You are called by your local organ procurement organization and offered a high-quality organ. They tell you “this will be a DCD donor.”
What does this mean? What implications does this have post-transplant?
As opposed to neurologically-deceased donors (NDD, i.e. “brain dead” donors), donors after cardiac death (DCD) are declared dead after a period of circulatory arrest (usually 5 minutes). This means that there is an obligatory period of period of warm ischemia before the organs are flushed and cooled. In kidney transplantation, DCD organs are associated with an increased incidence of delayed graft function (DGF – often defined as the need for dialysis in the first week after transplantation). Nevertheless, multiple groups have shown that long-term outcomes are similar whether patients receive kidneys from a standard criteria donor (SCD) who is either NDD or DCD. Results of liver transplantation with DCD organs are also good, although a higher incidence of biliary ischemic strictures has been described. Lung and pancreas transplants are also performed using organs from selected DCD donors.
A 56-year-old woman is eight years post-heart transplant for familial dilated cardiomyopathy. She has not had any episodes of rejection since the first year post-transplant, and has enjoyed an excellent level of function. Immunosuppression includes tacrolimus and mycophenolate mofetil. She now describes some mild shortness of breath on exertion, and her echocardiogram demonstrates abnormal left ventricular filling indicating moderate diastolic dysfunction. Coronary angiography reveals no flow limiting stenoses. Her right heart catheterization reveals a right atrial pressure of 10 mmHg that increases to 16mmHg with inspiration (Kussmaul’s sign).
What do you expect to see on biopsy?
Chronic allograft dysfunction in heart transplants is often associated with histologic findings of myocyte hypertrophy and interstitial fibrosis. There may also be evidence of small vessel vasculopathy. While any change in allograft function may be related to acute cellular rejection or acute antibody mediated rejection (AMR), chronic allograft dysfunction usually results from a combination of coronary allograft vasculopathy (leading to ischemia) and interstitial fibrosis. Donor age is a powerful predictor of cardiac allograft dysfunction.
Across all organs, vascular changes and fibrosis are common biopsy findings in chronic allograft dysfunction. Often, there is no evidence of acute cellular or antibody-mediated rejection, although previous rejection episodes may contribute to the chronic changes. These changes are likely multifactorial, and may develop secondary to immune injury/rejection, endothelial dysfunction, metabolic factors (dyslipidemia, diabetes), toxins such as alcohol (in liver) or cigarette smoking (in lung transplants), viruses (such as hepatitis B or C in a liver transplant) and chronic CNI toxicity.
A 22-year-old woman with end-stage liver disease secondary to primary sclerosing cholangitis received a liver transplant four months ago. She presents with a rise in her liver enzymes. A biopsy shows acute cellular rejection.
What biopsy findings would you expect with this diagnosis? How would you treat her?
Acute rejection can be either cellular (T-cell mediated) or humoral (antibody-mediated). The characteristic findings of acute cellular rejection vary by organ. This reflects the obvious differences in the organs themselves, as well as differences in histologic findings that are significant in each organ. In liver transplants, typical findings include an infiltrate of mixed cellularity (lymphocytes, plasma cells, monocytes, eosinophils and often even neutrophils). It is also important to note that the correlation between a patient’s clinical symptoms or tests results and the histologic picture is not perfect. For example, a patient may have significant rejection on biopsy with no obvious organ dysfunction.
Treatment of acute cellular rejection depends on the severity (grading) of the rejection episode, whether acute humoral rejection or chronic changes are present and the patient’s clinical status. In general, milder acute rejections are generally treated with pulses steroids. More sever rejections may require thymoglobulin. In all cases, an episode of rejection requires re-evaluation of the patient’s baseline immunosuppression.
A 32-year-old woman with a history of blood transfusions and one pregnancy underwent a living-donor renal transplant three weeks prior to presentation. Creatinine on discharge was 98 µmol/L. Her next blood test three days later shows a creatinine of 240 µmol/L. You suspect she has antibody-mediated rejection.
What are the findings on renal biopsy that suggest acute humoral rejection? How would you treat her?
The hallmark of acute humoral rejection is positive staining for C4d, a complement degradation product. Other histologic features vary by organ. In kidney transplants, these include peritubular capillaritis and glomerulitis. In addition, documentation of donor-specific antibodies (DSA) and typical morphologic changes on allograft biopsies are expected.
Treatment of acute humoral rejection requires removal of circulating donor-specific antibodies as well as suppression of the antibody-producing cells (plasma cells) producing them. Conventional immunosuppression has only limited effect in humoral rejection, although steroids and thymoglobulin do have some activity against B cells. Conventional maintenance immunosuppression is still required, as control of T-cell activity is required to control B-cell activation and proliferation.
Rapid removal of antibodies can be achieved by plasmapheresis. Intravenous immunoglobulin (IVIg) has multiple effects, among them the suppression of antibody production. Rituximab has been used to eliminate B cells. More recently, there is interest in using newer agents such as eculizumab (an inhibitor of terminal complement activation) and bortezomib (a proteasome inhibitor).
A 50-year-old man receives a liver transplant for hepatitis C-related cirrhosis. What is the natural history of this virus post-transplant?
In patients who are HCV RNA-positive at the time of liver transplant, recurrence is universal. In addition, progression to cirrhosis more rapid in transplanted than native livers; 10-30% of patients will develop cirrhosis within 5 years post-liver transplant for hepatitis C, and long-term survival of HCV-positive liver recipients is decreased compared to patients who receive liver transplants for other indications. Factors associated with accelerated progression of recurrent HCV post-liver transplant include older donor age and use of high-dose steroid boluses for treating acute cellular rejection.
Hepatitis C may also progress more rapidly post-transplant in recipients of non-liver transplants as well. Careful assessment of patients with HCV pre-transplant should include an assessment of viral load, liver synthetic function, portal pressures and histologic changes. Treatment of HCV post-transplant is currently limited, as interferon, which is the cornerstone of therapy, may precipitate episodes of rejection.