By Ramsey Hachem, M.D.
February, 2008
The advent of cyclosporine revolutionized solid organ transplantation and made lung transplantation a clinical reality. Cyclosporine and tacrolimus are calcineurin inhibitors, and they inhibit the proliferation of the primary immune cells responsible for rejection after organ transplantation. Prior to the introduction of cyclosporine, high doses of prednisone were necessary to reduce the risk of rejection. In the early 1980s, surgical techniques were refined and the introduction of cyclosporine allowed the prevention of rejection, making clinical lung transplantation a reality. Tacrolimus was then introduced in the 1990s and has been shown to be modestly superior to cyclosporine in preventing rejection. Unfortunately however, both drugs have some potentially serious side effects that can be essentially unavoidable. Obviously, as immunosuppressants they can predispose to opportunistic infections and even increase the risk of cancer, since the immune system plays a role in detecting and inhibiting the proliferation of pre-cancers. Furthermore, both cyclosporine and tacrolimus can cause high blood pressure and kidney disease. They constrict the arteries supplying blood to the kidneys and reduce overall blood flow to the kidneys. They can also lead to progressive kidney scarring over time. In the early stages, the kidney injury is completely reversible but over time, chronic kidney damage becomes irreversible.
Chronic kidney disease is typically asymptomatic until the late stages. The serum creatinine is a rough estimate of kidney function that is somewhat dependent on age, gender, body size, and muscle mass. Before transplantation, the serum creatinine is usually normal reflecting normal kidney function, but it often begins to rise and reach abnormally high levels in the first year after transplantation. This mild degree of abnormal kidney function is not usually associated with any physical signs or symptoms. Indeed, kidney disease progresses silently until advanced stages. Some of the earliest overt physical signs of kidney disease include fluid retention and high blood pressure; the serum creatinine is usually abnormal at this stage. As the kidney disease progresses, fluid retention and high blood pressure become more difficult to control but other symptoms are usually absent until kidney failure is imminent. Symptoms of kidney failure include nausea, anorexia, fatigue, weight loss, and shortness of breath with activities as the lungs become congested with fluid.
Approximately 25% of patients have an abnormal serum creatinine within one year of lung transplantation. At this stage, most patients have few symptoms related to their kidney disease. However, 1-2% of patients develop kidney failure requiring dialysis within one year; these patients have typically suffered severe kidney injury in the immediate post-operative recovery period after the transplant. Within five years of transplantation, approximately 35% of patients have an abnormal serum creatinine and 3-4% are on dialysis or have had a kidney transplant. Clearly, kidney failure is a serious problem after lung transplantation and its complications can seriously jeopardize the outcome.
Unfortunately, there are few interventions to slow the progression of kidney disease since cyclosporine and tacrolimus are the primary causes. The main approach has been to target lower blood levels of the drugs when a patient develops kidney disease, but this can sometimes be difficult when managing rejection. In some patients who have had little or no rejection but have developed early kidney disease, substituting sirolimus for cyclosporine or tacrolimus may be a viable option. Sirolimus, by itself, is not nephrotoxic, but when used in combination with cyclosporine or tacrolimus can worsen the kidney disease. So, some patients can be managed with a combination of sirolimus, prednisone, and azathioprine or mycophenolate mofetil. However, sirolimus is not a panacea; it has multiple side effects that often limit its use including fluid retention, nausea, diarrhea, low white blood cell count, and it can rarely injure the lungs. In addition, lung function needs to be carefully monitored when a patient is managed with a drug combination that does not include cyclosporine or tacrolimus since some patients have developed late rejection on this combination. Since there is little latitude to adjust the immunosppressive regimen to mitigate the progression of kidney disease, optimal control of other risk factors such as diabetes and high blood pressure becomes paramount. In addition, avoiding other medicines that can be toxic to the kidneys, such as non-steroidal anti-inflammatory drugs like ibuprofen, is also very important.
Unfortunately, kidney disease is a common complication after lung transplantation because of the necessary immunosuppressive regimen. Clearly, this has a negative impact on quality of life and survival after transplantation, but hopefully, the progression of kidney disease can be prevented as new immunosuppressive regimens become available.