ContextTumor necrosis factor (TNF) plays an important role in host defense and tumor growth control. Therefore, anti-TNF antibody therapies may increase the risk of serious infections and malignancies.ObjectiveTo assess the extent to which anti-TNF antibody therapies may increase the risk of serious infections and malignancies in patients with rheumatoid arthritis by performing a meta-analysis to derive estimates of sparse harmful events occurring in randomized trials of anti-TNF therapy.Data SourcesA systematic literature search of EMBASE, MEDLINE, Cochrane Library, and electronic abstract databases of the annual scientific meetings of both the European League Against Rheumatism and the American College of Rheumatology was conducted through December 2005. This search was complemented with interviews of the manufacturers of the 2 licensed anti-TNF antibodies.Study SelectionWe included randomized, placebo-controlled trials of the 2 licensed anti-TNF antibodies (infliximab and adalimumab) used for 12 weeks or more in patients with rheumatoid arthritis. Nine trials met our inclusion criteria, including 3493 patients who received anti-TNF antibody treatment and 1512 patients who received placebo.Data ExtractionData on study characteristics to assess study quality and intention-to-treat data for serious infections and malignancies were abstracted. Published information from the trials was supplemented by direct contact between principal investigators and industry sponsors.Data SynthesisWe calculated a pooled odds ratio (Mantel-Haenszel methods with a continuity correction designed for sparse data) for malignancies and serious infections (infection that requires antimicrobial therapy and/or hospitalization) in anti-TNF–treated patients vs placebo patients. We estimated effects for high and low doses separately. The pooled odds ratio for malignancy was 3.3 (95% confidence interval [CI], 1.2-9.1) and for serious infection was 2.0 (95% CI, 1.3-3.1). Malignancies were significantly more common in patients treated with higher doses compared with patients who received lower doses of anti-TNF antibodies. For patients treated with anti-TNF antibodies in the included trials, the number needed to harm was 154 (95% CI, 91-500) for 1 additional malignancy within a treatment period of 6 to 12 months. For serious infections, the number needed to harm was 59 (95% CI, 39-125) within a treatment period of 3 to 12 months.ConclusionsThere is evidence of an increased risk of serious infections and a dose-dependent increased risk of malignancies in patients with rheumatoid arthritis treated with anti-TNF antibody therapy. The formal meta-analysis with pooled sparse adverse events data from randomized controlled trials serves as a tool to assess harmful drug effects.

/pdf/anti-tnf-antibody-therapy-in-rheumatoid-arthritis-and-the-4pipx1jwuu.pdf

Anti-TNF Antibody Therapy in Rheumatoid Arthritis and the Risk of Serious Infections and Malignancies: Systematic Review and Meta-analysis of Rare Harmful Effects in Randomized Controlled Trials

https://onlinelibrary.wiley.com/doi/epdf/10.1111/j.1600-6143.2004.00332.x

Lack of Improvement in Renal Allograft Survival Despite a Marked Decrease in Acute Rejection Rates Over the Most Recent Era

ContextProlonged calorie restriction increases life span in rodents. Whether prolonged calorie restriction affects biomarkers of longevity or markers of oxidative stress, or reduces metabolic rate beyond that expected from reduced metabolic mass, has not been investigated in humans.ObjectiveTo examine the effects of 6 months of calorie restriction, with or without exercise, in overweight, nonobese (body mass index, 25 to <30) men and women.Design, Setting, and ParticipantsRandomized controlled trial of healthy, sedentary men and women (N = 48) conducted between March 2002 and August 2004 at a research center in Baton Rouge, La.InterventionParticipants were randomized to 1 of 4 groups for 6 months: control (weight maintenance diet); calorie restriction (25% calorie restriction of baseline energy requirements); calorie restriction with exercise (12.5% calorie restriction plus 12.5% increase in energy expenditure by structured exercise); very low-calorie diet (890 kcal/d until 15% weight reduction, followed by a weight maintenance diet).Main Outcome MeasuresBody composition; dehydroepiandrosterone sulfate (DHEAS), glucose, and insulin levels; protein carbonyls; DNA damage; 24-hour energy expenditure; and core body temperature.ResultsMean (SEM) weight change at 6 months in the 4 groups was as follows: controls, −1.0% (1.1%); calorie restriction, −10.4% (0.9%); calorie restriction with exercise, −10.0% (0.8%); and very low-calorie diet, −13.9% (0.7%). At 6 months, fasting insulin levels were significantly reduced from baseline in the intervention groups (all P<.01), whereas DHEAS and glucose levels were unchanged. Core body temperature was reduced in the calorie restriction and calorie restriction with exercise groups (both P<.05). After adjustment for changes in body composition, sedentary 24-hour energy expenditure was unchanged in controls, but decreased in the calorie restriction (−135 kcal/d [42 kcal/d]), calorie restriction with exercise (−117 kcal/d [52 kcal/d]), and very low-calorie diet (−125 kcal/d [35 kcal/d]) groups (all P<.008). These “metabolic adaptations” (~ 6% more than expected based on loss of metabolic mass) were statistically different from controls (P<.05). Protein carbonyl concentrations were not changed from baseline to month 6 in any group, whereas DNA damage was also reduced from baseline in all intervention groups (P <.005).ConclusionsOur findings suggest that 2 biomarkers of longevity (fasting insulin level and body temperature) are decreased by prolonged calorie restriction in humans and support the theory that metabolic rate is reduced beyond the level expected from reduced metabolic body mass. Studies of longer duration are required to determine if calorie restriction attenuates the aging process in humans.Trial RegistrationClinicalTrials.gov Identifier: NCT00099151

/pdf/effect-of-6-month-calorie-restriction-on-biomarkers-of-3ylslte4h4.pdf

Effect of 6-month calorie restriction on biomarkers of longevity, metabolic adaptation, and oxidative stress in overweight individuals: a randomized controlled trial.

https://aasldpubs.onlinelibrary.wiley.com/doi/epdf/10.1002/lt.22091

Validation of a current definition of early allograft dysfunction in liver transplant recipients and analysis of risk factors

Background Availability of cadaveric kidneys for transplantation is far below the growing need, leading to longer waiting time and more deaths while waiting. Methods. Using national data from 1995 to 2000, we evaluated graft survival by donor characteristics and the rate of discard of retrieved organs, with the goal of increasing use of kidneys that are associated with increased risk of graft failure, that is, expanded donor kidneys. Results. Cox models identified four donor factors that independently predicted significantly higher relative risk of graft loss compared with a low-risk group. These factors included donor age, cerebrovascular accident as the cause of death, renal insufficiency (serum creatinine >1.5 mg/dL), and history of hypertension. Expanded donor kidneys were defined as those with relative risk of graft loss greater than 1.70 and included all donors aged 60 years and older and those aged 50 to 59 years with at least two of the other three conditions (cerebrovascular cause of death, renal insufficiency, hypertension). The expanded donor group accounted for 14.8% of transplanted kidneys. Among organs procured from expanded donors, 38% were discarded versus 9% for all other kidneys. The risk of graft loss of expanded donor kidneys was increased in both older and younger recipients but to a greater extent in those recipients older than 50 years. Conclusion. By identifying donor factors associated with graft failure, these analyses may help to expand the number of transplanted kidneys by increasing the utilization of retrieved cadaveric kidneys.

Donor characteristics associated with reduced graft survival: an approach to expanding the pool of kidney donors.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1600-6143.2006.01242.x

Characteristics associated with liver graft failure: the concept of a donor risk index.

Background. Laparoscopic live donor nephrectomy for renal transplantation is being performed in increasing numbers with the goals of broadening organ supply while minimizing pain and duration of convalescence for donors. Relative advantages in terms of recovery provided by laparoscopy over standard open surgery have not been rigorously assessed. We hypothesized that laparoscopic as compared with open surgical live donor nephrectomy provides briefer, less intense, and more complete convalescence. Methods. Of 105 volunteer, adult, potential living-renal donors interested in the laparoscopic approach, 70 were randomly assigned to undergo either hand-assisted laparoscopic or open surgical live donor nephrectomy at a single referral center. Objective data and subjective recovery information obtained with telephone interviews and validated questionnaires administered 2 weeks, 6 weeks, and 6–12 months postoperatively were compared between the 23 laparoscopic and 27 open surgical patients. Results. There was 47% less analgesic use (P =0.004), 35% shorter hospital stay (P =0.0001), 33% more rapid return to nonstrenuous activity (P =0.006), 23% sooner return to work (P =0.037), and 73% less pain 6 weeks postoperatively (P =0.004) in the laparoscopy group. Laparoscopic patients experienced complete recovery sooner (P =0.032) and had fewer long-term residual effects (P =0.0015). Conclusions. Laparoscopic donor nephrectomy is associated with a briefer, less intense, and more complete convalescence compared with the open surgical approach.

Randomized controlled trial of hand-assisted laparoscopic versus open surgical live donor nephrectomy.

Background. Acute rejection (AR) remains a major risk factor for the development of chronic renal allograft failure (CAF), which is a major cause of late graft loss. With the introduction of several newer immunosuppressive agents (e.g., mycophenolate mofetil, tacrolimus and neoral) acute rejection rates have been steadily decreasing. However, the incidence of CAF has not decreased as dramatically as the incidence of acute rejection. One possible explanation is that the impact of AR on CAF is changing. The goal of this study was to analyze the relative impact of AR era on the development of CAF. Methods. We evaluated 63,045 primary renal transplant recipients reported to the USRDS from 1988 to 1997. CAF was defined as graft loss after 6 months posttransplantation, censored for death, acute rejection, thrombosis, infection, surgical complications, or recurrent disease. A Cox proportional hazard model correcting for 15 possible confounding factors evaluated the relative impact of AR on CAF. The era effect (years 1988-1989, 1990-1991, 1992-1993, 1994-1995 and 1996-1997) was evaluated by an era versus AR interaction term. Results. An AR episode within the first 6 months after transplantation was the most important risk factor for subsequent CAF (RR=2.4, CI 2.3-2.5). Compared with the reference group (1988-89 with no rejection), having an AR episode in 1988-89, 1990-1991, 1992-1993, 1994-1995, and 1996-1997, conferred a 1.67, 2.35, 3.4, 4.98 and 5.2-fold relative risk for the subsequent development of CAF (P<0.001). Conclusions. Independently of known confounding variables, the impact of AR on CAF has significantly increased from 1988 to 1997. This effect may in part explain the relative lack of improvements in long term renal allograft survival, despite a decline in AR rates.

Increased impact of acute rejection on chronic allograft failure in recent era.

http://deepblue.lib.umich.edu/bitstream/handle/2027.42/73788/j.1600-6143.2007.01790.x.pdf

Risk factors for urinary complications after renal transplantation.

https://deepblue.lib.umich.edu/bitstream/handle/2027.42/35271/500040506_ftp.pdf;sequence=1

J. D. Punch

Papers

Characteristics associated with liver graft failure: the concept of a donor risk index.

Randomized controlled trial of hand-assisted laparoscopic versus open surgical live donor nephrectomy.

Increased impact of acute rejection on chronic allograft failure in recent era.

Risk factors for urinary complications after renal transplantation.

Transjugular Intrahepatic Portosystemic Shunts and Liver Transplantation in Patients With Refractory Hepatic Hydrothorax