Renal transplantation: Trends and challenges

Introduction

Renal replacement therapy with renal transplantation or chronic dialysis is the only life-saving treatment for the end-stage renal disease (ESRD). Renal transplantation when compared to chronic dialysis is however the preferred treatment, where feasible, due to attendant improved quality of life and survival as well as reduced long-term cost of medical care.¹Galichon P, Xu-Dubois YC, Finianos S, et al. Clinical and histological predictors of long-term kidney graft survival. Nephrol Dial Transplant. 2013;1-8.   Overall, regardless of the age or comorbidities, such as diabetes, renal transplantation in ESRD patients lowers the mortality risk by 68% when compared to those on dialysis and waiting for transplant. More specifically, approximately 11 years of extra life can be gained with renal transplantation in diabetic and elderly (>70 years of age) ESRD patients.²Pesavento TE. Kidney Transplantation in the Context of Renal Replacement Therapy. Clin J Am Soc Nephrol. 2009;4:2035-2039.  

Annually in India, about 1,75,000 patients develop ESRD, of which only <10% undergo renal replacement therapy and a mere 2% receive renal transplantation.³Srivastava A. Renal transplantation: An update. Indian J Urol. 2007 Jul-Sep;23(3):270-271.  ^,4Patel HV, Kute VB, Ghelani GH, et al. Outcome of deceased donor renal transplantation – A single-center experience from developing country. Saudi J Kidney Dis Transpl. 2013;24:403-7.   This enormous gap between patients requiring transplant and those receiving it is attributed to the organ demand greatly outpacing the supply. As a consequence of this, the proportion of waitlist candidates as well as their waiting time has increased substantially, resulting in higher risk of death. It is noteworthy that the vast disparity between the demand and supply is despite the fact that sincere efforts and multiple new avenues (e.g., expanded criteria of organ donation and donation of organ after cardiac death) are being employed to increase the donor kidney pool.²Pesavento TE. Kidney Transplantation in the Context of Renal Replacement Therapy. Clin J Am Soc Nephrol. 2009;4:2035-2039.  ^,5Knoll G. Trends in kidney transplantation over the past decade. Drugs. 2008;68 Suppl 1:3-10.   In the following treatise, clinically relevant contemporary issues related to renal transplantation are comprehensively discussed.

Advancements In Renal Transplant Immunosuppression

Since the transplanted kidney is foreign to the host’s immune system, it receives formidable resistance from it which if left unchecked would result in graft loss and patient death.²Pesavento TE. Kidney Transplantation in the Context of Renal Replacement Therapy. Clin J Am Soc Nephrol. 2009;4:2035-2039.   This warrants the necessity for immunosuppressive therapies to ensure transplantation success and improve graft and patient survival. However, it is a paradox that immunosuppressants themselves may compromise the graft and patient survival due to nephrotoxicity and various metabolic changes induced by them.¹Galichon P, Xu-Dubois YC, Finianos S, et al. Clinical and histological predictors of long-term kidney graft survival. Nephrol Dial Transplant. 2013;1-8.   To prevent immunosuppressant-induced adverse effects and improve the longevity of transplants, researchers over the last few decades have intensely worked to develop novel immunosuppressive therapies and strategies which would achieve their target with acceptable safety profile. Introduction of tacrolimus and mycophenolate mofetil as immunosuppressive therapies has, to a large extent, served this purpose; the 3-year renal graft survival has improved from 65%-75% with cyclosporine to 77%-86% with widespread use of tacrolimus and mycophenolate mofetil.⁵Knoll G. Trends in kidney transplantation over the past decade. Drugs. 2008;68 Suppl 1:3-10.  ^,6Chakkera HA, Chertow GM, O’Hare AM, et al. Regional Variation in Kidney Transplant Outcomes: Trends Over Time. Clin J Am Soc Nephrol. 2009 Jan; 4(1): 152-159.   Refer to box 1 for the list of commonly used immunosuppressive agents in renal transplantation.⁷Shen LJ, Wu FL. Nanomedicines in renal transplant rejection – focus on sirolimus. Int J Nanomedicine. 2007 Mar;2(1):25-32.   Additionally, introduction of strategies such as use of combination therapies instead of monotherapy have further enhanced the clinical outcomes, since utilization of immunosuppressive agents with complementary mechanisms of action in a combination not only achieves adequate immunosuppression by attacking at various levels of lymphocytic activation and proliferation, but blunts the risk of side-effects as well, as combination allows the possibility of lowering the dosages of individual agents, thus producing fewer drug-related toxicities.⁸Lee RA, Gabardi S. Current trends in immunosuppressive therapies for renal transplant recipients. Am J Health Syst Pharm. 2012;69(22):1961-75.  

With this background, we can proceed to classification of immunosuppressive therapies which can be broadly divided into 3 stages: Induction therapy, maintenance therapy and treatment of an acute rejection episode (box 1).⁷Shen LJ, Wu FL. Nanomedicines in renal transplant rejection – focus on sirolimus. Int J Nanomedicine. 2007 Mar;2(1):25-32.  ^,8Lee RA, Gabardi S. Current trends in immunosuppressive therapies for renal transplant recipients. Am J Health Syst Pharm. 2012;69(22):1961-75.   In majority of the cases, induction immunosuppression is achieved with monoclonal or polyclonal antilymphocytic antibodies

which is followed by maintenance therapy utilizing a combination of a calcineurin inhibitor (tacrolimus or cyclosporine), an antimetabolite (mycophenolate mofetil or mycophenolic acid) and a corticosteroid. With these treatment protocols, acute rejection episodes can be reduced to <15% and 1-year graft survival can be enhanced to over 90%.⁹Zivčć-Ćosić S, Trobonjača Z, Rački S. Immunosuppressive treatment for kidney transplantation. Prilozi. 2011;32(2):87-103.  

Another challenge encountered with immunosuppressive therapy is poor water solubility and hence large intra- and inter-individual variability in pharmacokinetic profile of many immunosuppressants, which may greatly blunt their efficacy in preventing acute graft rejection episodes. This challenge has been overcome to a large extent with utilization of advanced formulation technologies, such as micronization and nanotechnology, to formulate more bioavailable formulations. To exemplify, nanotechnology is being utilized to formulate sirolimus (a water insoluble immunosuppressant) into an oral solid dosage form which increases its water solubility and hence the bioavailability. This solid formulation not only offers less fluctuations in the blood levels of sirolimus but is also associated with improved palatability and more convenience for long-term use. Overall, development and formulation of potent and better tolerated immunosuppressants with enhanced bioavailability has reduced acute rejection episodes and improved graft and patient survival.⁷Shen LJ, Wu FL. Nanomedicines in renal transplant rejection – focus on sirolimus. Int J Nanomedicine. 2007 Mar;2(1):25-32.  

Static Cold Storage vs Machine Perfusion For Renal Graft Preservation: A Review

Since there is limited availability of live donors, renal transplant from deceased donor has emerged as a practically viable solution to narrow the widening gap between the organ demand and supply. Additionally, the use of marginal or expanded criteria donors for organ procurement has also served towards this purpose.¹⁰Swami YK, Singh DV, Gupta SK, et al. Deceased donor renal transplantation at army hospital research and referral: Our experience. Indian J Urol. 2013; 29(2):105-109.  ^,11Gopalakrishnan G, Gourabathini SP. Marginal kidney donor. Indian J Urol. 2007;23(3):286-293.   However, cadaveric renal transplants encounter a practical conundrum of adequate preservation, which is a determinant of its survival post transplantation. This challenge becomes even more pronounced in relation to preservation of marginal or expanded criteria donor kidneys. To override this challenge, the focus from static cold storage as organ preservation methodology has shifted towards hypothermic machine perfusion, which is now increasingly being utilized to preserve donor renal grafts. This change in trend is based upon robust clinical data which shows improved outcomes of grafts preserved with hypothermic machine perfusion than static cold storage.¹²Balfoussia D, Yerrakalva D, Hamaoui K, et al. Advances in machine perfusion graft viability assessment in kidney, liver, pancreas, lung, and heart transplant. Exp Clin Transplant. 2012;10(2):87-100.   A study published in The New England Journal of Medicine, 2012, which evaluated 3-year graft survival of cadaveric donor kidneys preserved either using static cold storage or hypothermic machine perfusion, showed better 3-year graft survival with machine-perfused than static cold storage kidneys (91% vs. 87%, respectively, figure 1). Remarkably, this superiority in 3-year graft survival of machine perfused kidneys over static cold storage kidneys was significant for the ones that were donated after brain death (91% vs. 86%) and not after circulatory death, and those procured from expanded criteria donors (86% vs. 76%). It was concluded that 3-year survival of renal grafts procured from brain dead individuals was significantly better for those preserved with machine perfusion than cold storage.¹³Moers C, Pirenne J, Paul A, et al. Machine perfusion or cold storage in deceased-donor kidney transplantation. N Engl J Med. 2012;366(8):770-1.   As to the reasons of these clinical benefits associated with machine perfusion over cold storage, it is proposed that they could be due to maintenance of vascular bed patency

and tissue metabolism, removal of toxic metabolites, increased expression of endothelial protective genes and ability to perform pharmacological interventions with the former methodology of organ preservation.¹²Balfoussia D, Yerrakalva D, Hamaoui K, et al. Advances in machine perfusion graft viability assessment in kidney, liver, pancreas, lung, and heart transplant. Exp Clin Transplant. 2012;10(2):87-100.  

Apart from the advantage of reduced risk of delayed graft function and improved graft survival with machine perfusion over cold storage kidney preservation, machine perfusion also allows for better assessment of viability of the donor kidney before transplantation using machine perfusion parameters and perfusate biomarkers. Accrued clinical as well as experimental trials indicate that low machine perfusion pressure, high machine perfusion flow rates and decreased renal resistance to arterial flow are associated with more favorable post-transplantation outcomes. In clinical settings, these parameters can be assessed with new imaging techniques, such as contrast-enhanced ultrasound, three-dimensional ultrasound and magnetic resonance spectrometry. Apart from these machine perfusion parameters, perfusate biomarkers have also been extensively reviewed and evaluated as predictors of post-transplantation outcomes. Interestingly, perfusate biomarkers, including lactate dehydrogenase, aspartate transaminase, glutathione-S-transferase, N-acetyl-β-D-glucosaminidase, heart-type fatty acid binding protein, lipid peroxidation products, redox-active iron and IL-18, have been correlated with delayed graft functions and graft survival. However, their utility in clinical practice encounters challenge due to lack of their adequate predictive values for transplant outcomes.¹²Balfoussia D, Yerrakalva D, Hamaoui K, et al. Advances in machine perfusion graft viability assessment in kidney, liver, pancreas, lung, and heart transplant. Exp Clin Transplant. 2012;10(2):87-100.  ^,14van Smaalen TC, Hoogland ER, van Heurn LW. Machine perfusion viability testing. Curr Opin Organ Transplant. 2013 Apr;18(2):168-73.  

Changing Phenotype of The Renal Transplant Waitlist Candidates And Its Clinical Implications

Shortage of donor kidneys than the demand and increase in waitlist patients is an issue of considerable concern. However, not all waitlist candidates are fit enough to undergo transplantation even if the organ were to become available. Accordingly, they are broadly rendered active or inactive status; inactive status signifies that the candidate is either too morbid or not morbid enough to receive the transplant. Thus, the waiting list as a whole cannot be used to accurately estimate organ shortage. To add to this conundrum, revision in Organ Procurement and Transplantation Network (OPTN) policy in November 2003, which allows renal transplant candidates to accrue waiting time while registered as inactive, has led to dramatic increase in inactive candidates while the proportion of active candidates has not changed. These phenotypic changes in waitlist candidates could have significant clinical implications.¹⁵Grams ME, Massie AB, Schold JD, et al. Trends in the Inactive Kidney Transplant Waitlist and Implications for Candidate Survival. Implications for Candidate Survival. Am J Transplant. 2013;13(4):1012-1018.  

Grams and colleagues assessed the clinical implications of the changes in OPTN policy by evaluating 262,824 adult first-time renal transplant

candidates listed between 2000 and 2011 (i.e., candidates both before and after policy amendment). They noted that the waitlist candidates initially listed as inactive increased from 2.3% in 2003 (pre-policy period) to 11.4% in 2004 (period immediately after policy change) and 31.9% in 2011 (figure 2). Another significant observation was that the proportion of candidates whose status changed from initially active to inactive and those who remained continuously inactive also increased substantially post policy amendment. Factors, such as older age, diabetes, higher BMI, peripheral vascular disease, hepatitis C virus infection, poor functional status and use of hemodialysis predicted reduced likelihood of subsequent activation. Overall, the inactive status was associated with lower rates of eventual transplantation and significantly higher waitlist mortality rates. It was concluded that due to the changes in the OPTN policy, the burden of inactive candidates has increased substantially. Hence, the current waitlist is not a reliable reflector of deficit between organ demand and supply, nor it should be used as a comparison group to evaluate transplant outcomes.¹⁵Grams ME, Massie AB, Schold JD, et al. Trends in the Inactive Kidney Transplant Waitlist and Implications for Candidate Survival. Implications for Candidate Survival. Am J Transplant. 2013;13(4):1012-1018.  

References

1. Galichon P, Xu-Dubois YC, Finianos S, et al. Clinical and histological predictors of long-term kidney graft survival. Nephrol Dial Transplant. 2013;1-8.
2. Pesavento TE. Kidney Transplantation in the Context of Renal Replacement Therapy. Clin J Am Soc Nephrol. 2009;4:2035-2039.
3. Srivastava A. Renal transplantation: An update. Indian J Urol. 2007 Jul-Sep;23(3):270-271.
4. Patel HV, Kute VB, Ghelani GH, et al. Outcome of deceased donor renal transplantation – A single-center experience from developing country. Saudi J Kidney Dis Transpl. 2013;24:403-7.
5. Knoll G. Trends in kidney transplantation over the past decade. Drugs. 2008;68 Suppl 1:3-10.
6. Chakkera HA, Chertow GM, O’Hare AM, et al. Regional Variation in Kidney Transplant Outcomes: Trends Over Time. Clin J Am Soc Nephrol. 2009 Jan; 4(1): 152-159.
7. Shen LJ, Wu FL. Nanomedicines in renal transplant rejection – focus on sirolimus. Int J Nanomedicine. 2007 Mar;2(1):25-32.
8. Lee RA, Gabardi S. Current trends in immunosuppressive therapies for renal transplant recipients. Am J Health Syst Pharm. 2012;69(22):1961-75.
9. Zivčć-Ćosić S, Trobonjača Z, Rački S. Immunosuppressive treatment for kidney transplantation. Prilozi. 2011;32(2):87-103.
10. Swami YK, Singh DV, Gupta SK, et al. Deceased donor renal transplantation at army hospital research and referral: Our experience. Indian J Urol. 2013; 29(2):105-109.
11. Gopalakrishnan G, Gourabathini SP. Marginal kidney donor. Indian J Urol. 2007;23(3):286-293.
12. Balfoussia D, Yerrakalva D, Hamaoui K, et al. Advances in machine perfusion graft viability assessment in kidney, liver, pancreas, lung, and heart transplant. Exp Clin Transplant. 2012;10(2):87-100.
13. Moers C, Pirenne J, Paul A, et al. Machine perfusion or cold storage in deceased-donor kidney transplantation. N Engl J Med. 2012;366(8):770-1.
14. van Smaalen TC, Hoogland ER, van Heurn LW. Machine perfusion viability testing. Curr Opin Organ Transplant. 2013 Apr;18(2):168-73.
15. Grams ME, Massie AB, Schold JD, et al. Trends in the Inactive Kidney Transplant Waitlist and Implications for Candidate Survival. Implications for Candidate Survival. Am J Transplant. 2013;13(4):1012-1018.