ESOT 2011 Report – Twenty first century immunosuppression in renal transplantation: Is evolution the solution?

Nephrotoxicity as the Primary Driver of Failure – Fact or Fiction? – Dr Philip Halloran, Alberta Applied Genomics Center, Alberta, Canada.  The calcineurin inhibitors (CNIs), ciclosporin and tacrolimus, are nephrotoxic drugs. CNIs have been known to be capable of causing end stage renal disease since the first ciclosporin experience in the late 1970s. The lesions are nonspecific and include afferent arteriolar hyalinosis, fibrosis and atrophy (nephron loss), often taking a striped pattern. While characteristic, the lack of specificity of these lesions is a concern because it has led many clinicians to overestimate the frequency of this form of injury. Protocol biopsy studies have created the impression that ciclosporin nephrotoxicity is an inevitable progressive state in kidney transplants but these studies are flawed in a number of ways.

The fact that chronic renal failure develops in some non-renal organ transplant recipients has been used as an argument for the intrinsic danger of CNIs. However, chronic renal failure developing in non-renal transplants is complex: many diseases contribute to this phenotype, including pre-existing chronic kidney disease, acute kidney injury at the time of transplantation, diabetes, hepatitis C, IgA disease in liver failure, as well as age, hypertension, and underlying vascular disease. There are also concerns about how such patients are managed.

The actual causes of late kidney graft loss have been studied in a population of patients selected on the basis of having indication biopsies. The hypothesis was that specific entities could be identified explaining progressive late graft loss, mainly specific diseases. The key concept is that the kidney transplant is inherently stable, not diseased, but some kidney transplants develop diseases, and these are the ones that will fail. The main cause of graft failure after indication biopsies was found to be immunologic, consisting of antibody mediated rejection and mixed rejection, as well as recurrent disease and failure in the context of complex medical and surgical illnesses.There was also a small number with polyomavirus nephropathy.^1,2 Thus in the Edmonton Genome Canada study, the 60 failures observed so far have been attributable to antibody mediated or mixed rejection (65%). Up to 48% were considered to be non-adherent by their attending physicians,³ at least to some degree.

What is not being seen in these studies is end stage renal disease attributable primarily to CNIs. (It remains possible that CNIs may accelerate progressive diseases such as antibody mediated rejection or recurrent glomerulonephritis, but there is no strong evidence for this.) Arteriolar hyalinosis was not predictive of progression. Indeed, hyalinosis is merely a component of the constellation of atrophy-scarring features. These studies have been confirmed by microarray studies, which now provide a “Molecular Microscope” for us to interrogate the phenotype of these deteriorating transplants. Comparable results have been reported in other studies of the actual phenotypes of graft failure in kidney transplants after indication biopsies.

In summary, “CNI nephrotoxicity as the primary driver of failure” is a dangerous fiction, because it can lead patients or their doctors to “minimise” their drugs or the patients to become non-adherent. Follow-up studies after indication biopsies have shown that many transplants fail due to immunologic causes, particularly antibody problems, inviting the conclusion that minimisation of immunosuppression might be exactly the wrong strategy for stabiliziing the population. All clinicians would eventually like to see the day when kidney transplants can be safely managed without nephrotoxic drugs. Until then, however, the message is that patients can be safely managed indefinitely on CNIs if carefully followed for adherence and drug levels. With proper management, progression of CNI toxicity to end stage renal disease in kidney transplants should almost never be seen.

 

Immunosuppressive Therapies: the Pros and Cons

Professor Henrik Ekberg, Lund University, Sweden

Although short-term renal allograft survival has shown marked improvements in recent decades, increases in long-term survival have been more modest, with the greatest effects seen in high-risk patients.¹ Acute rejection is still the most important predictor of long-term graft survival, hence the need for treatment strategies to focus on its prevention.

The emergence of new immunosuppressive agents in recent years has left the clinician with a range of treatment options. Ideally, the regimen should be efficacious, providing graft protection and preventing acute and chronic rejection, be calcineurin inhibitor (CNI) and corticosteroid sparing, and have a good safety and tolerability profile, with no nephrotoxicity and a low risk for comorbid diseases.

Based on findings from the Symphony study, a low-dose tacrolimus-based regimen currently offers the best approach. Graft function and survival were superior with low-dose, tacrolimus compared with low-dose ciclosporin (CsA) or sirolimus regimens (all including mycophenolate mofetil [MMF], daclizumab induction and corticosteroids) or standard-dose CsA (plus MMF and corticosteroids) after 12 months.² Biopsy-proven acute rejection rates were significantly lower with low-dose tacrolimus than with other treatments, and low-dose tacrolimus was effective across a range of recipients, including those receiving sub-optimal kidneys.

Despite the efficacy of CNI-based therapy, concerns exist over nephrotoxicity and its potential effects on long-term graft function. The recent DeKAF study, however, demonstrated that antibody-mediated injury was a predictor of graft loss, whereas biopsy diagnosis of ‘CNI nephrotoxicity’ was not.^3,4 In addition, although emerging alternative immunosuppressive therapies may show improved graft function compared with CNIs, acute rejection rates are highter, with negative implications for long-term outcomes.^5-7 Currently we remain dependent on CNI-based immunosuppression as CNIs are the only agents proven to be effective in controlling immunologic injury to the allograft. Optimising CNI use should therefore be the way forward for immunosuppression at this time.

 

Optimising CNI-based Immunosuppression

Dr Frank Lehner, Hannover Medical School, Germany

Calcineurin inhibitors (CNIs) currently form the cornerstone of immunosuppression regimens in renal allograft transplantation. Tacrolimus-based treatments offer excellent efficacy and short– and long–term outcomes; however, improvements in two aspects of tacrolimus therapy – within-patient variation in blood drug concentrations and treatment adherence – could have beneficial effects on outcomes, especially when trageting lower levels than in the past. High intrapatient variability in tacrolimus exposure has been shown to be a predictor of graft failure following kidney transplantation and may be due to a variety of factors.¹ Subclinically non-compliant transplant recipients showed an increased risk of late acute rejection and greater increases in serum creatinine compared with compliant patients.²

The once-daily, prolonged-release formulation of tacrolimus has the potential to address these issues. It provides a smoother plasma concentration-time profile than twice-daily, immediate-release tacrolimus, with a single lower morning peak and no evening peak.  Prolonged-release tacrolimus treatment was associated with lower intrapatient variability in tacrolimus exposure in stable transplant recipients following their conversion from immediate-release tracrolimus therapy.^3,4 The prolonged-release formulation was also preferred by almost all (99.4%) patients in a large conversion study in routine clinical practice, due to the increased convenience of less frequent administration (66%) and improved adherence  (the remaining 34%).⁵ Two studies in de novo kidney transplant recipients showed that a greater percentage of patients on prolonged-release tacrolimus were within the trough level range of 5-15ng/mL in the first few days post-transplant compared with immediate-release tacrolimus.^6,7

Furthermore, fewer patients receiving prolonged-release tacrolimus were exposed to potentially toxic tacrolimus blood levels over 20ng/mL during the initial post-transplant period. Studies of patients converted from immediate-release to prolonged-release tacrolimus have provided indicators of potential benefits of the prolonged-release formulation. Improvements in renal function (which appeared to be independent of a slight reduction in trough levels) and lowered glucose and triglyceride levels have been observed.^8,9

In conclusion, the evidence suggests that the best outcomes are likely to be achieved if we do what we can to ensure that patients receive effective and consistent immunosuppression throughout their lifetime. Prolonged-release tacrolimus may help clinicians to optimise their CNI-based regimens and achieve this aim.

References:

Section One:

1. Einecke G, Sis B, Reeve J, Mengel M, Campbell P et al.  Am J Transplant 2009; 9(11): 2520-31
2. Sellares J, Frietas D, Mengel M, Sis B, Hidalgo H et al.  Am J Transplant 2011; 11(3): 489-99
3. Sellares J et al.  Manuscript under review. 2011

Section Two:

1. Lamb KE, Lodhi S, Meier-Kriesche H-U.  Am J Transplant 2011; 11(3): 450-462
2. Ekberg H, Tadesco-Silva H, Demirbas A, Vitko S, Nashan B et al.  N Engl J Med 2007 Dec; 357(25): 2562-2575
3. Gaston RS, Cecka JM, Kasike BL, Fieberg AM, Leduc R et al.  Transplantation 2010; 90(1): 68-74
4. Mannon RB, Matas AJ, Grande J, Leduc R, Connett R  et al.  Am J Transplant 2010; 10(9): 2066-2073
5. Flechner SM, Glyda M, Cockfield S, Grinyó J, Legendre Ch et al.  Am J Transplant 2011; 11(8): 1633-1644
6. Friman S, Arns S, Nashan B, Vincenti F, Banas K et al.  Am J Transplant 2011; 11(7): 1444-1455
7. Vincenti F, Charpentier B, VanrenterghemY, Rostaing L, Bresnahan B et al.  Am J Transplant 2010; 10(3): 535-546

Section Three:

1. Borra LC, Roodnat JI, Kal JA, Mathot RA et al.  Nephrol Dial Transplant 2010; 25(8): 2757-2763
2. Vlaminck H et al.  Am J Transplant 2004; 4(9): 1509-1513.
3. Alloway R, Steinberg S, Khalil K, Gourishankar S et al.  Transplant Proc 2005; 37(2): 867-870
4. Florman S, Alloway R, Kalayoglu M, Lake K et al.  Transplant Proc 2005; 37(2): 1211-1213
5. Guirado L et al.  Am J Transplant 2011; Epub ahead of print.
6. Viklicky O et al.  NDT Plus 2011; 4(Suppl 2): 4.s2.1-4.s2.9.
7. Krüger B et al.  J Am Soc Nephrol 2010; 21(201):3B.
8. Tinti F, Merçule A, Poli L, Bachetoni A et al.  Transplant Proc 2010; 42(10): 4047-4048
9. Meçule A, Poli A, Nofroni I, Bachetoni A et al.  Transplant Proc 2010; 42(4): 1317-1319