Reducing the Risk of Rejection Following Kidney Transplant in Patients with End-stage Renal Disease

The powerful immunosuppressive drugs used to prevent allograft rejection are associated with severe side effects. A “mixed chimerism” strategy in which patients undergo simultaneous bone marrow and kidney transplant from the same donor may improve transplant survival and reduce the need for these drugs.

A leading researcher in the field of organ transplantations, David Sachs, MD, spoke about ways to prevent the human body from rejecting a newly transplanted kidney during a state-of-the art lecture at Kidney Week 2012, held in San Diego and sponsored by the American Society of Nephrology.

Sachs is the director of the Transplantation Biology Research Center at Massachusetts General Hospital and the Paul S. Russell/Warner-Lambert Professor of Surgery (Immunology) at Harvard Medical School in Boston. He is one of the three North American editors of Transplantation and was the founding editor of Xenotransplantation.

According to Sachs, one of the main limitations in the field of transplantation today is complications from the drugs used to prevent acute rejection and chronic rejection. A patient may have to take numerous medications each day following transplant in order to stave off allograft rejection, including immunosuppressants (eg, corticosteroids, tacrolimus, cyclosporine, mycophenolate mofetil, etc) and the medications needed to treat the range of side effects associated with these powerful immunosuppressive agents (including nausea, vomiting, low white blood cell count, headache, hypertension, increased risk of infections, cataracts, fluid retention, several types of cancer, etc), said Sachs.

In relation to transplantation, tolerance is defined by the specific absence of destructive immune response to a transplanted tissue or organ, said Sachs. In other words, the body does not reject the organ as an intruder but accepts it as its own. He said that in his research he explores several methods for inducing transplantation tolerance in order to avoid acute and chronic rejection without the use of long-term immunosuppressive medications. Sachs described several scientific animal models used to explore the principle of mixed chimerism leading to central tolerance.

Sachs said that chimerism is the only one of the many methods used to induce tolerance in mice has worked in larger animals, primates, and humans. The mixed chimerism method (whereby the recipient undergoes simultaneous bone marrow and kidney transplant from the same donor, in effect “reprogramming the immune system of the recipient” and suppressing immune response) has worked in various animal models (including mouse to mouse, pig to pig, and monkey to monkey), and now human to human, Sachs said.

Later in his presentation, Sachs reviewed his research from a clinical trial of a renal allograft recipient who was among a small group of patients who received transplants based on this new mixed chimerism methodology of combined kidney and bone marrow transplant from the donor.

He showed a video of his first patient, a woman who had two transplants, the first by conventional methods in 1994 with immunosuppressive drugs for end-stage renal disease. She had rejected the first kidney donated from her father and had terrible complications, including warts all over her body and at times on the bottoms of her feet, Sachs said. “She heard about our trial and came and volunteered to be our first patient because she wanted another transplant. She didn’t want to go back on immunosuppression and didn’t want to go on dialysis,” Sachs said.

In the video, the young woman said that she is 25 years old and feels better than when she was a teenager, adding that she works out every day and feels alert mentally and physically. “That’s what it’s really all about, returning a patient to feeling normal,” said Sachs.

At this time, the clinical trial is closed after treatment of 10 patients, with a new protocol possibly in the works, Sachs said. Meanwhile, 10 years later the first patient is still doing well and actually running marathons on a regular basis. “At this point we feel quite encouraged about the usefulness of this approach toward the induction of tolerance and we hope we’ll be able to take it further,” Sachs said.

Kidney Transplant Clinical Trials with David Sachs, MD, principal investigator

Reducing the Risk of Transplant Rejection: Simultaneous Kidney and Bone Marrow Transplant (Official Title: Renal Allograft Tolerance Through Mixed Chimerism)

This study has been completed

Combined Kidney and Bone Marrow Transplantation to Prevent Kidney Transplant Rejection

This study is ongoing, but not recruiting participants