John M. Holman

Alemtuzumab induction in renal transplantation.

BACKGROUND There are few comparisons of antibody induction therapy allowing early glucocorticoid withdrawal in renal-transplant recipients. The purpose of the present study was to compare induction therapy involving alemtuzumab with the most commonly used induction regimens in patient populations at either high immunologic risk or low immunologic risk. METHODS In this prospective study, we randomly assigned patients to receive alemtuzumab or conventional induction therapy (basiliximab or rabbit antithymocyte globulin). Patients were stratified according to acute rejection risk, with a high risk defined by a repeat transplant, a peak or current value of panel-reactive antibodies of 20% or more, or black race. The 139 high-risk patients received alemtuzumab (one dose of 30 mg, in 70 patients) or rabbit antithymocyte globulin (a total of 6 mg per kilogram of body weight given over 4 days, in 69 patients). The 335 low-risk patients received alemtuzumab (one dose of 30 mg, in 164 patients) or basiliximab (a total of 40 mg over 4 days, in 171 patients). All patients received tacrolimus and mycophenolate mofetil and underwent a 5-day glucocorticoid taper in a regimen of early steroid withdrawal. The primary end point was biopsy-confirmed acute rejection at 6 months and 12 months. Patients were followed for 3 years for safety and efficacy end points. RESULTS The rate of biopsy-confirmed acute rejection was significantly lower in the alemtuzumab group than in the conventional-therapy group at both 6 months (3% vs. 15%, P<0.001) and 12 months (5% vs. 17%, P<0.001). At 3 years, the rate of biopsy-confirmed acute rejection in low-risk patients was lower with alemtuzumab than with basiliximab (10% vs. 22%, P=0.003), but among high-risk patients, no significant difference was seen between alemtuzumab and rabbit antithymocyte globulin (18% vs. 15%, P=0.63). Adverse-event rates were similar among all four treatment groups. CONCLUSIONS By the first year after transplantation, biopsy-confirmed acute rejection was less frequent with alemtuzumab than with conventional therapy. The apparent superiority of alemtuzumab with respect to early biopsy-confirmed acute rejection was restricted to patients at low risk for transplant rejection; among high-risk patients, alemtuzumab and rabbit antithymocyte globulin had similar efficacy. (Funded by Astellas Pharma Global Development; INTAC ClinicalTrials.gov number, NCT00113269.).

Family support, physical impairment, and adherence in hemodialysis: An investigation of main and buffering effects

Patient noncompliance is a pervasive problem among end-stage renal disease (ESRD) patients. Previous studies have implicated social support as an important correlate of adherence behavior in other chronic illness groups, but little research has examined this relationship in a hemodialysis population. The present study examined the main and interactive effects of social support in the family and illness-related physical impairment with regard to patient compliance in a sample of 78 hemodialysis patients. Results indicated that patients holding perceptions of a more supportive family environment exhibited significantly more favorable adherence to fluid-intake restrictions than did patients reporting less family support. Family support was not associated with adherence to dietary restrictions. The effect of family support on fluid-intake adherence was not moderated by level of physical impairment. This pattern suggests that the influence of support on adherence is more attributable to a main or direct effect, as opposed to a buffering process in the face of increased physical impairment.

Laparoscopic treatment of post renal transplant lymphoceles

Background: Traditionally, a post transplant lymphocele (PTL) is drained by widely opening the wall connecting the lymphocele cavity to the intraperitoneal space via laparotomy. We hypothesize that laparoscopic techniques can be effectively used for the treatment of PTL.Methods: Patients requiring intervention for PTL between 1993 and 2002 were identified via a retrospective review. Results of drainage via laparotomy and laparoscopy were compared.Results: During the study period 685 renal transplants (391 cadaveric, 294 living) were performed. The incidence of lymphocele was 5% [34/685 (36 cases)]. The indications for surgical drainage were local symptoms (69%), graft dysfunction (14%), or both (17%). The mean time to surgical therapy was 4.9 months. Laparoscopic drainage was performed in 25 patients (74%) and open drainage in 9 patients (26%). Open procedures were performed in cases for: previous abdominal surgery (5), undesirable lymphocele characteristics or location (2), or with concomitant open procedures (3). There were no conversions or operative complications in either group. There was no difference in operative time for the laparoscopic group vs the open group (108 ± 6 vs 123 ± 18 min, p = 0.8). Hospital stay was significantly shorter for the laparoscopic group (1.7 ± 0.8 vs 3.8 ± 1.0, p = 0.0007), with 88% of laparoscopic patients being either overnight admissions or same day surgery. Two patients (5%) developed symptomatic recurrences requiring reoperation [1 laparoscopic (4%), 1 open (10%)].Conclusions: Laparoscopic fenestration of a peritransplant lymphocele is a safe and effective treatment. The large majority of patients treated with laparoscopic fenestration were discharged within one day of surgery. Unless contraindications exist, laparoscopy should be considered first-line therapy for the surgical treatment of posttransplant lymphocele.

Gadolinium-enhanced Breathhold Three-dimensional Time-of-Flight Renal MR Angiography in the Evaluation of Potential Renal Donors☆

PURPOSE To evaluate the utility of gadolinium-enhanced three-dimensional (3D) time-of-flight (TOF) magnetic resonance angiography (MRA) of the renal arteries in the evaluation of potential renal donors. MATERIALS AND METHODS Fifty consecutive patients underwent gadolinium-enhanced 3D-TOF MRA of the renal arteries as part of their evaluation as possible renal donors. All imaging was performed on a 1.5-T system with use of a torso phased-array coil. Conventional T1-weighted axial spin-echo and T2-weighted axial fast spin-echo imaging was performed to evaluate the renal parenchyma. Coronal dynamic MRA was performed during bolus injection of 40 mL of gadolinium with use of a 3D-TOF sequence requiring a breathhold of approximately 30 seconds. Maximum-intensity-projection reconstructions were obtained of the renal arterial and venous anatomy. All studies were prospectively evaluated by a single radiologist experienced with body MRA. Intraoperative findings were used as the reference standard in 35 patients. To evaluate interobserver variability, each examination was evaluated for image quality, renal artery number, and anatomy by two radiologists experienced with MRA and blinded to the others interpretations and surgical results. RESULTS Ninety-eight percent of all MRAs were graded as diagnostic quality (Kappa value = 0.38; P < .05). Multiple renal arteries were identified in 29 (29%) of 100 kidneys. Four of 50 patients studied (8%) had renal parenchymal abnormalities identified with MR imaging. Sensitivity and specificity for accessory renal artery detection was 71% and 95%, respectively. Overall, accuracy for MRA in determining renal artery number was 90%. CONCLUSION Gadolinium-enhanced breathhold 3D-TOF renal MRA is sufficient to assess the renal arteries in potential donors.

The effects of oral pentoxifylline on the cytokine release syndrome during inductive OKT3

The cytokine release syndrome (CRS) accompanying OKT3 therapy is a major cause of posttransplant morbidity. The pathogenesis of this syndrome has been attributed to the synthesis of tumor necrosis factor, interleukin 2 (IL-2), interleukin 6 (IL-6), and gamma-interferon in response on T lymphocyte stimulation by OKT3. The hemorrheologic agent pentoxifylline (PTX) inhibits the synthesis of TNF alpha in vitro in response to a variety of stimuli, including OKT3. We performed a randomized, double-blinded trial of PTX during OKT3 induction in recipients of cadaveric renal allografts. Patients received either PTX 800 mg or placebo 2 hr before the initial dose of OKT3 and every 8 hr thereafter during the first 3 posttransplant days. Serum TNF alpha and IL-6 concentrations were measured pre-OKT3 and at 2 and 6 hr post-OKT3 on the first 3 posttransplant days. Despite the achievement of apparently adequate plasma levels of PTX and its active metabolites, no difference was observed in the incidence or severity of clinical manifestations of CRS. Serious manifestations of CRS--including acute pulmonary edema, encephalopathy, and aseptic meningitis--were not seen in either group. Serum TNF alpha and IL-6 concentrations were similar in PTX and control patients throughout the course of the study. Plasma levels of PTX and its active metabolites did not correlate with serum TNF alpha levels, serum IL-6 levels, or the incidence and severity of clinical manifestations of CRS.

Autoimmune and pregnancy complications in the daughter of a kidney transplant patient.

BACKGROUND Immunosuppressive agents taken by pregnant organ transplant recipients readily cross the placenta during development of the fetal immune system. There are few data on the long-term implications for the progeny, but evidence from animal studies suggest that second and third generations of organ transplant patients may be at risk for autoimmune disorders and reproductive problems. METHODS We present the 23-year-old daughter of a renal allograft recipient exposed to azathioprine 75 mg/day and prednisone 5 mg/day throughout her mothers pregnancy. RESULTS During the daughters first pregnancy, she developed multiple autoantibodies, Raynauds phenomenon, and fetal death occurred at 20 weeks gestation. The second pregnancy was complicated by systemic lupus erythematosus, preeclampsia, and the birth of a preterm male infant. CONCLUSIONS It is uncertain whether the autoimmune manifestations and obstetric complications in this patient were related to fetal exposure to immunosuppressive drugs. Nevertheless, further studies on the health and pregnancies of adult offspring of transplant patients are warranted.

Assessment of Efficacy and Safety of FK778 in Comparison With Standard Care in Renal Transplant Recipients With Untreated BK Nephropathy

Background. BK polyomavirus infection has been reported in 10% to 60% of renal transplant recipients with progression to BK nephropathy (BKN) occurring in 1% to 5% of patients. Graft loss occurs in up to 60% of renal transplant recipients with BKN. Because BK polyomavirus infection is believed, in part, to be a manifestation of overimmunosuppression, the current standard of care involves the reduction of immunosuppressants. This strategy has been associated with clearance of viral load, preservation of renal function, and improvement in graft survival; however, this may come at a risk of rejection. A safe and effective immunosuppressive agent that does not predispose to viral infection is needed in transplantation. Methods. In a phase 2, proof-of-concept, randomized, open-label, parallel-group, 6-month study in renal transplant patients, FK778 (an investigational immunosuppressant from the malononitrilamides class) was compared with the current standard of care (reduction of immunosuppression) for treatment of newly diagnosed or untreated BKN, which was confirmed by renal biopsy. Results. Demographic characteristics were similar between the two groups, except there were numerically more females in the FK778 group than in the standard care group. Although the treatment with FK778 decreased BK viral load in this study, it was associated with a less favorable rejection profile and renal function and a higher incidence of serious adverse events compared with reduction of immunosuppression. Conclusions. Data from this study are consistent with the findings of previous studies that found no benefit of drug therapy in the treatment of BKN in kidney transplant recipients.

Calciphylaxis: Is There a Role for Parathyroidectomy?†

Objective Calciphylaxis, a rare disorder typically affecting renal failure patients, results in vascular calcification with subsequent skin necrosis, gangrene, and often death from sepsis. Parathyroid hormone is thought to act as a tissue sensitizer leading to these soft tissue changes. As such, parathyroidectomy is often advocated to control this complicated condition. A discussion of calciphylaxis does not exist in the otolaryngology literature, and head and neck surgeons performing parathyroidectomy should be aware of this phenomenon. This study evaluates the success of parathyroidectomy in reversing the ill effects of calciphylaxis in both our patient population and the literature.

Lack of economic benefit with basiliximab induction in living related donor adult renal transplant recipients.

Study Objective. To assess the effect of basiliximab (BAS) induction therapy on acute rejection rates and overall costs in adult living related donor (LRD) renal transplant recipients.