New secrets of kidney transplant rejection unlocked
Despite huge advances, around half of kidney transplants will be rejected by the host’s immune system within 10 years of the operation. Research using molecular profiling sheds new light on the mechanisms behind this frustrating rejection.The medical technology that makes kidney transplants possible has grown in leaps and bounds since the first successful transplant in 1950.
Recent statistics show that by the end of the first month, 97% of new kidneys are functioning, 93% at the end of 1 year and 83% at the end of 3 years.
As impressive as these figures are, they also mean that after 3 years, 17% of kidney transplants have failed. That equates to roughly 6,000 America transplant recipients.
There are a number of reasons why a transplant can fail, one of the most common is rejection. In other words, the host’s immune system recognizes the new tissue as “foreign” and mounts an immune response against it, slowly destroying it. Acute versus chronic rejection
There are two types of rejection: acute and chronic. Acute rejection occurs rapidly, and the organ is rejected within a year; chronic rejection takes longer and slowly develops over years, finally ending in failure.
Acute rejection is treated with an increase in immunosuppressant drugs to keep the body’s natural defenses under wraps. Chronic rejection is considered a different beast; it is regarded as untreatable, and organ loss is seen as inevitable.
These two problems have been, until now, considered to be different diseases.
New research, carried out at the Scripps Research Institute (TSRI) in La Jolla, CA, has recently discovered that acute and chronic rejection are not separate diseases, they are both part of the same continuum.
The researchers, led by Prof. Daniel Salomon, used a technique called gene expression profiling to investigate the activity of acute and chronic rejection. This technology allows researchers to compare the activity of thousands of genes at once and search for differences, and similarities, between patients.
Gene expression profiling
For the current research, published in the American Journal of Transplantation, the team analyzed 234 kidney biopsies. They found that 80% of the genes expressed in acute rejection were shared in the tissues of chronic rejection kidneys.
With chronic rejection, clinicians are normally under pressure to reduce immunosuppressants because of their inherent toxicity, but this only compounds the issue as the immune system steadily eats away at the new kidney.
With these findings comes new hope for the future treatment of chronic transplant rejection. It means that the immunosuppressant drugs used for acute rejection can also be used for chronic rejection; they are, for all intents and purposes, the same disease.
Prof. Salomon believes that these results will probably hold true for liver, heart and lung transplants.
How to predict failure
As it stands, chronic rejection moves so slowly and silently that it is not until the rejection has become a serious problem that it is picked up.
The team at TSRI have found a potential way of spotting the failing organ before it reaches the point of no return. They studied a cellular hallmark of rejection, called interstitial fibrosis and tubular atrophy (IFTA).
This specific type of lesion has previously been shown to correlate with increased rejection. However, the TSRI team recognize that IFTA is not simply a sign of past injury, as was previously thought, but it is a sign of an ongoing process of rejection.
In the future, taking regular biopsies of kidney transplant patients might allow clinicians to chart these changes in pathology and spot any downturns in the kidney’s cellular integrity. Although kidney biopsies are invasive, Prof. Salomon hopes that, in the not-too-distant future, modern molecular profiling could be achieved through simple blood sampling.
One such blood test is currently being trialed as part of the Clinical Trials in Organ Transplantation consortium.
Gene expression profiling marks a leap forward in our ability to observe gene activity; it looks set to have far-flung impacts on medicine at large. The team at TSRI is already planning on investigating other diseases with a substantial immune component, such as ulcerative colitis and asthma.