INVITED REVIEW
Xenotransplantation of developing kidneys

Marc R. Hammerman

George M. O'Brien Kidney and Urological Disease Center, Renal Division, and Departments of Medicine and Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110


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The number of kidney transplants performed per year is limited by the availability of donor organs. One novel solution to this shortage envisions "growing" new kidneys in situ via xenotransplantation of renal anlagen. We have shown that developing metanephroi transplanted into the omentum of animal hosts undergo differentiation and growth, become vascularized by blood vessels of host origin, and exhibit excretory function. Metanephroi can be stored for up to 3 days in vitro before transplantation with no impairment in growth or function postimplantation. Metanephroi can be transplanted across both concordant (rat right-arrow mouse) and discordant/highly disparate (pig right-arrow rodent) xenogeneic barriers. This review summarizes experimental data relating to the transplantation of developing kidneys.

acute vascular rejection; cellular transplant; costimulatory blockade; hyperacute rejection; metanephros


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END-STAGE CHRONIC RENAL FAILURE is treated using dialysis, a procedure with considerable morbidity, or renal allotransplantation, which is limited by the number of organs available to transplant. One possible solution to the lack of organ availability is the use of renal xenografts. The clinical renal xenografts performed to date have utilized primate donors. However, nonhuman primates will never be suitable as kidney donors for humans for a variety of reasons, not the least of which is the fact that they comprise endangered species (19). In that humans and pigs are of comparable size and share a similar renal physiology, and because pigs are plentiful and can be bred to be pathogen free, it has been proposed that pigs could be an ideal donor species for kidney transplantation (19).


    XENOTRANSPLANTATION OF PORCINE KIDNEYS
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Unfortunately, the transplantation of vascularized organs originating from the pig into the group of primates that includes humans, the great apes, and old-world monkeys is rendered problematic because of the processes of hyperacute and acute vascular rejection that occur across this xenogeneic barrier.

Hyperacute rejection occurs as a result of the binding of preformed or natural xenoreactive antibodies present in the circulation of hosts to cells of the donor species, followed by activation of the hosts' complement system. Approximately 85% of the natural antibodies in humans that bind to pig cells are directed predominantly against galactose-alpha -1,3-galactose (alpha -Gal), a sugar expressed on the vascular endothelium of cells in most mammals but not in humans, great apes, or old-world monkeys (1, 19).

Hyperacute rejection after the transplantation of pig kidneys into nonhuman primates can be overcome through the use of genetically altered organs originating from pigs transgenic for the human complement activators, human decay-accelerating factor (hDAF), and CD59. Another strategy for overcoming hyperacute rejection that is as yet untested is the use of organs from transgenic pigs that do not express the alpha -Gal antigen (1).

When hyperacute rejection is avoided through the use of kidneys from hDAF and CD59 transgenic pigs, for example, vascularized grafts transplanted to susceptible primates become subject to acute vascular rejection. At the present time, acute vascular rejection probably represents the primary obstacle to the use of porcine organs in human hosts. Its etiology is multifactorial and incompletely defined. Several processes implicated as causative of acute vascular rejection reflect a fundamental incompatibility between host proteins/protein systems and the vascular endothelium of the donor. Factors thought to contribute include circulating xenoreactive antibodies that trigger adverse reactions in endothelial cells of the transplant; the failure of primate natural killer cells to recognize the myosin heavy chain (MHC) I molecules of pigs; and molecular incompatibilities between porcine proteins/receptors and circulating primate/human protein systems, such as clotting factors (19).

Soin et al. (21) reported the results of transplanting kidneys from hDAF transgenic pigs into cynomolgus monkeys. All recipients received induction and maintenance immunosuppression.

After recovery from the transplantation procedure, monkeys ate normally and showed normal behavior and activity. Experiments were usually ended because of the development of renal failure or complications of immunosuppression (21).

Serum electrolytes were monitored in 22 monkeys that survived at least 20 days. After an initial period of graft dysfunction, plasma urea, sodium, chloride, and potassium remained within normal limits so long as the animals remained well. Plasma creatinines were reduced after the initial period of dysfunction but remained higher than the normal levels for nontransplanted primates. Levels of circulating calcium remained normal, but plasma phosphate fell progressively over time. Recipients developed proteinuria and became progressively anemic, necessitating termination of the experiment in the longest-lasting survivors. However, monkeys treated with recombinant human erythropoietin did not become markedly anemic (21).

While no monkey lived for longer than 78 days posttransplantation, pig kidneys were able to maintain fluid and electrolyte homeostasis, consistent with a physiological compatibility between renal function in pigs and that in a primate species. Exceptions to normal homeostasis included an apparent unresponsiveness to pig erythropoietin, proteinuria, and hypophosphatemia of unknown etiology (21).


    XENOTRANSPLANTATION OF PORCINE NONVASCULARIZED TISSUES
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In contrast to vascularized grafts, nonvascularized or cellular grafts can be transplanted from pig to susceptible primate without triggering hyperacute or acute vascular rejection. For example, porcine fetal islets of Langerhans, vascularized subsequently by host vessels, can be transplanted into humans without eliciting hyperacute or acute vascular rejection (8), as can porcine fetal neurons (2).

Theoretically, a nonvascularized fetal kidney would fare as well posttransplantation into a primate as porcine fetal islets or neurons. The possibility of employing such a strategy in lieu of transplantation of developed kidneys has been the subject of investigation for at least two decades. Metanephroi have been transplanted successfully into a number of sites, including the chorioallantoic membrane of developing birds (20), the anterior chamber of the eye (11), and beneath the renal capsule (3-6, 17, 25).


    ADVANTAGES OF TRANSPLANTING METANEPHROI
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There are three reasons why the use of transplantation of developing metanephroi might be advantageous relative to developed kidneys. First, if developing metanephroi are obtained at a sufficiently early stage, antigen-presenting cells (APCs) that mediate "direct" host recognition of alloantigen or xenoantigen would be expected to be absent from the renal anlagen because they would not yet have developed in the donor and migrated into the metanephros (13). Second, donor antigens such as MHC class I and II may not be expressed on developing metanephroi to the extent they are expressed in adult kidney (22). Third, one might expect a transplanted metanephros to be supplied by blood vessels of host origin (14).

Antigen Presentation

The first studies to address the question of APC depletion in metanephroi were performed by Foglia et al. (7), who transplanted metanephroi obtained from outbred Sprague-Dawley rat embryos aged embryonic day 15 (E15)-E21 beneath the renal capsule of adult Sprague-Dawley hosts. Fetal renal allograft growth and survival were age dependent in that the growth and differentiation in situ over a 15- to 30-day period was best for metanephroi obtained from E15 embryos and worsened progressively for renal anlagen obtained on E16-E21. The developed E15 metanephroi showed maturation of renal elements when examined 10 days posttransplantation and no sign of rejection, whereas E20 metanephroi had a poor renal architecture and a dense lymphocytic infiltrate after a comparable period of time (7).

In contrast to metanephroi obtained on E15, liver tissue harvested on E15 and transplanted beneath the renal capsule of hosts underwent little growth and prompt rejection (7).

Velasco and Hegre (23) transplanted metanephroi or liver tissue from E15, E17, E18, or E19 Fisher rat embryos (RT1lv1) beneath the renal capsule of MHC (RT1)-incompatible Wistar-Furth adult rats (RT1u). All fetal hepatic grafts were rejected by 10 days posttransplantation. In contrast, the degree of rejection of the metanephroi was age dependent, those from E15 embryos showing minimal or moderate rejection and those from older embryos showing more intense rejection. If liver tissue and metanephroi from E15 embryos were cotransplanted at different sites into Wistar-Furth rats, metanephroi underwent a more severe rejection than if they were implanted without liver tissue (23).

APCs populate the liver well before E15 in rats but are not present in the circulation until several days later (13). It was speculated that the absence of APCs in metanephroi obtained from E15 embryos together with their presence in liver tissue obtained concurrently could explain the differential fate of metanephroi transplanted with or without liver tissue. Under the former conditions, but not the latter, direct presentation of donor antigens to host T cells could take place (23).

Expression of Class I and II Antigens

Statter et al. (22) transplanted renal tissue originating from E14 adult C57BL/6 mice (H-2b) beneath the renal capsule of adult congenic B10.A hosts (H-2a). Expression of donor and host-specific class I (H2Kb) and class II (Abeta b) transcripts in donor tissue was low at E14 and increased progressively in renal tissue from older mice. After transplantation, surviving kidney grafts showed enhanced expression of class I and class II transcripts. However, neither class I nor class II protein could be detected in transplanted metanephroi, in contrast to its presence in transplanted adult renal tissue (22).

Dekel and co-workers (3) have carried out a series of investigations in which human adult or embryonic kidney tissue is transplanted beneath the kidney capsule of immunodeficient rats [severe combined immunodeficiency (SCID/Lewis and SCID/nude chimeric rats)] (4-6) or subcapsularly and intra-abdominally in NOD/SCID mice (3).

Human adult kidney fragments transplanted beneath the renal capsule of such rats survive for as long as 2 mo posttransplantation. The overall architecture of the transplanted kidney tissue and the normal structure of individual cells in glomeruli are preserved. The intraperitoneal infusion posttransplantation of allogeneic human peripheral blood mononuclear cells results in rejection of adult human grafts (4, 5).

Human fetal kidney fragments transplanted beneath the renal capsule of immunodeficient rats display rapid growth and development. Glomeruli and tubular structures are maintained for as long as 4 mo posttransplantation. In contrast to the case for transplanted adult human kidney fragments, infusion of allogeneic human peripheral blood mononuclear cells into hosts results in either minimal human T cell infiltration or T cell infiltrates that do not result in rejection and do not interfere with the continued growth of human fetal renal tissue (4, 5).

Human fetal grafts have reduced expression of tissue HLA class I and II relative to the adult human grafts, consistent with a reduced effectiveness in inducing an alloantigen-primed T cell response (4).

Vascularization of Transplanted Metanephroi

The major vessels supplying the kidney originate from the embryonic aorta through a process of angiogenesis. It is a matter of controversy whether the renal microvasculature arises exclusively via this angiogenic process or also in part from endothelial cells resident in the developing metanephros via vasculogenesis. However, it is clear that during its development, the metanephros is able to attract at least the major portion of its vasculature from the developing aorta (24). In that its blood supply originates from outside of the developing renal anlage, the kidney may be regarded as a chimeric organ. Its ability to attract its own vasculature in situ establishes the potential for a transplanted metanephros to attract a vasculature from an appropriate vascular bed.

Insight into the origin of the renal blood supply is provided by experiments in which developing kidneys are transplanted into ectopic sites. However, the results of these experiments are somewhat contradictory. One explanation for the different findings may be that the means of vascularization is site specific. In the case of 11-day-old xenograft mouse or chick metanephroi grafted onto the chorioallantoic membrane of the quail, the vasculature is derived entirely from the host (20). In the case of 11- to 12-day-old isograft mouse metanephroi grafted onto the anterior chamber of the eye, the glomerular microvascular endothelium derives from both donor and host (11). In either case, large external vessels derive from the host.


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It was speculated that developing nephrons implanted beneath the renal capsule might become incorporated into the collecting system of the host and thereby increase host renal function. However, such incorporation and a consequent enhancement of renal function have never been demonstrated. In addition, space limitation beneath the renal capsule has proven to be an impediment to the growth of transplants (17, 25).

In contrast to the case for metanephroi transplanted beneath the renal capsule, metanephroi transplanted into a fold of omentum in hosts undergo differentiation and growth that are not confined by a tight organ capsule (14-18). Transplanted metanephroi have a normal kidney structure and ultrastructure postdevelopment in situ and become vascularized via arteries that originate from the superior mesenteric artery of hosts (9).

Developed metanephroi transplanted onto the omentum clear inulin infused into the host's circulation after ureteroureterostomy between transplant and host, a procedure that can be readily carried out if metanephroi are implanted in close proximity to the host's ureter (9, 10, 14, 16, 17).

Using inbred congenic rats (PVG-RT1C and PVG-RT1avl), we have shown that metanephroi can be transplanted across the RT1 locus into non-immune-suppressed hosts.

A state of peripheral immune tolerance secondary to T cell "ignorance" permits the survival of transplanted metanephroi (16). Most likely, the ignorance results from the absence of dendritic cells originating from the donor in the embryonic renal tissue and the consequent absence of direct presentation of transplant antigen to host T cells (presentation by donor dendritic cells to host T cells), as was shown previously for subrenal capsular transplants (22).


    AVAILABILITY OF SOURCE MATERIAL FOR METANEPHROS TRANSPLANTS
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In the case of human renal allotransplantation, there is an unavoidable delay between the time of harvest from donors and the time of implantation into recipients. Before removal from the donor, human renal allografts are flushed with a preservation solution, often University of Wisconsin (UW) solution, and stored subsequently in ice-cold UW solution. The risk of delayed graft function is minimized by keeping the duration of warm ischemia, the length of time between lack of blood flow to the kidneys and the beginning of cold storage, below 20 min and by keeping the time in cold storage, cold ischemia, below 30 h (15).

Theoretically, metanephroi could be harvested immediately before implantation into humans. However, practically it would be best if, like most human renal allografts, metanephroi could be stored in vitro for a period of time before transplantation.

To determine whether metanephroi can be stored in vitro before transplantation, we either transplanted metanephroi from E15 rat embryos into the omentum of nonimmunosuppressed uninephrectomized (host) rats directly or transplanted those that had been suspended in ice-cold UW preservation solution for 3 days before implantation. The size and extent of tissue differentiation preimplantation of E15 metanephroi implanted directly were not distinguishable from the size and differentiation of metanephroi preserved for 3 days.

By 4 wk posttransplantation, metanephroi that had been preserved for 3 days had grown and differentiated such that glomeruli, proximal and distal tubules, and collecting ducts with normal structure had developed. At 12 wk posttransplantation, inulin clearances of preserved metanephroi were comparable to those of metanephroi that had been implanted directly, consistent with the viability of preserved metanephroi (15).


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Rat to Mouse

We transplanted metanephroi from an E15 Lewis rat embryo across a concordant xenogeneic barrier into the peritoneum of 10-wk-old C57BL/6J mice. Two weeks later, either no trace of the metanephros could be found in mice, or a yellowish piece of tissue, too small to embed, was observed in the omentum (14). In contrast, in mice that received costimulation blocking agents hCTLA4Ig, anti-CD45RB, and anti-CD154, the transplanted rat metanephros underwent differentiation and growth in situ (14).

To gain insight into the origin of the vasculature (donor vs. host) of metanephroi transplanted in the omentum, using our rat right-arrow mouse model, we stained developing rat metanephroi using mouse-specific antibodies directed against the endothelial antigen CD31.

Shown in Fig. 1 are photomicrographs of paraffin-embedded sections containing developed glomeruli in a Lewis rat metanephros after 2 wk of transplantation into a C57BL/6J mouse (Fig. 1, A and B) or a Lewis rat (Fig. 1, C and D) stained using anti-mouse CD31 (14). Positively stained glomeruli (rat right-arrow mouse) are shown in Fig. 1A. Negatively stained glomeruli (rat right-arrow rat) are shown in Fig. 1C (arrowheads). The vasculature of the transplanted developed rat kidney transplanted into the mouse is of mouse origin, including glomerular capillary loops (Fig. 1B). In contrast, glomerular capillary loops in rat metanephroi transplanted into rats do not stain for mouse CD31 (Fig. 1D).


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Fig. 1.   Photomicrographs of stained sections of rat metanephroi 2 wk posttransplantation into a mouse omentum (A and B) or a rat omentum (C and D) using anti-mouse CD31. Arrowheads, positively stained glomeruli (A) and negatively stained glomeruli (C). Arrow, positively stained glomerular capillary loops (B). g, Glomeruli.

Pig to Rodent

Using techniques identical to those employed in rat right-arrow rat intraomentum transplantation in a discordant (12)/highly disparate (26) model in which preformed xenoreactive antibodies are present (pig right-arrow rat), we have transplanted E28 pig metanephroi, consisting only of a branched ureteric bud and undifferentiated metanephric blastema (Fig. 2A) into the peritoneum of Lewis rats. Rat hosts were treated to induce tolerance with hCTLA4Ig (0.5 mg/day, Genetics Institute, Cambridge, MA) on days 2 and 1 before transplantation, on the day of transplantation, and on day 5 posttransplantation; anti-CD2 (0.5 mg/day, Pharmingen, San Diego, CA) on the day of transplantation and on days 3, 7, and 10 posttransplantation; and anti-rat CD4 (0.7 mg/day iv, OX35, Pharmingen) on days 2 and 4 posttransplantation. Shown in Fig. 2, B-D, are sections of paraffin-embedded metanephroi after 20 days in rat omentum. The nephrogenic zone (nz) is delineated in Fig. 2B. Developing nephrons are labeled in Fig. 2C (ub, ureteric bud; s, s-shaped body). A developed glomerulus (g) beneath the nz is also shown (Fig. 2D).


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Fig. 2.   Hematoxylin- and eosin-stained sections of pig metanephroi. A: embryonic day 28 metanephros. Developing nephrons are shown as follows: mb and ub, undifferentiated metanephric blastema and ureteric bud branch, respectively. B-D: pig metanephros 20 days postimplantation in the omentum of a Lewis rat. nz, Nephrogenic zone; s, s-shaped body.

Development also occurs after transplantation of pig metanephroi into mice (10).


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Unlike developed kidneys, metanephroi are nonvascularized or minimally so. Because porcine fetal metanephroi are nonvascularized, they would be expected not to be subject to hyperacute rejection after transplantation into primates or humans.

If our experience and the experience of others in the use of rodents can be extrapolated to the use of pigs, direct presentation of transplant antigens to host T cells should not occur and expression of SLA class I and II antigens should be minimal after transplantation of pig metanephroi. Indirect presentation across this discordant xenogeneic barrier could be prevented through the use of tolerance-inducing agents, as we have shown to be the case for concordant rat right-arrow mouse metanephros xenografts and for discordant/highly disparate pig right-arrow mouse xenografts we have performed.

Our studies demonstrate the feasibility of xenotransplantation of metanephroi. The applicability of this technique as a means of increasing renal function in humans will require that pig right-arrow primate experiments be performed first. Because the anti-alpha -Gal response includes an elicited component that contributes to acute vascular rejection (19), alpha -Gal-deficient pigs (1) may prove to be appropriate donors.


    ACKNOWLEDGEMENTS

M. R. Hammerman was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grants DK-45181 and DK-53487 and by a grant from Intercytex, Ltd., Manchester, UK. M. R. Hammerman and Washington University may receive income based on a license of related technology by Washington University to Intercytex, Ltd., and based on equity holdings in Intercytex, Ltd.


    FOOTNOTES

Address for reprint requests and other correspondence: M. R. Hammerman, Renal Div., Box 8126, Dept. of Medicine, Washington Univ. School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110 (E-mail: mhammerm{at}im.wustl.edu).

10.1152/ajprenal.00126.2002


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11.   Hyink, DP, Tucker DC, St. John PL, Leardkamolkarn V, Accavitti MA, Abrass CK, and Abrahamson DR. Endogenous origin of glomerular endothelial and mesangial cells in grafts of embryonic kidneys. Am J Physiol Renal Fluid Electrolyte Physiol 270: F886-F889, 1996[Abstract/Free Full Text].

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