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Systolic Dysfunction in Renal Transplant Candidates

Systolic Dysfunction Tied to Mortality in Renal Transplant Candidates

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NEW YORK (Reuters Health) May 20 - In patients awaiting kidney transplants, the presence of systolic dysfunction -- defined as an ejection fraction no greater than 40%, which is often asymptomatic -- nearly doubles the risk of death, according to a report in the Journal of the American Society of Nephrology for June.

The link between overt heart failure and mortality in patients with end-stage renal disease is well documented, the report notes. The extent to which lesser degrees of cardiac dysfunction reduce survival, however, was unclear.

Dr. Angelo M. de Mattos, from the University of California in Sacramento, and colleagues sought to answer this question by analyzing data from 2718 renal transplant candidates seen at one center.

Overall, 681 patients died during a median follow-up period of 27 months, the report indicates.

The median survival period for patients with systolic dysfunction was 49 months, significantly shorter than the 72 months seen in patients without dysfunction, but on par with the 48 months noted in patients with ischemia.

After adjusting for diabetes, ventricular hypertrophy, and other risk factors, the mortality hazard ratio with systolic dysfunction was 1.7. Moreover, an inverse, graded association between ejection fraction and mortality was noted.

"The cumulative mortality for patients who had systolic dysfunction and were awaiting transplantation was almost six-fold higher than the reported mortality for similar left ventricular ejection fractions in the general population," the authors point out. "Widely available and minimally invasive testing could identify this high mortality risk subset of the chronic kidney disease population."

J Am Soc Nephrol 2008.
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Experimental Diabetes Treatment Shows Promise

Stephanie Doyle

May 19, 2008 (Orlando, Florida) — New research monitoring the effects of islet cell transplantation resulted in near-normal metabolic control and decreased hypoglycemia, according to the findings presented here at American Association of Clinical Endocrinologists 17th Annual Meeting and Clinical Congress.

Islet cell transplantation, which has been used experimentally to treat type 1 diabetes, places cells from an organ donor into the pancreas of a person with type 1 diabetes. Islets are cells found in clusters throughout the pancreas. The islets themselves contain beta cells, which make insulin, the hormone that helps the body use glucose for energy.

During the 18-month study, physicians used a continuous glucose monitoring system (CGMS) to monitor the effects of the islet cell transplant procedure on patients with type 1 diabetes. The results were intriguing.

"We did find CGMS to be useful in telling us how well our patients were doing after transplantation," Lisa Gorn, DO, from the Diabetes Research Institute at the University of Miami, in Florida, said during her presentation. "It was also useful in telling us when our patients were not doing well after transplantation."

For the study, glycemic control was assessed in 25 patients with type 1 diabetes — 12 underwent islet transplantation (ITx group) and 13 were controls. In all patients, weight, body mass index, insulin use, hemoglobin A1c (HbA1c), 90-minute glucose after a mixed-meal tolerance test, and fasting C-peptide/glucose ratio (CPGR) were monitored.

Mean interstitial glucose, standard deviation, glucose variability, and time in hyperglycemia (% glucose tolerance [GT] > 140 mg/dL), hypoglycemia (%GT < 54 mg/dL), and normoglycemia (%GT between 54 and 140 mg/dL) were measured in 72-hour periods with CGMS, in the control group at baseline and in the ITx group at 3, 6, 9, 12, 15, and 18 months after transplantation; these measurements were analyzed as indicators of graft dysfunction. Linear mixed-model regressions were assessed if CGMS findings at the time of graft dysfunction were significantly different than those at preceding time points.

At all time points except at 3 and 15 months, mean interstitial glucose and glucose variability were significantly lower in the ITx group than in the control group. At all time points, the percentage of time in hypoglycemia was significantly lower in the ITx group than in the control group.

In the ITx group, there was no association between insulin use and time in hypoglycemia. Time in normoglycemia was higher in the ITx group than in the control group at all times except at 15 months. Time in hyperglycemia was significantly lower at 6, 9, 12, and 18 months in the ITx group than in the control group. HbA1C, 90-minute glucose, and CPGR were significantly better at all time points after transplantation. Mean interstitial glucose, standard deviation, glucose variability, and percent time in hyperglycemia were indicators of graft dysfunction, and increased by 19.4 mg/dL,15.1 mg/dL,19.8 mg/dL, and 19.4%, respectively, when graft dysfunction occurred.

"This could be the gold standard — but with some modifications to it,'' said Rhoda Cobin, MD, a clinical professor of medicine at Mount Sinai Medical Center in New York, and a past president of the American Association of Clinical Endocrinologists. Dr. Cobin was not involved in the study.

Funding was provided from the National Institutes of Health (NIH) National Center for Research Resources, the Juvenile Diabetes Research Foundation, and the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Gorn disclosed no relevant financial relationships.

American Association of Clinical Endocrinologists 17th Annual Meeting and Clinical Congress: Abstract 225. Presented May 16, 2008.

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Sirolimus Linked to New-Onset Diabetes Following Renal Transplant

NEW YORK (Reuters Health) Jun 03 - For kidney transplant recipients, use of the anti-rejection drug sirolimus may increase the risk of diabetes, according to findings from a large registry study reported in the Journal of the American Society of Nephrology for July.

"Patients who develop diabetes after transplantation have roughly the same risk of transplant failure as patients who develop acute transplant rejection," Dr. John S. Gill, at the University of British Columbia in Vancouver, Canada, states in a press release.

Because single-center studies indicating that sirolimus may be diabetogenic have not been replicated in larger trials, Dr. Gill's team evaluated data from the United States Renal Data System for the period between 1995 and 2003. Their analysis included 20,124 nondiabetic adult recipients of a first kidney transplant. Nearly 2600 were prescribed sirolimus in combination with other immunosuppressants.

The 3-year cumulative incidence of new-onset diabetes was highest for patients treated with sirolimus plus cyclosporine A (21.9%) and sirolimus plus tacrolimus (21.5%). Sirolimus in combination with mycophenolate mofetil or azathioprine (MMF/AZA) was associated with a cumulative incidence of 17.8%.

In comparison, the cumulative incidence of diabetes was 19.0% among those treated with tacrolimus and MMF/AZA. The lowest incidence was observed among patients treated with cyclosporine A plus MMF/AZA (15.6%).

After adjustment for multiple confounders, including corticosteroid use and acute rejection during the first posttransplantation year, treatment with sirolimus in any combination was associated with increased risk for new-onset diabetes compared with the reference group (patients treated with cyclosporine A and MMF/AZA). Hazard ratios ranged from 1.36 to 1.66.

"Given the importance of new-onset diabetes as a determinant of posttransplantation outcomes and the current use of sirolimus in both pancreas and islet cell transplantation," Dr. Gill's team concludes, "the findings of our study should be confirmed in further prospective studies or in meta-analyses of existing trials using sirolimus."

J Am Soc Nephrol 2008.
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Tacrolimus Monotherapy Effective After Living Kidney Donor Transplant
Louise Gagnon

June 3, 2008 (Toronto) — Using tacrolimus alone as an immunosuppressive agent and gradually tapering the frequency of the calcineurin inhibitor in living kidney donor transplant (LKDT) recipients after transplantation does not result in greater rejection, retrospective data presented here at the American Transplant Congress suggest.

Surgeons from the University of Pittsburgh Medical Center/Thomas E. Starzl Institute have put into practice a protocol to wean both their adult and pediatric kidney transplant patients off immunosuppressive agents. The regimen is also aimed at keeping patients steroid free, according to Henkie P. Tan, MD, PhD, FACS, an associate professor of kidney, liver, and pancreas transplantation and the director of living donor surgery at the University of Pittsburgh Medical Center, Thomas E. Starzl Institute, in Pennsylvania.

Dr. Tan and colleagues performed 200 consecutive living donor kidney transplants (183 adult recipients and 17 pediatric recipients) between March 14, 2003, and March 12, 2005. Kidneys were removed from donors in a laparascopic fashion.

Researchers administered 30 mg (0.5 mg/kg) of alemtuzumab for induction before transplantation and started patients on tacrolimus monotherapy posttransplantation. The protocol called for patients to receive 2 daily doses of tacrolimus in the first 6 months after transplantation, and when possible, space-weaning with administration reduced to once-daily administration, every other day administration, three times weekly, twice weekly, and once weekly.

"Least Amount of Immunosuppression Possible"

"We know that alemtuzumab induction would likely decrease the incidence of rejection for the first 9 months or so," Dr. Tan told Medscape Transplantation. "We want to use the least amount of immunosuppression possible, which is to use 1 agent instead of a triple immunosuppressive regimen that traditionally includes a calcineurin inhibitor like tacrolimus, plus a steroid, plus mycophenolate mofetil."

Because of concerns over adverse events with steroids, such as weight gain, fluid gain, hip necrosis and growth retardation in the pediatric population, Dr. Tan and colleagues opted to implement a steroid-free protocol, he said.

The mean follow-up of patients was 35.7 months, and the mean age of the recipients was 42.3 years. A total of 80 recipients (40%) were female, and 34 (17%) were African American. A total of 9 recipients were aged 70 years or older. Fifty-six recipients (28%) had diabetes mellitus prior to transplantation. There were 25 retransplants of kidneys (25%), including 18 grafts that were a second graft and 7 transplants that were either third or fourth grafts.

Investigators found actuarial recipients' survival was 99.0% at 1 year, 96.4% at 2 years, and 93.3% at 3 years. Similarly, graft survival was 98.0% at 1 year, 90.8% at 2 years, and 86.3% at 3 years. The majority of recipients (60.1%) were weaned to a dosing frequency of once daily or less of tacrolimus monotherapy. A total of 94.4% recipients have not yet had to resort to steroid therapy.

Acute cellular rejection (ACR) occurred in 50 recipients (89 episodes). Dr. Tan stressed that most (79 [89%] of 89 episodes) were mild cases of ACR, categorized as either Banff1a (43 or 48.3%) or Banff1b (36 or 40.4%). Nine patients had antibody-mediated rejection. A total of 13 patients were successfully treated with alemtuzumab to resolve the ACR. There were no cases of delayed allograft function or cytomegalovirus infection.

Strong Antirejection Drugs Not Needed

"The vast majority of patients who had rejection had mild rejection and they are easily treated with steroids," Dr. Tan told Medscape Transplantation. "We don't need to use strong antirejection medications to treat the patients."

Mark Pescovitz, MD, a transplant surgeon and professor in the Department of Surgery, Microbiology, and Immunology at Indiana University in Indianapolis, who moderated the oral session in which the research was presented, said the practice in Pittsburgh cannot be applied at other institutions because the surgeons have not yet distinguished between which kidney transplant recipients will do well with a protocol of space-weaning with a single immunosuppressive agent and which will not.

"They don't have specific criteria as to who will be weaned off therapy and who will not," he told Medscape Transplantation. "It's very difficult to transfer that knowledge to another center if there are no specific criteria. Even with this large number [n = 200], they are not able to provide specific criteria."

Dr. Pescovitz noted that the data suggest that rejections appear to occur later, 2 years or more posttransplantation, when patients are not being followed as closely as in the first few months after transplantation.

The study was independently funded. Dr. Tan and Dr. Pescovitz have disclosed no relevant financial relationships.

American Transplant Congress 2008: Abstract 221. Presented June 2, 2008.
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