Cytomegalovirus incidence between everolimus versus mycophenolate in de novo renal transplants: pooled analysis of three clinical trials.

Everolimus (EVR) in heart and renal transplant (RTx) recipients may be associated with a decreased incidence of cytomegalovirus (CMV). A detailed analysis of the association between EVR versus mycophenolic acid (MPA) and CMV events has not been reported. CMV data from 2004 de novo RTx recipients from three-randomized, prospective, EVR studies A2309 (N = 833), B201 (N = 588) and B251 (N = 583) were retrospectively analyzed to identify differences between two EVR dosing groups and MPA. EVR groups received 1.5 mg/day, or 3 mg/day with either standard (SD-CsA) or reduced dose cyclosporine (RD-CsA). Controls received MPA with SD-CsA. CMV prophylaxis was as per center practice. CMV incidence (infection/syndrome, disease, viremia) was captured per local center evaluations. Kaplan-Meier analyses demonstrated that freedom from CMV viremia and infection/syndrome was significantly greater for EVR versus MPA for recipients without CMV prophylaxis. Among recipients who received prophylaxis, freedom from viremia was greater for EVR 3.0 mg; freedom from infection/syndrome was greater for EVR 3.0 and 1.5 mg. Although freedom from organ involvement was numerically greater for EVR, it was not statistically significant. This analysis documents significant reductions in the incidence of CMV infection/syndrome and viremia in EVR-treated de novo RTx recipients, especially those who did not receive CMV prophylaxis versus MPA.

Everolimus plus reduced-exposure CsA versus mycophenolic acid plus standard-exposure CsA in renal-transplant recipients.

Everolimus allows calcineurin-inhibitor reduction without loss of efficacy and may improve renal-transplant outcomes. In a 24-month, open-label study, 833 de novo renal-transplant recipients were randomized to everolimus 1.5 or 3.0 mg/day (target troughs 3-8 and 6-12 ng/mL, respectively) with reduced-exposure CsA, or mycophenolic acid (MPA) 1.44 g/day plus standard-exposure CsA. Patients received basiliximab +/- corticosteroids. The primary endpoint was composite efficacy failure (treated biopsy-proven acute rejection, graft loss, death or loss to follow-up) and the main safety endpoint was renal function (estimated glomerular filtration rate [eGFR], by Modification of Diet in Renal Disease [MDRD]) at Month 12 (last-observation-carried-forward analyses). Month 12 efficacy failure rates were noninferior in the everolimus 1.5 mg (25.3%) and 3.0 mg (21.9%) versus MPA (24.2%) groups. Mean eGFR at Month 12 was noninferior in the everolimus groups versus the MPA group (54.6 and 51.3 vs 52.2 mL/min/1.73 m(2) in the everolimus 1.5 mg, 3.0 mg and MPA groups, respectively; 95% confidence intervals for everolimus 1.5 mg and 3.0 mg vs MPA: -1.7, 6.4 and -5.0, 3.2, respectively). The overall incidence of adverse events was comparable between groups. The use of everolimus with progressive reduction in CsA exposure, up to 60% at 1 year, resulted in similar efficacy and renal function compared with standard-exposure CsA plus MPA.

Assessment of differences in HLA-A, -B, and -DRB1 allele mismatches among African-American and non-African-American recipients of deceased kidney transplants.

Among recipients of deceased donor kidney transplants, African-Americans experience a more rapid rate of kidney allograft loss than non-African-Americans. The purpose of this study was to characterize and quantify the HLA-A, -B, and -DRB1 allele mismatches and amino acid substitutions at antigen recognition sites among African-American and non-African-American recipients of deceased donor kidney transplants matched at the antigen level. In recipients with zero HLA antigen mismatches, the degree of one or two HLA allele mismatches for both racial groups combined was 47%, 29%, and 11% at HLA-DRB1, HLA-B, and HLA-A, respectively. There was a greater number of allele mismatches in African-Americans than non-African-Americans at HLA-A (P < .0001), -B (P = .096), and -DRB1 loci (P < .0001). For both racial groups, the HLA allele mismatches were predominantly at A2 for HLA-A; B35 and B44 for HLA-B; but multiple specificities for HLA-DRB1. The observed amino acid mismatches were concentrated at a few functional positions in the antigen binding site of HLA-A and -B and -DRB1 molecules. Future studies are ongoing to assess the impact of these HLA mismatches on kidney allograft loss.

A comparison of the survival of shipped and locally transplanted cadaveric renal allografts.

BACKGROUND: The effect on allograft survival of the shipment of cadaveric renal allografts from one organ-procurement organization to another is uncertain. METHODS: Using data from the Organ Procurement and Transplantation Network of the United Network for Organ Sharing, we identified 5446 pairs of cadaveric kidneys (10,892 allografts) in which one kidney was shipped and the other was transplanted locally. We compared the risk of graft failure using statistical models that accounted for confounding variables, including the degree of HLA mismatching. RESULTS: After adjustment for the degree of HLA mismatching, shipped organs had a significantly higher rate of allograft failure than locally transplanted organs in the first year after transplantation (adjusted hazard ratio, 1.17; 95 percent confidence interval, 1.05 to 1.31; P=0.004), but not thereafter. An association between the shipment of organs with no HLA mismatches and allograft failure was not confirmed. CONCLUSIONS: The shipment of cadaveric renal allografts increases the risk of failure of HLA-mismatched grafts during the first year after transplantation.

Effect of the use or nonuse of long-term dialysis on the subsequent survival of renal transplants from living donors.

BACKGROUND: The effect on allograft survival of the transplantation of kidneys from living donors without the previous initiation of long-term dialysis is controversial. METHODS: Using data from the U.S. Renal Data System, we performed a retrospective cohort study of 8481 patients who were or who were not treated by long-term dialysis before receiving a kidney transplant from a living donor. The relative rate of allograft failure for patients who received a transplant without previously undergoing long-term dialysis, as compared with patients who underwent long-term dialysis before transplantation, was assessed by proportional-hazards analysis, with adjustment for potential confounding variables, including the transplantation center and median household income. The association between the receipt of a kidney transplant from a living donor without previous dialysis ("preemptive transplantation") and the risk of biopsy-confirmed acute rejection within six months after transplantation was evaluated by conditional logistic-regression analysis, with adjustment for the transplantation center. RESULTS: Transplantation of a kidney from a living donor without previous long-term dialysis was associated with a 52 percent reduction in the risk of allograft failure during the first year after transplantation (rate ratio, 0.48; P=0.002), an 82 percent reduction during the second year (rate ratio, 0.18; P=0.001), and an 86 percent reduction during subsequent years (rate ratio, 0.14; P=0.001), as compared with transplantation after dialysis. The reduction in the rate of allograft failure during the first year was attenuated when adjustment was made for the timing of acute rejection within the first year (rate ratio, 0.69; 95 percent confidence interval, 0.44 to 1.10; P=0.10). Increasing duration of dialysis was associated with increasing odds of rejection within six months after transplantation (P=0.001). CONCLUSIONS: Preemptive transplantation of kidneys from living donors without the previous initiation of dialysis is associated with longer allograft survival than transplantation performed after the initiation of dialysis.

Arterial hypertension and renal allograft survival.

CONTEXT: Several observational studies have investigated the significance of hypertension in renal allograft failure; however, these studies have been complicated by the lack of adjustment for baseline renal function, leaving the role of elevated blood pressure in allograft failure unclear. OBJECTIVE: To examine the relationship between blood pressure adjusted for renal function and survival after cadaveric allograft transplantation. DESIGN: Nonconcurrent historical cohort study conducted from 1985 through 1997. SETTING: University teaching hospital. PARTICIPANTS: A total of 277 patients aged 18 years or older who underwent cadaveric renal transplantation without another simultaneous organ transplantation and whose allograft was functioning for a minimum of 1 year. Follow-up continued through 1997 (mean follow-up, 5.7 years). MAIN OUTCOME MEASURE: Time to allograft failure (defined as death, return to dialysis, or retransplantation) by systolic, diastolic, and mean arterial blood pressure measurements at 1 year after transplantation. RESULTS: Multivariate Cox proportional hazards modeling demonstrated that nonwhite ethnicity, history of acute rejection, and nondiabetic kidney disease were significant predictors of failure (P = .01 for all). In addition, the calculated creatinine clearance at 1 year had an adjusted rate ratio (RR) for allograft failure per 10 mL/min (0.17 mL/s) of 0.74 (95% confidence interval [CI], 0.62-0.88). The RR per 10-mm Hg increase in blood pressure measured at 1 year after transplantation, after adjustment for creatinine clearance, was 1.15 (95% CI, 1.02-1.30) for systolic pressure, 1.27 (95% CI, 1.01-1.60) for diastolic pressure, and 1.30 (95% CI, 1.05-1.61) for mean arterial pressure. Supplemental analyses that did not include death as a failure event or reduce the minimum allograft survival time for study subjects to 6 months yielded results consistent with the primary analysis. There was no evidence of modification of the blood pressure-allograft failure relationship by ethnicity or diabetes mellitus. CONCLUSIONS: Systolic, diastolic, and mean arterial blood pressures at 1 year posttransplantation strongly predict allograft survival adjusted for baseline renal function. More aggressive control of blood pressure may prolong cadaveric allograft survival.

Focal acute tubular necrosis in a renal allograft.

Nuclear imaging is used to evaluate renal allografts demonstrating delayed function after transplantation. Interpretation of the nuclear scan in the context of clinical data, provides helpful information in the management of the transplant recipient. The better quality of images obtained with technetium-99m mercaptoacetyltriglycine (Tc-99m MAG3) has made it the radiotracer of choice compared to technetium-99m diethylenetriamine pentaacetic acid (Tc-99m DTPA) for imaging of the renal allograft. Tc-99m MAG3 is cleared from the kidney by tubular secretion, whereas Tc-99m DTPA is cleared by glomerular filtration. In this report, we discuss a unique abnormality found on nuclear imaging of a renal allograft. Utilizing our understanding of the characteristic handling of various radiotracers by the kidney, we were able to demonstrate that the renal scan was consistent with an area of focal acute tubular necrosis in the newly transplanted kidney.

Language guiding therapy: the case of dehydration versus volume depletion.

Indiscriminate use of the terms dehydration and volume depletion, so carefully crafted by our predecessors, risks confusion and therapeutic errors. These two conditions should be distinguished at the bedside and in how we speak to one another. Dehydration largely refers to intracellular water deficits stemming from hypertonicity and a disturbance in water metabolism. The diagnosis of dehydration cannot be established without laboratory analysis of p[Na +] or calculation of serum tonicity. In contrast, volume depletion describes the net loss of total body sodium and a reduction in intravascular volume and is best termed extracellular fluid volume depletion. The diagnosis of this condition relies principally on history, careful physical examination, and adjunctive data from laboratory studies. The pathophysiology of both dehydration and extracellular fluid volume depletion must be understood if these conditions are to be recognized and appropriately treated when they occur separately or together. There is no inclusive therapy for all situations. For example, indiscriminate treatment with 0.45% saline cannot be recommended when these conditions coexist because extracellular fluid volume depletion is often treated rapidly with 0.9% saline and dehydration is often treated more slowly with 5% dextrose.

Course of motor recovery in the zone of partial preservation in spinal cord injury.

Thirty-nine C4 to C6 motor complete Frankel A or B spinal cord injured subjects were included in this prospective study to determine the course of recovery in the zone of partial preservation (ZPP) during the first 6 months postinjury. Subjects had initial manual muscle testing and neurologic examination between 3 and 7 days postinjury. Subjects whose most rostral key muscle in the ZPP had a motor power of grade 1 or 1+/5 (group 1, n = 22) were compared with subjects whose most rostral key muscle had a motor power of grade 2 or 2+/5 (group 2, n = 17). Subjects had manual muscle testing weekly for 1 month and then monthly for 6 months postinjury. Comparisons were made for recovery to: (1) grade 3/5; (2) grade 4/5; (3) an increase of one grade; and (4) an increase of two grades. Analyses were made at monthly intervals by the Fisher Exact test and between median times of recovery by the Kruskal-Wallis Ranking test. There was earlier recovery to grade 3/5 for group 2. At one month 11 of 17 (65%) group 2 subjects had reached grade 3/5 compared with 4 of 22 (18%) group 1 subjects (p less than 0.01). At 2 months postinjury, 14 of 17 (82%) group 2 subjects versus 10 of 22 (45%) group 1 subjects had reached grade 3/5 strength (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Recovery of strength at the zone of injury in motor complete and motor incomplete cervical spinal cord injured patients.

This study compared the time of recovery at the zone of injury between motor complete (Frankel A and B) and motor incomplete (Frankel C and D) cervical spinal cord injured patients for the biceps (C5), extensor carpi radialis (C6), and triceps (C7) muscles. Manual muscle testing was performed initially three to seven days postinjury, then weekly for four weeks, and then monthly for six months. Subjects between the ages of 15 and 70 years with C4, C5, C6, or C7 neurologic levels were classified according to whether their selected muscle was greater than 0/5 and less than 3/5 grade (n = 32) or greater than or equal to 3/5 grade (n = 28) at initial evaluation. Subjects were further classified based on their Frankel score. Motor incomplete patients with muscle strength less than 3/5 had an average time of recovery to grade 3/5 of 0.9 months (median = 2 weeks), and all seven patients achieved grade 3/5 by two months postinjury. Motor complete patients had an average time of recovery to grade 3/5 of 1.8 months (median = 2 months), and 18 of 25 patients achieved grade 3/5 by two months postinjury (p = 0.1). For muscles greater than or equal to 3/5, motor incomplete subjects had an average time for improvement of one full grade of 1.5 months (median = 2 months), and motor complete subjects had an average time for improvement of one grade of 2.3 months (median = 1 month, p = 0.1).(ABSTRACT TRUNCATED AT 250 WORDS)