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Update in immunosuppression.

The start of the modern era of transplantation has been attributed to Sir Peter Medawar's paper on allogeneic skin grafts in rabbits (1944-46). This paper described using skin transplants in differing breeds of rabbits and resulted in a basic understanding of the immune system (Medawar, 1944). While this was the beginning of the science of immunology, it was not until 10 years later, on December 23, 1954, that Joseph Murray performed the first successful kidney transplant with identical twins (Merrill et al., 1960). This first transplant constitutes the start of human transplantation, but it was not until the advent of cyclosporine in 1985 that transplantation became a more viable option for patients with chronic kidney disease (CKD). Previous therapies using prednisone, Imuran[R] (azathioprine), total lymphoid irradiation, splenectomy, donor specific transfusions, and chemotherapy were black and white--the transplant worked or it didn't. Cyclosporine also allowed transplantation of more marginal candidates, the start of extra renal transplantation (heart, liver, lung, pancreas, and small bowel), and increased transplant graft survival rate to between 50% and 85% at 1 year posttransplant. Since that time, other agents have entered the market: MALG[R] (Minnesota Anti-Lymphocyte Globulin), ATGAM[R], Thymoglobulin[R], OKT3[R], Prograf[R] (tacrolimus), CellCept[R] (mycophenolate mofetil), Simulect[R] (basiliximab), Zenapax[R] (daclizumab), and Rapamune[R] (sirolimus). There are also two newer agents about to enter the market that are analogs of these agents: Everolimus (Certican, which is an analog of Rapamune) and Myfortic[R] (enteric coated mycophenolic acid, the prodrug of CellCept[R]).

One year cadaveric graft survival rates now stand at over 90% (U.S. Department of Health and Human Services, 1999) (see Figure 1), with living donors having a graft survival advantage over cadaveric recipients as measured by graft half-life. Graft half-life is the time it takes for the 50% of a group of 100 transplants to fail. This measurement gives an idea of how long a transplant can be expected to last. The projected graft half-life for cadaveric grafts is now almost 9 years (see Figure 2) and almost 15 years for a living donor transplant (U.S. Renal Data System, 2000) (see Figure 3). It should be noted that graft half-life is calculated on older transplant data (1995-1996). The full effect of the newer immunosuppressants has not yet been seen in this projected data, and it is reasonable to expect that graft half-life will increase with each successive year. It is also important to note the difference between statistical significance and clinical significance. While there may be a statistical difference between a 1-year transplant survival of 96% and 98%, when analyzing 10,000 renal transplants, there is no clinical difference. These transplants have failed. Therefore, while acute transplant rejection has become a decreasing concern, chronic rejection remains a major problem. The focus is now on the known, long-term complications such as cardiovascular disease, malignancies, and the creation of individualized immunosuppressive regimens. There are now a number of studies in existence looking at decreasing immunosuppressive drugs in the hopes of equivalent graft survival but with reduced toxicity. None of these new studies will be addressed in this article, as there are a multitude of combination protocols presently in clinical trials. Rather, an attempt will be made to review three major paradigms in transplant immunology: costimulation, quantifying immunosuppression, and re-trafficking of lymphocytes. A review of new agents in each one of those paradigms is included at the end of each discussion.

[FIGURE 1-3 OMITTED]

Co-stimulation

In basic form, the immune system has two types of cells that fight infection: B cells and T cells. B cells are our "memory" cells and produce antibodies, whereas T cells are the active fighters in the immune system. T cells are turned on (upregulated) by cell damage or injury, infections, or foreign matter (like a transplant). The immune system is turned on in two stages, the direct and indirect pathways. The direct pathway is where a foreign protein (think of the transplanted kidney) is presented to a major histocompatibility complex (MHC) cell. This cell would turn on and produce cytokines, which results in the attack of the graft by T cells. However, there is a safety trigger on the MHC, without which it may "misfire" and cause an attack on our own cells. That safety trigger is called costimulation (Laferty, Prowse, & Simeonvic, 1983; Mueller, Jenkins, & Schwartz, 1989). Without this necessary second signal, the immune system cannot fire. Recognition of foreign matter in the absence of co-stimulation can lead to T cell anergy. That means that the body will decide not to attack that particular foreign protein. While it is important to note that anergy can be overcome, it means that if the safety trigger is on, rejection cannot occur. Much of the most recent immunosuppressive work is focused on co-stimulation.

A new co-stimulation molecule: BMS-224818. There is a significant unmet medical need in renal transplantation: decreased toxicity with improved graft survival. Cyclosporine or tacrolimus-based immunosuppression have substantial known toxicities. BMS-224818 is a second generation CTLA4Ig, meaning it is improved over the original CTLA4Ig molecule. It has increased binding to CD80 and CD86, which stops T-cell response. This increased binding shows BMS-224818 to be 5 to 10 fold more effective in vitro than its parent agent. This blocks the second (co-stimulatory) signal needed for T cell activation and the resultant immune response. Animal testing at doses nine times higher than proposed for this study did not reveal any significant drug-related toxicities. The ability of this agent to block the costimulatory signal has been shown in multiple animal models (Perico, Imberti, Bontempelli, & Remuzzi, 1995). Single dose Phase I studies (studies in healthy human volunteers) showed this agent to be well tolerated. A Phase II study of BMS-224818 versus placebo in rheumatoid arthritis is presently ongoing.

The hypothesis is that the use of BMS-224818 will allow for equivalent renal transplant survival compared to a cyclosporine-based regimen. By removing cyclosporine (or tacrolimus) from the immunosuppressive regimen, secondary toxicities of these agents should be prevented, such as nephrotoxicity, hyperlipidemia, hypertension, diabetes, and gingival hyperplasia. However, the use of a co-stimulatory molecule is a new paradigm in renal transplantation and should be treated with the caution that is taken with all new immunosuppressive molecules.

Quantifying Immunosuppression

Immunosuppression can be considered in two ways: complete or partial (see Figure 4). Complete inhibition (or immunosuppression) involves preventing the ability of the immune system to react to foreign matter. OKT3 is an example of a complete inhibitor. It binds to the CD3 molecule, stopping the immune system response. However, while easily done, long-term complete suppression results in the death of the patient. The patient is no longer able to fight the smallest infection, and cells start to transform into malignant cells. Therefore, while these agents may be useful in treating acute rejection on a short-term basis, they are dangerous when used to prevent rejection on the long-term. The obvious step is partial inhibition. The goal is the prevention of transplant rejection while allowing the immune system to retain its ability to fight infection. It would be easier if there was standard dosing for all patients, however, each person's immune system is unique. There is no commercial assay to detect your immune activity. There is some basic science work looking at calcineurin, a phosphatase enzyme needed for the movement of regulatory proteins through the cell nuclear membrane (Batiuk, Kung, & Halloran, 1997). Therefore, the inhibition of calcineurin results in a limited cytokine production and limited proliferation of lymphocytes further down the immune stream (Batiuk & Halloran, 1997; Halloran, 2001). Measurement of calcineurin is presently being used as an additional assay in a ongoing Phase II trial of IS[A.SUB.TX]247, but it needs to be noted that it remains a basic science tool at this point, and further work needs to be done to examine its potential as a "real world" assay.

A new calcineurin inhibitor: IS[A.sub.TX]247. Cyclosporine A (CsA)is known to inhibit lymphocyte function, in particular T-lymphocytes, as well as to inhibit lymphocyte production and release. Neoral[R] has generally replaced Sandimmune[R] due to Neoral's microemulsion formulation, thereby eliminating the bile dependency and unreliable absorption of the reference product. The mechanism of action of the two products remains the same: the inhibition of calcineurin. CsA also enhances the expression of TGF-beta, which also inhibits IL-2 and T-lymphocyte generation. Calcineurin inhibitor agents (CNi), which include all the cyclosporines (Neoral, Sandimmune, and the several generic compounds of Neoral) and Prograf (tacrolimus), have remained the primary immunosuppressive agents for kidney transplantation despite their nephrotoxicity. It should be noted, however, that the first generic compound of Neoral was SangCyA. It was withdrawn from the market due to lack of consistent bioequivalence; a generic compound needs to receive the AB rating from the Food and Drug Amdinistration (FDA) before it can be allow for substitution.

ISA is a CsA analogue presently in Phase II clinical trials for use in the prevention of renal transplant graft rejection. It is a novel agent belonging to the same class as cyclosporine and tacrolimus and has an oral bioavailiability similar to that of Sandimmune. While containing similar pharmacokinetic characteristics to cyclosporine, it has a three-fold greater inhibition of calcineurin. In vivo studies using a Wistar Furth rat heart transplant model have shown that ISA resulted in a three-fold longer graft life compared to CsA at equivalent doses. Several toxicity studies have been completed in rats, dogs, and rabbits to assess multiple dose toxicity of ISA, as well as its potential to produce mutations and chromosome aberrations in in vitro systems. Acute and chronic oral toxicity studies of ISA have been completed in the rabbit, rat, dog, and monkey. Rabbits that received ISA at doses of 10 and 15 mg/kg/d for 30 days did not exhibit any significant change in renal function as compared to control animals. Rabbits receiving CsA at 10 mg/kg/d experienced a 30% increase in serum creatinine levels. In two separate studies, ISA was administered to rats at doses up to 80 mg/kg/d for 28 days without any change in serum creatinine and with no noted significant morbidity or mortality. This dosing level is important, as it was greater than 40 times that needed for human renal transplantation. Similar rats receiving CsA had a 50% increase in creatinine, and female rats had a doubling of certain hepatic enzymes (ALT and Alk phos). A similar lack of significant side effects was also noted in dog and primate models. Therefore, in these four animal models, ISA was shown to exhibit fewer side effects compared to CsA, while preserving renal function. It was this finding (greatly reduced nephrotoxicity) that lead to Phase I trials in healthy volunteers.

Multiple Phase 1 studies have been conducted in normal volunteers to assess the pharmacokinetics and safety of ISA. The data indicate that ISA is safe and well tolerated in normal healthy male and female subjects (Abel et al., 2001). The pharmacokinetic parameters obtained from these studies indicate that ISA is rapidly absorbed following oral administration, with median time to maximal serum concentration of ISA ([T.sub.max]) values of approximately 2.0 hr for all dose groups (Abel, Aspeslet, Freitag, Naicker, et al., 2001). This is similar to the [T.sub.max] for Neoral. Mean maximal concentration ([C.sub.max])levels and areas under the curve (AUCs) appeared to increase linearly with dose, indicating dose proportionality for ISA in healthy male and female subjects. No significant change in the AUCs was noted between fed and fasting states. In addition, the level of immunosuppression, as determined by the measurement of calcineurin activity, suggests an increased potency when compared to a comparable dose of cyclosporine. Studies have shown that in patients receiving CsA the calcineurin activity is only inhibited by 50% at therapeutic levels, whereas in patients receiving equivalent doses of ISA, the approximate mean inhibition of calcineurin increased to 90%. Since ISA exhibits increased inhibition of calcineurin activity, a dose of one-half equivalence to the pre-study CsA dose has been proposed.

In summary, the preclinical studies indicate that ISA is more potent and less toxic than cyclosporine. It is well absorbed, does not appear to produce any significant side effects at normal doses, and has potential as a new agent in the immunosuppressive arsenal. This assumes that CNi agents are needed at all. There are numerous studies looking at CNi free protocols using sirolimus, mycophenolate mofetil, and steroids. Recent abstracts presented at the 2000 American Society of Transplantation meeting reported improved renal function, while others used low CNi protocols using Rapamune (sirolimus). ISA may succeed only if its promise of lower toxicity holds true.

Changing the Direction of Lymphocytes

In order for an immune system to be intact, all the components must play their part at the right time and in the right place. If an agent can move or re-traffic members of the immune system to where they cannot be effective, this may allow for use of immunosuppression while keeping the immune system intact. The only concern is that any such agent must be reversible, or a patient may be open to attack from infection or malignant cell transformation.

A new re-trafficking molecule: FTY720. FTY720 is an analogue of myriocin, a metabolite of Isaria sinclairii. FTY720 interferes with the ability of lymphocytes to respond to triggers (chemokines) and decreases the ability of these lymphocytes to enter the peripheral circulation (Brinkmann, Pinschewer, Feng, & Chen, 2001; Kahan, 1998). Consequently, T cells cannot infiltrate the transplant and start the rejection process. In essence, FTY720 re-routes activated lymphocytes to the lymph glands, so that they cannot carry out their duties in the transplanted organ. In animal models, FTY720 was able to prolong graft survival in combination with various other immunosuppressive agents (Nikolova et al., 2000; Nikolova, Hof, Baumlin, & Hof, 2001). Over 200 kidney transplant patients have been treated with FTY720 in single or multiple doses. These patients show an immediate and dose-dependent decrease in lymphocyte counts in the peripheral circulation (PBL), which could reach 70% of baseline (Brinkmann et al., 2001). This effect is reversed once patients stopped the medication. In other studies, FTY720 was safe when used with Neoral and steroids (Stepkowski et al., 1998; Troncoso et al., 1999) in the initial 30 days of the study. This Phase II study was recently put on hold due to concerns regarding bradycardia in patients, however, the analysis is pending.

Inhibiting Antibody

Renal transplant graft failure is one of the most common reasons for patients returning to dialysis. The optimal treatment for these patients, both in terms of quality of life and life expectancy, remains retransplantation. Unfortunately, many of these individuals have developed anti-HLA antibodies due to their previous transplant and are, therefore, "sensitized." Other risk factors for sensitization include multiple transfusions, infections, and pregnancies. The degree of sensitization is determined by the level of panel reactive antibodies (PRA). Patients with a PRA level greater than 50% are considered highly sensitized and face many years on the transplant waiting list. While cross-match negative during an initial assessment for transplantation, highly sensitized patients can have a retrospective positive cross-match using more specialized techniques. Presensitation can result in an antibody-mediated rejection. Historically, the prognosis of antibody-mediated rejection following renal transplantation is poor.

An antibody inhibitor: IVIG with CellCept. In vivo administration of specific and unselected polyclonal intravenous immunoglobulin (IVIG) preparations have been shown to inhibit anti-HLA alloantibodies in highly sensitized patients. It is felt that this may be due to deletion of B and T cells by apoptosis (programmed cell death). A number of strategies have been employed to try to reduce or remove anti-HLA antibodies using IVIG (Glotz et al., 1993; Higgins, Bevan, Carey, et al., 1996). These include plasma exchange (Reisaeter et al., 1994; Reisaeter et al., 1995) or immunoadsorption (Palmer et al., 1989; Palmer et al., 1987; Taube et al., 1989). Plasma exchange and immunoadsorption are often combined with prednisone and cyclophosphamide and IVIG infusions. Cyclophosphamide was used early in these protocols, but due to the toxicities associated with its use, many centers have now chosen to use CellCept. A number of centers have reported success with IVIG given to patients at the end of their hemodialysis session (Higgins, Bevan, Vaughan, et al., 1996; Montgomery et al., 2000; U.S. Renal Data System, 2000). Recent studies have been reported the use of IVIG in the place of OKT3 either to prevent rejection or treat steroid resistant rejection (Schweitzer et al., 2000). In short, IVIG is effective in decreasing the amount of antibody produced. Once transplanted, these patients may need further therapy with IVIG or plasmapheresis, however, this strategy allows for the possibility of transplantation for patients who were once considered nontransplantable. There are difficulties associated with the use of IVIG: expense (a course of IVIG can cost over $10,000); not all patients have a decrease in antibody in response to IVIG; and it requires continued use, thereby, exponentially increasing the cost for those who do not get transplanted immediately. Some centers have reduced the difficulties of IVIG by transplanting those patients on IVIG therapy as priorities even if other patients have a higher degree of matching.

Drug Development Hurdles in the Future

While BMS-224818 and FTY720 show great promise as new immunosuppressive agents, the concern is that increased or improved immunosuppression will equally increase comorbidities in the future (cardiovascular disease, malignancies, toxicity) (see Figure 5). First, caution must be used with these new agents to ensure that there is no increased risk for improved graft survival. Second, the new economic realities may dictate which agents may be used. The number of CKD patients continues to increase at an alarming rate, and the total renal population is expected to double by 2010. The high cost of maintenance immunosuppression cannot continue without increasing the cost of CKD care overall. Therefore, as new therapies become available, there is a need to determine under what conditions they can be used. It seems unlikely that all therapies can be used for all patients (see Table 1). Last, the problem of deciding which immunosuppressive protocol to use has become even more difficult considering the number of agents available, the possible combinations of all of these agents, and the potential to eliminate any one of those agents (see Table 2). The next few years in renal transplantation promise to produce increasingly immunologic specific agents, with the potential for equivalent or increased efficacy with reduced toxicity.

[FIGURE 5 OMITTED]

Figure 4 Conceptualizing Immunosuppression

* Complete inhibition--e.g. reversing acute transplant rejection (OKT3)

* Partial inhibition (maintenance)--Neoral/Prograf, CellCept, steroids

Table 1

Immunosuppressive Drug Development Hurdles

Improve long-term results

* concern over long-term comorbidities

Reducing co-morbidities

* organ toxicities, coronary artery disease, cancer

New economic realities

* need to decrease cost due to increasing numbers of surviving transplant patients

Creating a Protocol

* too many combinations

* which drug to eliminate?

Table 2

Protocol Combinations

Calcineurin inhibitor based:

* CsA/FK, CsA/FK-MMF, CsA/FK-Rapamycin

Target of Rapamycin (TOR) inhibitor based:

* Rapamycin, Rapamycin-MMF, Rapamycin-Aza, Certican (RAD) in place of Rapamycin

Mycophenolate mofetil (IMPDH inhibitor) based:

* MMF, Zenapax-MMF, Rapamycin-MMF, Myfortic in place of MMF, Simulect in place of Zenapax

Incorporating anti CD25 Induction:

* Zenapax-CsA/FK, Zenapax-CsA/FK-MMF, Zenapax-FK-MMF, Zenapax-MMF, Zenapax-Rapamycin, Simulect in place of Zenapax

References

Abel, M.D., Aspeslet, L.J., Freitag, D.G., et al. (2001). Phase 1 evaluation of a novel calcineurin inhibitor IS[A.SUB.TX]247. American Journal of Transplantation, 1 (Suppl.) A 1319, 470.

Abel, M.D., Aspeslet, L.J., Freitag, D.G., Naicker, S., Trepanier, D.J., Kneteman, N.M., Foster, R.T, & Yatscoff, R.W. (2001). IS[A.sub.TX]247: A novel calcineurin inhibitor. Journal of Heart Lung Transplant, 20, 161.

Batiuk, TD., & Halloran, P.F. (1997). The downstream consequences of calcineurin inhibition. Transplantation Proceedings, 29, 1239-1240.

Batiuk, T.D., Kung, L., & Halloran, P.F. (1997). Evidence that calcineurin is rate-limiting for primary human lymphocyte activation. Journal of Clinical Investigation, 100, 1894-1901.

Brinkmann, V., Pinschewer, D.D., Feng, L., &Chen, S. (2001). FTY720: Altered lymphocyte traffic results in allograft protection. Transplantation, 72, 7(34-769.

Glotz, D., Haymann, J.P., Sansonetti, N., Francois, A., Menoyo-Calonge, V., Bariety, J., et al. (1993). Suppression of HLA-specific alloantibodies by high-dose intravenous immunoglobulins (IVIG). A potential tool for transplantation of immunized patients. Transplantation, 56, 335-337.

Halloran, P.F. (2001). Mechanism of action of the calcineurin inhibitors. Transplantation Proceedings, 33, 30673069.

Higgins, R.M., Bevan, D.J., Carey, B.S., Lea, C.K., Fallon, M., Buhler, R., Vaughn, R.W., O'Donnell, B.A., Snowen, S.A., Beuthch, B., & Hendry, M. (1996). Prevention of hyperacute rejection by removal of antibodies to HLA immediately before renal transplantation. Lancet, 348, 1208-1211.

Higgins, R.M., Bevan, D.J., Vaughan, R.W., Phillips, A.O., Snowden, S., Bewick, M., et al., (1996). 5-year follow-up of patients successfully transplanted after immunoadsorption to remove anti-HLA antibodies. Nephron, 74, 53-57.

Kahan, B.D. (1998). FTY720: A new immunosuppressive agent with novel mechanism(s) of action. Transplantation Proceedings, 30, 2210-2213.

Laferty, K.J., Prowse, S.J., & Simeonvic, C.J. (1983). Immunobiology of tissue transplantation: A return to the passenger leukocyte concept. Annual Review of Immunology, I, 143-173.

Medawar, P.B. (1944). The behavior and fat of skin autografts and skin homografts in rabbits. Journal of Anatomy, 78, 176-199.

Merrill, J.P., Murray, J.E., Hartwell Harrison, J., Friedman, E.A., Dealy, J.B., Jr., & Dammin, G.J. (1960). Successful homotransplantation of the kidney between nonidentical twin. New England Journal of Medicine, 262(25), 1251-1260.

Montgomery, R.A., Zachary, A.A., Racusen, L.C., Leffell, M.S., King, K.E., et al. (2000). Plasmapheresis and intravenous immune globulin provides effective rescue therapy for refractory humoral rejection and allows kidneys to be successfully transplanted into cross-match-positive recipients. Transplantation, 70, 887895.

Mueller, D.L.,Jenkins, M.K., & Schwartz, R.H. (1989). Clonal expansion versus functional clonal inactivation: A costimulatory signaling pathway determines the outcome of T-cell antigen receptor occupancy. Annual Review of Immunology, 7, 445-480.

Nikolova, Z., Hof, A., Baumlin, Y., & Hof, R.P. (2001). Efficacy of SDZ RAD compared with CsA monotherapy and combined Rad/FTY720 treatment in a murine cardiac allotransplantation model. Transplantation Immunology, 9, 43-49.

Nikolova, Z., Hof, A., Rudin, M., Baumlin, Y., Kraus, G., & Hof, R.P. (2000). Prevention of graft vessel disease by combined FTY720/cyclosporine. A treatment in a rat carotid artery transplantation model. Transplantation, 69, 2525-2530.

Palmer, A., Taube, D., Welsh, K., Bewick, M., Gjorstrup, P., & Thick, M. (1989). Removal of anti-HLA antibodies by extracorporeal immunoadsorption to enable renal transplantation. Lancet, 1, 10-12.

Palmer, A., Taube, D., Welsh, K., Brynger, H., Delin, K., Gjorstrup, P., et al. (1987). Extracorporeal immunoadsorption of anti-HLA antibodies: Preliminary clinical experience. Transplantation Proceedings, 79, 37503751.

Perico, N., Imberti, O., Bontempelli, M., & Remuzzi, G. (1995). Toward novel anti-rejection strategies: In vivo immunosuppressive properties of CTLA4Ig. Kidney International, 47, 241-246.

Reisaeter, A.V., Fauchald, P., Leivestad, T., Holdaas, H., Hartmann, A., Pfeffer, P., et al. (1994). Plasma exchange in highly sensitized patients as induction therapy after renal transplantation. Transplantation Proceedings, 26, 1758.

Reisaeter, A.V., Leivestad, T., Albrechtsen, D., Holdaas, H., Hartmann, A., Sodal, G., et al. (1995). Pretransplant plasma exchange or immunoadsorption facilitates renal transplantation in immunized patients. Transplantation, 60, 242-248.

Schweitzer, E.J., Wilson, J.S., Fernandez-Vina, M., Fox, M., Gutierrez, M., Wiland, A., et al. (2000). A high panel-reactive antibody rescue protocol for cross-match-positive live donor kidney transplants. Transplantation, 70, 1531-1536.

Stepkowski, S.M., Wang, M., Qu, X., Yu, J., Okamoto, M., Tejpal, N., et al., (1998). Synergistic interaction of FTY720 with cyclosporine or sirolimus to prolong heart allograft survival. Transplantation Proceedings, 30, 2214-2216.

Taube, D., Palmer, A., Welsh, K., Bewick, M., Snowden, S., & Thick, M. (1989). Removal of anti-HLA antibodies prior to transplantation: An effective and successful strategy for highly sensitized renal allograft recipients. Transplantation Proceedings, 21, 694-695.

Troncoso, P., Stepkowski, S.M., Wang, M.E., Qu, x., Chueh, S.C., Clark, J, et al. (1999). Prophylaxis of acute renal allograft rejection using FTY720 in combination with sub-therapeutic doses of cyclosporine. Transplantation, 67, 145-151.

U.S. Department of Health and Human Services. (1999). 2000 annual report of the U.S. scientific registry for transplant recipients and the organ procurement and transplantation network: Transplant data: 1990-1999. Rockville, MD: Author.

U.S. Renal Data System (USRDS). (2000). USRDS 2000 annual data report. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases.

Robert Huizinga, MSC(c), RN, NNC, CNeph(C), is Clinical Research Coordinator, University of Alberta Hospital, Edmonton, Alberta, Canada.
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Author:Huizinga, Robert
Publication:Nephrology Nursing Journal
Geographic Code:1USA
Date:Jun 1, 2002
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