A prominent high mortality cause of renal failure is now allograft failure. Patients approach dialysis burdened by years of immunosuppression, advanced CV disease, but become sensitized and untransplantable if immunosuppression is withdrawn. Strategies for management of this population of patients are lacking.
There is significant irreversible kidney injury during process of kidney removal and transport from deceased donors. More than 50% of kidneys are discarded by some OPO's. Novel biomarkers of kidney injury can guide allocation and reduce discard rate.
Despite significant work documenting stark race disparities in access to transplantation, there is little research identifying strategies (at patient, provider, and system levels) that are effective in narrowing disparities. Studies of interventions to improve attitudes, behaviors, and practice patterns that have been linked to disparities are needed.
A major limitation to expanding donor criteria for procurement of cadaveric renal allografts is our continued reliance on the use of hypothermic preservation. Cold preservation limits the warm ischemic times to recover kidneys to less than 60-minutes post-cardiac arrest. In the era of molecular biology and proteomics, hypothermic preservation - a 60-year old technology can be thought of as the "ice age". Technologies ...more »
A major limitation to expanding donor criteria for procurement of cadaveric renal allografts is our continued reliance on the use of hypothermic preservation. Cold preservation limits the warm ischemic times to recover kidneys to less than 60-minutes post-cardiac arrest. In the era of molecular biology and proteomics, hypothermic preservation - a 60-year old technology can be thought of as the "ice age". Technologies such as effective prospective evaluations of viability and function, treatments to repair damage to the cytoskeleton, prevention of reperfusion injury, etc. could impact the ability to procure increased numbers of warm ischemically damaged kidneys. Rather than fabricating a 3-trillion cell construct containing stem cells that must differentiate into the heterogeneous cells required for renal function, as a first step why not attempt to replace the several million acutely damaged renal cells in an ischemically damaged allograft with human progenitor cells.
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Nakauchi recently described a method for making replacement organs using interspecies chimeras. When combined with the Yamanaka method for making stem cells this opens the door for the production of autologous organs. Many challenges remain. Not just the specific organ, but the vasculature and hematopoietic system might also need to be strictly patient derived. Could genetically engineered pigs work, or would we need ...more »
Nakauchi recently described a method for making replacement organs using interspecies chimeras. When combined with the Yamanaka method for making stem cells this opens the door for the production of autologous organs. Many challenges remain. Not just the specific organ, but the vasculature and hematopoietic system might also need to be strictly patient derived. Could genetically engineered pigs work, or would we need to go to a more closely related species? Cell. 2010 Sep 3;142(5):787-99.
Generation of rat pancreas in mouse by interspecific blastocyst injection of pluripotent stem cells.
Kobayashi T, Yamaguchi T, Hamanaka S, Kato-Itoh M, Yamazaki Y, Ibata M, Sato H, Lee YS, Usui J, Knisely AS, Hirabayashi M, Nakauchi H.
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Based on recent FDA warnings about the link between immunosuppressant drugs and BK virus infection in transplanted kidneys, it seems prudent to conduct research into the mechanistic causes of BK-induced nephropathy in transplant patients so that appropriate and standardized prevention and treatment measures, and potentially a cure, can be developed. Does BK infection originate from the allograft, the environment, or both? ...more »
Based on recent FDA warnings about the link between immunosuppressant drugs and BK virus infection in transplanted kidneys, it seems prudent to conduct research into the mechanistic causes of BK-induced nephropathy in transplant patients so that appropriate and standardized prevention and treatment measures, and potentially a cure, can be developed.
Does BK infection originate from the allograft, the environment, or both? What tests can be developed to better detect BK in a donor kidney? Are there any lifestyle changes that the transplant recipient can make to reduce the chances of BK infection? What is the likelihood that a patient who has lost an allograft to BK will contract the virus in a second transplant?
There is evidence that the initially prescribed dose of mycophenolate mofetil is too high in some patients and that it acts as a gateway to BK. Blood tests for MMF levels are contraindicated because they are so expensive. Why are tacrolimus levels followed very closely after transplant while MMF levels are not? The FDA has issued warnings about the link between both these drugs and BK.
Many transplant centers do not routinely analyze the blood/urine of transplant patients for BK, so it is often not detected until significant damage has been done. Are routine analyses needed? How can biopsies of the allograft be prescribed and analyzed to better detect BK early?
Currently, there is conflicting information regarding treatment -- do high doses of steroid help or hinder? Which immunosuppressants should be reduced (and by exactly how much) or stopped altogether? Can an antiviral medication be developed to cure BK infection?
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We don't see BKV Nephropathy as much in HIV patients on HAART therapy. Or to our knowledge it has been widely studied. This might be important in transplant world as perhaps BKV is suppressed by one of the HAART medications and a potential drug target for BK Nephropathy. We must look at other places besides Kidney Transplant for BKV Nephropathy for understanding the disease better perhaps.
Young, healthy, caucasians who donate kidneys have been shown to have excellent long term medical outcomes. However, there is no long term data on outcomes after donation by those who are African-American, hypertensive and/or overweight. There is a pressing medical need to better define risks of kidney donation for these and other groups at higher risk, to protect the safety of future living donors. The general nephrology ...more »
Young, healthy, caucasians who donate kidneys have been shown to have excellent long term medical outcomes. However, there is no long term data on outcomes after donation by those who are African-American, hypertensive and/or overweight. There is a pressing medical need to better define risks of kidney donation for these and other groups at higher risk, to protect the safety of future living donors. The general nephrology community is increasingly being asked to evaluate donors, and make decisions on which risks are acceptable. In addition, general nephrologists are increasingly seeing former donors with estimated GFRs that place them in "CKD stage 3 or 4." Some of these patients may just require reassurance, while others may require further evaluation and managment. Further awareness of living donor issues would be helpful for nephrologists, and further research on former living donors is needed to help guide living donor evaluations.
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Important progress has been made in improving short term outcomes in kidney transplantation. However, long-term outcomes have not improved during the last decades. One key reason for explaining the lack of evident improvement of graft survival is the lack of objective biomarkers accurately reflecting allograft status and reliably predicting outcome for a single patient. There is a critical need for biomarkers for early ...more »
Important progress has been made in improving short term outcomes in kidney transplantation. However, long-term outcomes have not improved during the last decades. One key reason for explaining the lack of evident improvement of graft survival is the lack of objective biomarkers accurately reflecting allograft status and reliably predicting outcome for a single patient. There is a critical need for biomarkers for early diagnosis of graft injury, treatment response, as well as surrogate endpoint and outcome prediction in organ transplantation, leading to a tailored and individualized treatment. Genomic and proteomic platforms have provided a multitude of promising new biomarkers during the last years. Nevertheless, there is still no routine application of any of these markers in clinical transplantation. Identification of biomarkers (ideally non-invasive) for monitoring the graft using prospective studies with appropriate patient follow-up and associated clinical data are needed.
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Teenagers are at high risk for losing their renal (and other solid organ) grafts due to medication non-compliance. With the use of social media a common way of communication in this age group, it would make sense to develop a multi-faceted platform to develop interventions that improve compliance in this age group.
Investigate the virome (viral metagenome) in the kidney (urine) in disease (eg, transplantation) and health
Why do we accomodate to some forms of donor specific anti-HLA antibodies but not to others? Increased research should focus on the pathogenic requirements on the ability of antibodies to fix complement, on the importance of binding affinity/avidity and on the identification/definition of pathogenic thresholds of antibody and strategies to normalize testing across different centers/platforms.
First of all I'm only trying to stimulate thoughtful, well meaning and useful dialogue and not start a controversial argument, but is it time for the government to get more aggressive in making more organs available for transplantation? I think one thing that is missing is a general lack of public awareness or central discussion about the need for all organs. I know where I live in rural America it seems like renal transplantation ...more »
First of all I'm only trying to stimulate thoughtful, well meaning and useful dialogue and not start a controversial argument, but is it time for the government to get more aggressive in making more organs available for transplantation? I think one thing that is missing is a general lack of public awareness or central discussion about the need for all organs. I know where I live in rural America it seems like renal transplantation is very slow to occur and kidney-pancreas, heart and liver is generally non existence. Would a government sponsored increase in public awareness make much of a difference or do Americans just generally want to keep their organs even after they have expired for religious or other reasons? Should patients who have used tax payer funding for their health care be "forced" to give up their organs if the deceased patient would be buried with viable and badly needed organs? Again this is something that I have long thought about but never heard discussed and I can honestly say that I haven't formed a solid opinion on this. But again please limit any feedback to thoughtful and well meaning dialogue and keep our emotions in check.
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I propose T-cell & antibody based vaccine development against BK virus. It is envisaged that suitably designed active and passive BKV vaccines will also show efficacy against related polyomavirus species JC and SV40. With at least 100,000 transplant procedures performed annually world wide, such a vaccine will result in health care savings of millions of dollars annually. To highlight the polyomavirus associated disease ...more »
I propose T-cell & antibody based vaccine development against BK virus. It is envisaged that suitably designed active and passive BKV vaccines will also show efficacy against related polyomavirus species JC and SV40. With at least 100,000 transplant procedures performed annually world wide, such a vaccine will result in health care savings of millions of dollars annually.
To highlight the polyomavirus associated disease burden in man, I note that 4.6 to 9.2% of U.S. kidney transplants are complicated by BKV-nephropathy or BK viremia. In addition, BKV causes hemorrhagic cystitis of variable severity in 5-60% of bone marrow transplantation recipients, and 5% of cancer patients treated with chemotherapy. JCV causes progressive multifocal encephalopathy, a functionally devastating and potentially fatal disease, in 0.5 to 5% of acquired immune deficiency syndrome (AIDS) patients. To put this in perspective, the World Health Organization (WHO) estimated 33.2 million HIV infected subjects in the year 2007. JCV has also been associated with human neoplasms, particularly brain tumors and cancer colon. SV40 DNA has been amplified from 40-100% of highly aggressive glial tumors, mesothelioma, and osteogenic sarcomas (estimated incidences of 6.7, 1.1, and 3.0 cases per 100,000 persons respectively, which implies approximately 100,000 affected patients in a world with 7 billion people).
In addition to the aforementioned direct clinical benefits, the proposed vaccine development program will enhance our understanding of interfering T-cells and antibodies that develop during the course of currently evolving gene therapy protocols using polyomavirus protein capsids as a vector.
Development of effective BKV T-cell and antibody based vaccines would eliminate health care costs currently incurred by regular virus screening programs in kidney transplant recipients. Developing a product that also affords protection against JCV and SV40 would be an added bonus. If successful, we have the potential of producing a product that will simultaneously reduce human suffering associated with both infectious disease and malignancy. For cancer patients the vaccine would not be a stand alone intervention, but a potential adjuvant to standard oncology therapies. Indeed, it could be argued that polyomavirus associated tumors are ideal candidates for antigen specific vaccination, since these malignancies express viral encoded tumor specific antigens not expressed by normal tissues.
Conceptually, both prophylactic and therapeutic vaccines can be designed. The best target for a prophylactic vaccine would be a polymer of VP1- protein arranged into 'virus like particles' . These virus-like particles elcit strong neutralizing antibodies, a fact that was exploited in the development of human papillomavirus vaccines. For a therapeutic vaccine we need to induce T-cell mediated immunity against cells already infected by BK virus. A number of viral epitopes on the large T antigen have been recently described and could be used as the starting point for development of a T-cell vaccine.
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The polyomaviruses are DNA viruses, with a 5 kb genome and virion diameter of approximately 45 nm. The most important human species is BK virus (BKV). This virus is latent in most healthy adults. In kidney transplant recipients, viral excretion in the urine is described in 20-60% of subjects, and BKV nephropathy, a disease characterized by damage to the graft parenchyma, develops in up to 10%. BKV is also commonly excreted ...more »
The polyomaviruses are DNA viruses, with a 5 kb genome and virion diameter of approximately 45 nm. The most important human species is BK virus (BKV). This virus is latent in most healthy adults. In kidney transplant recipients, viral excretion in the urine is described in 20-60% of subjects, and BKV nephropathy, a disease characterized by damage to the graft parenchyma, develops in up to 10%. BKV is also commonly excreted in the urine of bone marrow transplant recipients. In this patient population, mild forms of hemorrhagic cystitis in up to 60%, while 5-10% develop severe disease characterized by pain and hematuria . BKV associated hemorrhagic cystitis also occurs in 5% of cancer patients treated with high dose cytotoxic agents, of which the best known is cyclophosphamide.
No effective drugs are currently available for the treatment of BKV infection. Cidofovir and Leflunomide are currently used empirically but efficacy has not been shown in well designed studies. Both drugs have significant toxicity. Importantly, their in-vitro efficacy in BK virus cultures is very modest. Not surprisingly, clinical benefit is only seen when these drugs are adminstered for weeks to months. Thus, there is currently an unmet need for potent and safe compounds for use in the transplant clinics. The ideal drug would also have prophylactic utility, and could potentially eliminate the need to undertake expnsive PCR or cytology based assays that are currently being used to screen for polyomavirus infections at major transpant centers. Rationally designed 'panpolyoma' drugs would likely also show efficacy against (i)SV40 virus that has been occasionally associated with renal disease, and (ii) JC virus, which may cause both nephropathy and a devastating neurologic disease called Progressive Multifocal Encephalopathy in AIDS patients.
Viral targets that could be targeted for drug development include the viral capsid binding protein that interacts with the cellular receptor, and Large T antigen which plays a key role in viral replication. Both targets are amenable to high throughput biochemical screens and protein crystal based computational methods to discover small molecule inhibitors of viral protein function.
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The national discard rate has ranged from 12% to 18% over the years. Approximately 50% of the criteria for discard have been based upon kidney biopsies; although there are reports that when the kidneys have been transplanted glomerulosclerosis does not correlate well with 1-year graft survival, while pretransplant functional evaluations such as CrCl do. The development of novel biomarkers to reduce the rate suggested ...more »
The national discard rate has ranged from 12% to 18% over the years. Approximately 50% of the criteria for discard have been based upon kidney biopsies; although there are reports that when the kidneys have been transplanted glomerulosclerosis does not correlate well with 1-year graft survival, while pretransplant functional evaluations such as CrCl do. The development of novel biomarkers to reduce the rate suggested by Dr. Parikh is important. Another approach would be to develop prospective ex vivo evaluation of kidneys procured for transplantation but later discarded according to standard institutional criteria. This would necessitate transferring the hypothermically stored discarded kidneys to a near-normothermic perfusion. Quantifiable parameters such as restored metabolism, vascular dynamics, potential for regeneration and function could be used to develop a calculated index that would provide an objective basis for lowering the discard rate.
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We spend a lot of resources on pre-operative cardiac evaluation of kidney transplant recipients. However, there are no trials of pre-operative cardiac evaluation in kidney transplantation. This is one of several examples of significant variation in how providers manage patients pre and post-kidney transplantation. The variation reflects uncertainty about the clinical standard and represents spending on potential ineffective ...more »
We spend a lot of resources on pre-operative cardiac evaluation of kidney transplant recipients. However, there are no trials of pre-operative cardiac evaluation in kidney transplantation.
This is one of several examples of significant variation in how providers manage patients pre and post-kidney transplantation. The variation reflects uncertainty about the clinical standard and represents spending on potential ineffective care and contributes to soaring healthcare costs. Future clinical trials can provide guidance on appropriate management pre and post-kidney transplantation.
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Multiple immunosuppressant drugs are now used in a variety of diseases affecting both the native and the transplant kidney, as well for systemic immunological disorders. The total amount of immunosuppression then achieved in each patient at a given point in time is unknown. This sets the patient up for complications of over-immunosuppression (infections) or under-immunosuppression (inadequate treatment). Studies of biomarkers ...more »
Multiple immunosuppressant drugs are now used in a variety of diseases affecting both the native and the transplant kidney, as well for systemic immunological disorders. The total amount of immunosuppression then achieved in each patient at a given point in time is unknown. This sets the patient up for complications of over-immunosuppression (infections) or under-immunosuppression (inadequate treatment). Studies of biomarkers that can be used to judge net state of immunosuppression would be of immediate clinical impact.
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