Long-Term Successes in Kidney Transplantation

Of the 876 primary kidney transplants performed at Cleveland Clinic from 1963 through 1984, 80 functioned for three decades or longer — 12 for more than four decades. In July 2020, the recipient with the longest functioning transplant of the 80 died at age 72. The transplanted kidney, donated by the recipient’s mother, had functioned for 52.2 years and had an age of 98.3 years.

“The success of these 80 cases isn’t due to any single factor,” says William E. Braun, MD, a nephrologist who joined Cleveland Clinic in 1968, retired from active practice in 2010 and continued clinical research through 2020. “We have reported on many aspects of our long-term patients since 1968, including a study of 20-year successes published in Transplantation in 1995 and other articles before and after that. Now these 30-47-year outcomes provide even more interesting data that eventually could be compared with current transplant results.”

Dr. Braun and a research team recently published a review of the 80 patients in Clinical Transplantation. Their study chronicles the cases and their outcomes, evaluates special clinical subsets, and details complications, both conventional ones and others previously unreported. The exceptionally long success of these patients allowed the team to identify the evolution of new clinical findings.

“Beginning just a few years after the nation’s first kidney allograft transplant program at Peter Bent Brigham Hospital in Boston, Cleveland Clinic’s kidney transplant program represented a very early, highly skilled, remarkably extensive and steadily progressive multidisciplinary achievement,” says Dr. Braun, who trained in transplant nephrology at Peter Bent Brigham Hospital from 1965 to 1968.

Long-term renal allograft recipients

The 80 primary transplant pairs in Cleveland Clinic’s long-term study had an average recipient age of 27.0 ± 9.5 years and donor age of 33.1 ± 12.0 years. Sixty-one of the 80 grafts (76.3%) came from living-related donors (34 [55.7%] two-haplotype-matched, 24 [39.3%] one-haplotype-matched, three [4.9%] no-haplotype-matched); 19 (23.8%) came from deceased donors.

During the 22-year span when these transplants were done, recipients were treated with three different immunosuppression programs:

• 1963-1970: Thymectomy, splenectomy, high-dose oral prednisone
• 1971-1979: Divided-dose intravenous methylprednisolone (DD-IVMP)
• 1980-1984: Antilymphocyte globulin

Long-term treatment included maintenance prednisone and azathioprine or mycophenolate mofetil much later, and often the antiplatelet medication dipyridamole for more than 25 years.

At 35 years:

• Death-censored graft survival was 85.3%.
• Death with a functioning graft was 84.2% (death censored).
• Overall graft survival was 69.5% (Kaplan–Meier).

Findings revealed

A closer look at the data in patient subsets showed that:

• Cardiovascular risk factors peaked within the first six years for hypertension and within 18-21 years for hypercholesterolemia and new-onset diabetes, all of which occurred before the peak in cardiovascular events from 24 to 36 years.
• Infections had peaks at 0-6 years (many viral) and 15-18 years, but were highest at 30-33 years.
• Non-cutaneous malignancies were highest at 21-36 years and disproportionately more frequent in females.
• When the 80 long-term recipients were compared with 80 matched controls, there was not only a significant overall survival benefit for the 80 long-term patients, but within the matched control group there was improved survival for those whose early acute rejections had been treated with DD-IVMP (from 1971 to 1979).
• Biopsies from some patients treated with DD-IVMP showed evidence of antibody-mediated rejection, but those allografts still functioned for more than 30 years.
• Most of the 19 patients who received a kidney from an unrelated deceased donor had a statistical possibility of a one-haplotype HLA match with their donor.

According to Dr. Braun, three remarkable and instructive patient “saves” included:

1. One patient with very early antibody-mediated rejection and microangiopathic hemolytic anemia successfully treated with DD-IVMP and heparin followed by 32 years of graft function.
2. Another patient with severe hypogammaglobulinemia (72 mg/dL) and tissue-invasive cytomegalovirus at 25 years managed by Cleveland Clinic’s infectious disease team, resulting in graft function for 34 years and a successful second transplant.
3. A patient with antibody-mediated rejection in the 30th year that was treated with plasmaphereses and IV immunoglobulin, a combination that preserved graft function for another eight years when a successful second transplant was done.

In addition, long-term data revealed these notable new findings:

• Late antibody-mediated rejection occurred after 30 years with combined but asynchronous donor-specific HLA-DR and HLA-A antibodies.
• Twice as many infections occurred in unselected patients with hypogammaglobulinemia after 20 years compared to patients with normal gammaglobulin levels.
• Monoclonal gammopathy of undetermined significance (MGUS) was associated with non-plasma-cell malignancies.
• A subset of 27 long-term patients treated with azathioprine had extremely low levels of naïve/immature T1/T2 B lymphocytes measured at 37 years — findings consistent with a low immunosuppression state of allograft acceptance and opposite to the very high T1/T2 B lymphocyte levels reported in operational tolerance.

Optimizing the care of kidney transplant recipients

“The patients in this study had remarkable achievements after their first renal transplants, even in the very early years,” says Dr. Braun. “Over 70% of the 38 patients who provided data worked for 20 years or longer post-transplant, including in medical and legal professions. Some went on to earn additional college degrees. Many got married; 17 became parents. They were compliant with treatments and enjoyed a good quality of life.”

Results from these long-term patients can be used to evaluate outcomes of kidney transplant recipients from the cyclosporine era, the continuing tacrolimus/mycophenolate mofetil era, and other protocols still to come, he notes.

“Hopefully this study provides clinicians with additional insights for monitoring the course of their patients and offers patients greater hope for truly long-term success with their first transplant,” concludes Dr. Braun.