Abstract The benefits of renal transplantation have been demonstrated to extend to the elderly. As a result, more seniors have been placed on the kidney transplant wait list and have received renal ...allografts in recent years. In June 2013 significant amendments to deceased donor kidney allocation policy were approved to be instituted in 2014 with the goal of increasing overall life years and graft years achieved compared to the current system. Going forward, it is conceivable that transplant centers may perceive a need to adjust practice patterns and modify evaluation and listing criteria for the elderly as the proportion of kidneys distributed to this segment of the wait list would potentially decrease under the new system, further increasing wait times. This review examines contemporary perspectives on access to transplantation for seniors and pertinent issues for this subgroup such as wait time, comorbidity, and evaluation and listing practices. Potential approaches to improve the evaluation of elderly patients being considered for transplant and to increase availability of expanded criteria donor (or higher kidney donor profile index) and living donor organ transplant opportunities while maintaining acceptable outcomes for seniors are explored.
Current success in organ transplantation is dependent upon the use of calcineurin‐inhibitor‐based immunosuppressive regimens. Unfortunately, current immunotherapy targets molecules with ubiquitous ...expression resulting in devastating non‐immune side effects. T‐cell costimulation has been identified as a new potential immunosuppressive target. The best characterized pathway includes CD28, its homologue CTLA4 and their ligands CD80 and CD86. While an immunoglobulin fusion protein construct of CTLA4 suppressed rejection in rodents, it lacked efficacy in primate transplant models. In an attempt to increase the biologic potency of the parent molecule a novel, modified version of CTLA4‐Ig, LEA29Y (belatacept), was constructed. Two amino acid substitutions (L104E and A29Y) gave rise to slower dissociation rates for both CD86 and CD80. The increased avidity resulted in a 10‐fold increase in potency in vitro and significant prolongation of renal allograft survival in a pre‐clinical primate model. The use of immunoselective biologics may provide effective maintenance immunosuppression while avoiding the collateral toxicities associated with conventional immunsuppressants.
Simultaneous pancreas‐kidney transplantation has gained acceptance as a therapeutic modality for patients with end‐stage renal disease secondary to diabetes mellitus. In some instances, performing ...the procedure as conventionally described with renal revascularization from the left iliac vessels and pancreatic arterial inflow from the right iliac vessels may be difficult or undesirable. We describe our experience with an alternate operative technique utilizing a single arterial conduit to vascularize both organs. We believe that this technique may be of use in certain patients undergoing simultaneous pancreas‐kidney transplantation.
Many genetic disorders result from a single point mutation, and many tumor oncogenes have been found to be altered by a point mutation. The ability to inhibit selectively the expression of the ...mutated form of a protein without affecting its normal counterpart is central to many therapeutic strategies, since the normal protein may serve indispensable functions. Antisense oligonucleoside methylphosphonates and their psoralen derivatives directed at either normal human Ha-ras p21 or ras p21 that is mutated at a single base in codon 61 have been examined for their efficacy and specificity as inhibitors of p21 expression. Mixed cultures of cells expressing both forms of p21 were treated with the antisense oligomer complementary to the normal p21 or with the antisense oligomer complementary to the point-mutated p21. Each of the antisense oligomers specifically inhibited expression of only the form of ras p21 to which it was completely complementary and left the other form of p21 virtually unaffected.
The widening gap between patients in need of a kidney transplant and the finite number of transplantable deceased donor organs resulted in critical review of kidney allocation policy in the USA. The ...process to reach consensus for change required compromise between arguments for utility and equity. Important amendments to address shortcomings of the old system and projected outcomes of the new system are reviewed. Potential unintended consequences and practical considerations to facilitate implementation of provisions intended to enhance utility and increase access to transplant for population subgroups in the new system are explored. Granular metrics provide built-in flexibility for the new system, making it amenable to modification based on outcomes.
A novel, structurally defined, and homogeneous oligodeoxynucleoside methylphosphonate (oligo-MP) neoglycopeptide conjugate, YEE(ah-GalNAc)3-SMCC-AET-pUmpT7, has been synthesized. The linkage between ...the carbohydrate ligand and the oligo-MP is a metabolically stable thioether. Experiments establish that uptake of this conjugate by human hepatocellular carcinoma (Hep G2) is cell-type specific when compared with its uptake by human fibrosarcoma (HT 1080) and human promyleocytic leukemia (HL-60). Uptake of the conjugate with Hep G2 cells can be totally inhibited by the addition of a 100-fold excess of free YEE(ah-GalNAc)3 in the culture medium indicating the observed cell uptake is ligand specific. The conjugate is rapidly taken in by Hep G2 cells in a linear fashion reaching a saturation plateau of 26 pmol per 10(6) cells after 24 h. Conjugation of oligo-MPs to ligands for hepatic carbohydrate receptors, such as YEE(ah-GalNAc)3, represents an efficient and ligand-specific method for the intracellular delivery of oligo-MPs.
The results after primary cadaveric renal transplantation in 665 consecutive patients were reviewed with respect to posttransplant serum lipids. Data were available for 182 of 665 patients on serum ...total cholesterol and triglycerides at 1 year posttransplant. Hypercholesterolemia (cholesterol > 200 mg/dl) developed in 141 of 182 patients (77%) and hypertriglyceridemia developed in 73 of 166 patients (44%). At 1 year posttransplant, hypercholesterolemia and hypertriglyceridemia both correlated with age at transplant (P = 0.0001, P = 0.01). Hypercholesterolemia and hypertriglyceridemia were also correlated with obesity as determined by body mass index (kg/m2) (P = 0.006, P = 0.01). Hypertriglyceridemia at 1 year posttransplant correlated with pretransplant triglyceride level (P = 0.006), but hypercholesterolemia did not correlate with pretransplant cholesterol level (P = 0.53). Hyperlipidemia was not correlated with cyclosporine (CsA) or prednisone dose (mg/kg), CsA trough levels, number of rejection episodes, or serum creatinine at 1 year. Despite significant differences in serum cholesterol and triglycerides, actuarial graft and patient survival were similar between the normolipidemic and hyperlipidemic groups.
The impact of pretransplant overweight/obesity was analyzed in a group of 268 consecutive primary pancreas renal transplant recipients. Obesity was defined as body mass index (BMI) greater than 27 ...kg/m2. BMI was available for 240 of the 268 patients. A total of 88% (212/240) of the patients had a BMI < or = 27 and 28/240 (12%) had BMI > 27. There were no significant differences in age, sex, or race between obese and nonobese patients. The incidence and degree of posttransplant hypertension, weight gain, increase in BMI, and hyperlipidemia did not differ on the basis of pretransplant BMI. Serum creatinine at one year posttransplant was slightly increased in obese patients, but the increase was not statistically significant. Cumulative prednisone dose (mg/kg) as well as cyclosporine (CsA) dose (mg/kg) at one year was not significantly different between obese and nonobese patients. However, there was a marginally significant negative correlation between BMI and one-year cumulative (mg/kg) prednisone dose (P = .06). Types and frequency of posttransplant complications were similar between obese and nonobese patients, although there was a slightly higher incidence of wound related complications in obese patients (11% vs. 6.8%) (P = NS). There was no difference in the frequency of acute rejection episodes in obese and nonobese patients. Actuarial patient survival was comparable between patients with BMI < or = 27 versus those with BMI > 27 (P = .10). However, actuarial graft survival, both pancreas and renal, were significantly decreased in patients with BMI > 27 (P = .029). The decrease in pancreas and kidney graft survival in obese patients could not be attributed to decreased "early" patient survival, increased incidence of perioperative or postoperative complications, differences in hypertension, acute rejection episodes, serum lipids, or immunosuppression dosage. The most common causes of graft loss were rejection and patient death in both obese and nonobese patients. After three years posttransplant, the decreased pancreas and renal graft survival in obese patients corresponded to decreased patient survival. The most common cause of patient death was cardiovascular complications in both obese and nonobese PKT recipients.
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