The American Society of Transplantation

I don’t believe that there is any one immunosuppression protocol that would be considered a “state of the art”. As with any other organ transplant and age group, many combinations are utilized currently. Most programs in the USA use some form of induction for children receiving a kidney transplant. The induction agent varies widely; rabbit anti-thymocyte globulin and basiliximab are probably most common, with very specialized centers using alemtuzumab (source UNOS database; www.unos.org). More than 80% of centers use tacrolimus and more than 90% use mycophenolate as part of maintenance immunosuppression in new transplants. Steroid use has dropped considerably, probably only 50-60% of new transplants now receive (source: NAPRTCS database; www.naprtcs.org). Anti-infective prophylaxis has become increasingly important, given the emergence of infections as an equal or bigger problem than acute rejection (1). Most centers will use some form of anti-fungal prophylaxis (nystatin or clotrimazole) for 3 months, anti-bacterial prophylaxis for 3-6 months (also covers pneumocystis) and anti-viral prophylaxis (typically valganciclovir) for 3-12 months. See the recently published KDIGO guidelines for recommendations (2). Published protocols are from specific research centers such as Pittsburgh and Stanford (3-6); they represent specialized protocols unique to those centers or consortia, not necessarily what the majority of centers currently do.

1. Dharnidharka VR, Stablein DM, Harmon WE. Post-transplant infections now exceed acute rejection as cause for hospitalization: a report of the NAPRTCS. Am J Transplant. 2004 Mar;4(3):384-9.
2. Chapman JR. The KDIGO clinical practice guidelines for the care of kidney transplant recipients. Transplantation. Mar 27;89(6):644-5.
3. Li L, Chang A, Naesens M, Kambham N, Waskerwitz J, Martin J, et al. Steroid-free immunosuppression since 1999: 129 pediatric renal transplants with sustained graft and patient benefits. Am J Transplant. 2009 Jun;9(6):1362-72.
4. Tan HP, Donaldson J, Ellis D, Moritz ML, Basu A, Morgan C, et al. Pediatric living donor kidney transplantation under alemtuzumab pretreatment and tacrolimus monotherapy: 4-year experience. Transplantation. 2008 Dec 27;86(12):1725-31.
5. Harmon W, Meyers K, Ingelfinger J, McDonald R, McIntosh M, Ho M, et al. Safety and efficacy of a calcineurin inhibitor avoidance regimen in pediatric renal transplantation. J Am Soc Nephrol. 2006 Jun;17(6):1735-45.
6. Benfield MR, Bartosh S, Ikle D, Warshaw B, Bridges N, Morrison Y, et al. A randomized double-blind, placebo controlled trial of steroid withdrawal after pediatric renal transplantation. Am J Transplant. Jan;10(1):81-8.

Although no randomized,prospective studies have been done to answer your question, a retrospective analysis using the USRDS and SRTR databases was performed to look at graft outcome in patients with FSGS that had a living donor kidney transplant (AJT 2003;3:64-67). In this analysis, patients with FSGS that received a zero mismatch living donor kidney transplant had similar death-censored graft survival as GN patients with a zero mismatch living donor kidney transplant (95% vs 93.3%). In addition, death-censored graft survival was superior for those FSGS patients that received a zero-mismatch living donor kidney transplant as compared to those FSGS patients that received a zero-mismatch deceased donor kidney transplant (95% vs 80.2%). Although this study does not address recurrence of FSGS directly, FSGS patients had similar graft outcomes as other patients with glomerulonephritis and should be offered living donor kidney transplant if available.

This is currently not possible. There are at least two major issues that need to be considered. First, one needs to generate functioning organs that can perform at the level necessary to replace the failing organ. This is not feasible at the moment. Aside from this, this organ should be accepted by the host by being “matched to the patients’ DNA” as you have mentioned. The latter is also almost impossible. As you know, the MHC antigens are the strongest transplantation antigens and can stimulate a primary immune response without priming. However, MHC molecules are highly polymorphic, as each MHC locus can express any one of hundreds of different molecules encoded by various alleles. Just to give you an idea, in clinical transplantation, the most important MHC genes are HLA-A,-B and –DR. The antigenic determinants of their six alleles are the focus of attempts at HLA matching to improve graft survival. Given the remarkable degree of polymorphism exhibited by MHC genes, there are 88 recognized antigens encoded by more than 1000 distinct alleles and the number of new alleles is still increasing. As you can see, while HLA gene polymorphism plays a critical role in protective immunity by enabling the binding and presentation of a wide variety of microbial peptides to T cells, it could potentially create a practical barrier to successful transplantation. That is why It is not feasible to select a completely HLA matched donor for every potential recipient because of the enormous polymorphism of the HLA system. Now add to above several studies demonstrating that minor histocompatibility antigens can also mediate rejection and you can see the complexity of the issue.

The first and only multicenter, randomized, double-blind placebo controlled trial investigating the efficacy of high dose IVIg as a desensitization modality – NIH IG02 Trial – was targeted to patients on the deceased donor list (1). Cedar-Sinai Hospital in Los Angeles, CA has the largest experience in desensitization of wait-listed patients using high dose IVIg (2g/Kg) first, and more recently high dose IVIg and rituximab (2). Rituximab alone in a dose escalating fashion was also used with some success for desensitization of patients active on the list (3). Other centers that have published their experience in desensitization of patients on the deceased donor list include Indiana University, Mount Sinai Hospital in New York City, University of Wisconsin-Madison and University of Washington-Seattle.

A major limitation in the development of desensitization programs for patients on the waiting list and without a living donor stems from lack of financial coverage and the logistic difficulties of long-term desensitization of dialysis patients. Transplant Programs that have implemented these protocols have received financial approval by their regional Centers for Medicare and Medicaid Services thereby ensuring access of dialysis patients with Medicare as their primary insurer. The frequency of approval varies among regions. For instance, while Region 5 reimburses desensitization protocols on a fee-for-service basis others do not.

Desensitization of patients on the list also poises logistical difficulties. The majority of patients require desensitization for an average of 12 months and it can take as long as 18 months. The Transplant Center is responsible for arranging outpatient administration of monthly IVIg and rituximab, and monthly monitoring of PRA and unacceptable antigens.

References:

1. Jordan SC, Tyan D, Stablein D, McIntosh M, Rose S, Vo A, et al. Evaluation of intravenous immunoglobulin as an agent to lower allosensitization and improve transplantation in highly sensitized adult patients with end-stage renal disease: report of the NIH IG02 trial. J Am Soc Nephrol. 2004;15(12):3256-62.
2. Vo AA, Lukovsky M, Toyoda M, Wang J, Reinsmoen NL, Lai CH, et al. Rituximab and intravenous immune globulin for desensitization during renal transplantation. N Engl J Med. 2008;359(3):242-51.
3. Vieira CA, Agarwal A, Book BK, Sidner RA, Bearden CM, Gebel HM, et al. Rituximab for reduction of anti-HLA antibodies in patients awaiting renal transplantation: 1. Safety, pharmacodynamics, and pharmacokinetics. Transplantation. 2004;77(4):542-8.

The patient you describe would not be considered optimal by most transplant centers. The presence of proteinuria, in particular, would be seen as an indicator of increased risk and possible underlying renal disease such as IgA nephropathy or Alport’s nephropathy. If he/she is highly motivated to donate and has clearly normal GFR it would be reasonable to offer to clarify the situation with a careful evaluation. This would include serial (at least 3) tests for microhematuria/glomerular RBCs, 1 or more 24 hour urine collections for total protein and albumin, imaging (e.g. CT urography) and, possibly, a renal biopsy with immunofluoresence and electron microscopy. Microhematuria alone with normal imaging and normal histology or thin basement membrane disease with no family history of end-stage renal disease (ESRD) could be seen as a minimal risk situation – some centers would be comfortable proceeding with donation. Confirmation of abnormal albuminuria with or without any other pathological diagnosis would be clear grounds for refusing donation and, possibly, advising future follow-up with a nephrologist. In this case donation would, almost certainly, be associated with increased or accelerated risk of future hypertension, chronic kidney disease and ESRD although the literature does not contain enough data to provide accurate figures. A nice presentation and discussion on this topic can be found in Vadivel et al Kidney Int 2007; 71: 173–177.