smedts FM, Harmsen MC, van Luyn MJ. The use of fibrous, supramolecular membranes and human tubular cells for renal epithelial tissue engineering: towards a suitable membrane for a bioartificial kidney. Macromol Biosci. 2010;10:1345–54. 142. Slater SC, Beachley V, Hayes T, Zhang D, Welsh GI, Saleem MA, et al. An in vitro model of the glomerular capillary wall using electrospun collagen nanofibres in a bioartificial composite basement membrane. PLoS One. 2011;6:e20802. 143. Ding F, Humes HD. The bioartificial kidney and bioengineered membranes in acute kidney injury. Nephron Exp Nephrol. 2008;109:e118–22. 144. Fissell WH, Manley S, Westover A, Humes HD, Fleischman AJ, Roy S. Differentiated growth of human renal tubule cells on thin-film and nanostructured materials. ASAIO J. 2006;52:221–7.