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Biomedical subjects

S M Flechner

Publications and source records attributed to S M Flechner.

At least 19 recordsLinked to original sources
PubMed2005

Alemtuzumab induction and sirolimus plus mycophenolate mofetil maintenance for CNI and steroid-free kidney transplant immunosuppression.

We performed a pilot study in which 22 kidney recipients (14 LD: 8 DCD) were given alemtuzumab induction (30 mg day 0 and 1), steroids (500 mg mp day 0 and 1, none thereafter), mycophenolate mofetil (MMF) maintenance (500 mg b.i.d) and sirolimus (concentration controlled 8-12 ng/mL). With a mean follow-up of 15.9 months, patient survival is (21/22) 96% and graft survival (19/22) 87%. Acute rejections occurred in (8) 36.3% (two humoral). Of 19 surviving grafts, 18 (95%) remain steroid and 15 (79%) CNI-free. At 1 year, mean creatinine was 1.43 mg/dL. Overall infection rates were low, but 2 patients developed severe acute respiratory distress syndrome (ARDS) at month 3 and 7, respectively, resulting in mortality in one and a graft loss in the other. No cancer or PTLD was observed. Leukopenia was common and MMF dose was reduced or eliminated in 6/22 (27%) patients. The reported higher than expected rate of acute rejection, leukopenia and possible pulmonary toxicity suggests excessive morbidity. Modifications such as an initial period of CNI use should be considered.

Acute Disease↗
PubMed2003

Minimizing calcineurin inhibitor drugs in renal transplantation.

Calcineurin inhibitor drugs (CNI), primarily cyclosporine then tacrolimus, have been the centerpieces of maintenance immunosuppression for kidney transplantation since their introduction in the 1980s. While these drugs have been responsible for improved short-term outcomes and diminished rates of acute rejection, they are nephrotoxic and can cause permanent renal injury in many patients. Indeed, some have found that at 10 years after transplantation, the benefits of CNI drugs have been lost compared to the previous generation of maintenance immunosuppression. The use of these agents over many years contributes to the antigen-independent decline in renal function referred to as chronic allograft nephropathy. However, it remains unclear to what degree the use of CNI drugs contribute to ultimate graft loss. For these reasons immunosuppressive alternatives to CNI drugs have begun to emerge during the past few years. The recent introduction of the potent immunosuppressive agent sirolimus has afforded an opportunity to develop a regimen designed to maximize prophylaxis of early acute rejection, absent drug-induced nephrotoxicity. It was our feeling that the combination of antibody induction therapy combined with sirolimus substitution in a three-drug maintenance regimen, would provide the best posttransplant renal function and lowest rates of acute rejection. We have developed a CNI-free immunosuppressive regimen consisting of basiliximab induction, followed by sirolimus, MMF and steroids. Using this protocol we demonstrated comparable transplant outcomes with improved renal function in adult recipients of primary renal transplants. Limiting nephrotoxic immunosuppression should be considered an important goal; but requires sufficient long-term follow-up to support the benefits suggested from initial analysis of the data.

Calcineurin Inhibitors↗
PubMed2002

Clinical characteristics of 13 solid organ transplant recipients with ganciclovir-resistant cytomegalovirus infection.

BACKGROUND: Ganciclovir-resistant (GCV-R) cytomegalovirus (CMV) is now being reported with increasing frequency in solid organ transplant recipients. OBJECTIVE: To describe the clinical characteristics and outcomes of all solid organ transplant patients with GCV-R CMV seen between 1990 and 2000 at a single center. METHODS: Patients with clinically suspected GCV resistance had viral isolates subjected to phenotypic analysis by plaque reduction assay, and also genotypic analysis. Medical records of the 13 patients with GCV-R CMV were reviewed for demographic, microbiologic, clinical, and pathologic data. RESULTS: Thirteen patients were identified, including 5 kidney, 1 heart, and 7 lung transplant recipients. All but one patient (92%) were CMV donor seropositive, recipient negative (D+/R-), and 11/13 (85%) had tissue-invasive CMV. CMV viremia was recurrent in 9/13 (69%); in 2 others, the first CMV episode was fatal. Overall, 9/13 (69%) of patients have died, all of CMV or its complications. Of the 10 who received foscarnet, only one survived. All patients had received GCV-based prophylactic regimens; 8/13 patients (62%) had received CMV hyperimmune globulin (CMVIG) as part of prophylaxis, 6/13 (46%) had received oral ganciclovir, and 5/13 (38%) had received intermittent (3 x/week) IV ganciclovir for prophylaxis. CONCLUSIONS: GCV-R CMV is associated with CMV D+/R- status, tissue-invasive disease, and high mortality even with foscarnet therapy. Exposure to less than fully therapeutic levels of GCV, in the form of oral or intermittent IV GCV, is common. The use of CMVIG in prophylaxis does not appear to prevent resistance. Further work remains to be done to elucidate the risk factors and optimal mode of prophylaxis and treatment for GCV-R CMV.

Cytomegalovirus↗
PubMed2000

A randomized prospective trial of low-dose OKT3 induction therapy to prevent rejection and minimize side effects in recipients of kidney transplants.

BACKGROUND: We attempted to minimize the undesired side effects and maximize the benefit of OKT3 induction therapy in renal transplantation. METHODS: One hundred and one recipients of kidney-only transplants were randomized to three groups. Each received low-dose 2.5-mg OKT3 induction for 7-14 days, but different premedication on days 0, 1, and 2. Group I was given 250 mg i.v. methylprednisolone at 1 and 6 hr, and group II received another 500 mg at 1 hr before initial OKT3. Group III received Atgam 15 mg/kg on day 0 and began OKT3 on day 1. A CD3+ T-cell cut-off of 50/mm3 was used to guide therapy. Maintenance therapy included cyclosporine and steroids for each patient. However, groups I and II were also given mycophenolate mofetil, and group III received azathioprine as a third agent. All rejections were biopsy confirmed and Banff scored. RESULTS: No differences in demographic or transplant characteristics were noted between groups I, II, and III, and mean follow-up was 25.7 (1-38) months. There was no significant difference in actuarial patient (90%, 91%, 94%) or graft survival (83%, 88%, 84%) at 3 years between the respective groups. Mean creatinine values and infectious complications were similar for each group. No patient experienced acute rejection during induction, and eight patients required dose escalation to sustain suppression of CD3 counts. The incidence of acute rejection at 6 and 12 months was significantly (P=0.004) greater in group III (38.2, 44.1%) than in either group I (15.1, 18.1%) or group II (14.7, 17.6%); relative risk 1.988 (95% CI 1.012-3.906). Formation of anti-OKT3 antibody was significantly (P=0.006) greater in group III (26.5%) than in group I (6%) or group II (2.9%). Group I recipients enjoyed significantly (P=0.001) fewer (2.17) OKT3 side effects on days 0, 1, and 2 than group II (3.03) or group III (2.49), and contained the largest number (61%) of recipients who experienced no side effects. Group I also exhibited the most suppressed profile of OKT3-induced release of tumor necrosis factor-alpha (P=0.006), interferon-gamma (P=NS), and interleukin-6 (P=0.01) on days 0 and 1. CONCLUSIONS: Low-dose 2.5-mg OKT3 with pretreatment of split-dose steroids on days 0, 1, and 2 provides the most effective method for OKT3 induction, which minimizes side effects for most patients. Subsequent maintenance therapy with cyclosporine, mycophenolate mofetil, and steroids provides effective rejection prophylaxis without increased complications for up to 3 years. Predepletion of T cells before exposure to OKT3 does not prevent cytokine release.

Acute Disease↗
PubMed2000

U-stitch ureteroneocystostomy: a new renal transplantation ureteral reimplantation technique associated with reduced urologic complications.

Urologic complications represent the most frequent complications following renal transplantation and are associated with significant morbidity. We present the results of the first 105 patients who underwent ureteroneocystostomy at our institution using a new surgical ureteral reimplantation technique designed to reduce the incidence of urologic complications after renal transplantation.

Adolescent↗
PubMed1999

Quantitative assessment of the first acute rejection as a predictor of renal transplant outcome.

BACKGROUND: Acute rejection (AR) of the transplanted kidney has been identified as the major risk factor for the development of chronic rejection and immunological graft loss. However, the clinical presentation and response to AR therapy can vary considerably between recipients. METHODS: We studied the first AR episode in 201 kidney-only recipients transplanted between January 1987 and June 1998 who were biopsied between April 1993 and June 1998 and were graded using the Banff schema. All patients received cyclosporine-based immunosuppression. There were 134 cadaver donor (66.7%) and 67 live donor (33.3%) recipients followed for a mean of 46.2 (range 4-128) months. All Banff grade 1-3 and 40/78 borderline (BL) cases were treated for rejection after biopsy. These patients were compared with a contemporaneous control population who did not experience AR. Demographic risk factors associated with graft loss were identified in both univariate and multivariate analysis. Daily (0-18) serum creatinine (SCr) values during and after the AR were plotted for each patient to generate curves and calculate area under the serum creatinine versus time curve (mg/dl/day). Four response patterns to treatment were identified according to the velocity of % increase (V1) and decrease (V2) of serum creatinine. These were identified as rapid rise and fall (n=62); rapid rise and slow fall (n=43); slow rise and fall (n=55); and slow rise and rapid fall (n=41). Kaplan-Meier graft survivals were compared between the groups. RESULTS: Any Banff grade was associated with increased risk for graft loss (P=0.0001). However, no significant differences were observed between the Banff BL and B1-3 groups, or among those BL patients who were treated or remained untreated for AR. Multivariate analysis identified a black recipient (P=0.03, risk ratio 2.0) and area under the serum creatinine versus time curve (P=0.0001, risk ratio 3.2) as significant risk factors for graft loss. The AR response pattern RS resulted in a significantly (P=0.0072) diminished 5-year graft survival (45%) compared with the other groups. Serum creatinine pattern, but not Banff grade, was also a significant (P=0.025) predictor of re-rejection. CONCLUSIONS: These data suggest that all Banff grades, including BL, carry a significant risk for graft loss, and the initial response to antirejection therapy can predict long-term graft outcome. They support the practice of treating AR promptly and definitively and suggest that the RS subgroup of rejecting grafts could be targeted for additional antirejection therapy. This subgroup can be identified by 10 days of AR therapy, and should be the subject of further study.

Acute Disease↗
PubMed1999

Acute colonic pseudo-obstruction (Ogilvie's syndrome) after renal transplantation.

BACKGROUND: Acute colonic pseudo-obstruction (Ogilvie's syndrome) in the immunosuppressed patient is associated with increased morbidity and mortality. Renal transplant recipients possess several comorbidities that increase the risk of acute pseudo-obstruction of the colon. The aims of this study were to present our experience with this syndrome and to evaluate the potentiating factors in these patients. A review of the literature for pseudo-obstruction following renal transplantation is presented. METHODS: Seven patients who developed Ogilvie's syndrome were identified in a retrospective review of 550 kidney-only transplants. Pretransplant data, potential risk factors, presentation, management, and outcome details were retrieved. The medical literature was reviewed using Medline. RESULTS: Seventy-eight patients with Ogilvie's syndrome in the early posttransplant period have been reported. The associated morbidity and mortality was heightened in this immunocompromised population. Obese transplant recipients (body mass index >30 kg/m2) were at significantly increased risk for developing this syndrome. CONCLUSION: A broad armamentarium of treatment options is available, but the key to successful resolution lies in early recognition.

Colonic Pseudo-Obstruction↗
PubMed1999

Artificial urinary sphincter insertion in renal transplant recipients.

The prosthetic urinary sphincter has contributed significantly to the improved management of urinary incontinence during the past 25 years. However, the safety of these devices in immunosuppressed patients is not well reported. We describe the successful insertion of the AMS 800 artificial urinary sphincter in two renal transplant recipients.

Adult↗
PubMed1999

Cryptococcal meningitis in renal transplant patients associated with environmental exposure.

Fungal infections in renal transplant recipients are less common than bacterial infections; however, the morbidity from fungal infections is high. There is limited information in the literature concerning post-transplantation cryptococcal infection due to environmental exposure of patients living in high-risk areas. We report three patients who were diagnosed with cryptococcal meningitis after kidney transplantation. Cryptococcal titers prior to transplant surgery were negative in all three patients. These patients all lived in rural areas and demonstrated evidence of environmental exposure leading to subsequent cryptococcal meningitis. All patients had exposure to pigeon and chicken excreta and, after treatment, two patients are alive and well with excellent allograft function. The third patient has marginal renal function but is currently not on dialysis. Early diagnosis is essential for salvage from these potentially lethal infections. Intense headache was a prominent feature in the clinical presentation of our patients, and should signal the need for early sampling and culture of spinal fluid. Meningismus was not present in any of our patients, even when other systemic symptoms were identified. We recommend a high index of suspicion post-transplantation for all patients who may have environmental or occupational exposure to cryptococcus. If infection is detected quickly and treatment instituted promptly, patient recovery and allograft survival are possible. Long-term therapy with fluconazole, a non-nephrotoxic agent, should permit eradication of the infection with preservation of kidney function.

Amphotericin B↗
PubMed1998

A randomized prospective controlled trial of oral acyclovir versus oral ganciclovir for cytomegalovirus prophylaxis in high-risk kidney transplant recipients.

BACKGROUND: Posttransplantation cytomegalovirus (CMV) infection remains a significant cause of morbidity in kidney transplant recipients. We performed a randomized prospective controlled trial of oral acyclovir versus oral ganciclovir for CMV prophylaxis in a group of renal allograft recipients considered at high risk for CMV disease due to the use of OKT3 induction therapy. METHODS: A total of 101 recipients of cadaveric (83) and zero haplotype-matched live donor (18) kidney transplants were entered into the trial. A total of 22 D-R- patients received no prophylaxis. Twenty-seven D+R-, 29 D+R+, and 23 D-R+ patients were randomized to receive 3 months of either oral acyclovir (800 mg q.i.d.) or oral ganciclovir (1000 mg t.i.d.). Doses were adjusted according to the level of renal function. The D+R- patients were also given CMV immune globulin biweekly for 16 weeks. Surveillance blood cultures were obtained at transplantation, at months 1, 2, 3, and 6, and when clinically indicated. The primary study end points were time to CMV infection and disease the first 6 months after transplantation. RESULTS: The mean follow up was 14.4 months. Both agents were well tolerated, and no drug interruptions for toxicity occurred. CMV was isolated in 14 of 39 (35.9%) acyclovir-treated and 1 of 40 (2.5%) ganciclovir-treated recipients by 6 months (P=0.0001). Symptomatic CMV disease occurred in 9 of 14 (64%) of the acyclovir patients, two with tissue-invasive disease. Infection rates for acyclovir vs. ganciclovir, respectively, stratified by CMV serology were: D+R-, 54 vs. 0%, P=0.0008; D+R+, 43 vs. 6.6%, P=0.01; D-R+, 8.3 vs. 0%, P=NS. No patient developed CMV infection while taking oral ganciclovir, however three delayed infections occurred 2-7 months after finishing therapy. Each patient had been previously treated for acute rejection. CONCLUSIONS: Oral acyclovir provides effective CMV prophylaxis only for recipients of seronegative donor kidneys. Oral ganciclovir is a superior agent providing effective CMV prophylaxis for recipients of seropositive donor kidneys. Recipients who are treated for acute rejection are at risk for delayed CMV infection during the first posttransplantation year.

Acute Disease↗
PubMed1998

Transplantation of pediatric en bloc cadaver kidneys into adult recipients.

BACKGROUND: To maximize the renal donor pool, cadaveric pediatric en bloc kidneys have been transplanted as a dual unit by some transplant centers. We compared the short- and long-term outcomes of adult recipients of cadaveric pediatric en bloc renal transplants versus those of matched recipients of cadaveric adult kidneys. METHODS: Thirty-three adults who received pediatric en bloc kidney transplants between April 1990 and September 1997 were retrospectively identified and were compared with 33 matched adults who received adult cadaveric kidney transplants. The groups were identical for transplantation era, immunosuppression, recipient sex, race, cause of renal failure, mean weight, and follow-up duration (37.8 vs. 37.5 months). The mean recipient age study versus control was lower (36.3 vs. 48.9 years, P=0.0003). Results. There was no difference between the en bloc and adult donor groups in the 3-year patient survival rates (95% vs. 87%, P=0.16) or the 3-year graft survival rates (87.3% vs. 84.2%, P=0.35). Further, there was no difference in en bloc patient or en bloc graft survival time stratified by recipient age (14-44 vs. >45 years, P=0.11), en bloc donor age (<24 vs. >24 months, P=0.39), or recipient weight (<60, 61-75, >75 kg; P=0.60). Differences in serum creatinine (mg/dl) for the en bloc versus the control group at the time of discharge (3.0 vs. 7.8 mg/dl, P=0.06), at 1 year (1.4 vs. 2.0 mg/dl, P=0.06), and at 2 years (1.1 vs. 1.6 mg/dl, P=0.14) had dissipated by the time of the 5-year follow-up examination (1.1 vs. 1.6 mg/dl, P=0.14). Vascular complications were more prevalent in the en bloc group: renal vein thrombosis (one case), thrombosis of donor aorta (two cases), arterial thrombosis of one renal moiety (two cases), and renal artery stenosis (two cases). There were no differences between groups in delayed graft function, acute or chronic rejection, posttransplant hypertension, posttransplant protein-uria, or long-term graft function. CONCLUSIONS: Collectively, these data indicate that transplanting pediatric en bloc kidneys into adult recipients results in equivalent patient and graft survival compared with adult cadaveric kidneys. Further, the data also suggest that pediatric en bloc kidneys need not be strictly allocated based on recipient weight or age criteria.

Adolescent↗
PubMed1998

Cyclosporine disposition and long-term renal function in a 500-pound kidney transplant recipient.

Patient size has been suggested as a risk factor in kidney transplantation. We have followed a recipient of a cadaver kidney who became massively obese (232 kg, 511 lbs) 5 years posttransplantation. He has maintained stable renal function with no rejection episodes and at 5 years has a measured serum creatinine of 2.2 mg/dL, creatinine clearance 42 mL/min, and urinary protein excretion of 320 mg/24h. Both oral and intravenous cyclosporine (Sandimmune) pharmacokinetic studies were done on a steady-state dose of 150 mg, which represents 0.65 mg/kg per dose. The patient exhibited very high bioavailability, F = 95%, and an oral elimination T1/2 of over 21 hours. These data confirm that stable cyclosporine delivery in very obese recipients can be sustained by dosing normalized to the ideal body weight and trough level monitoring.

Biological Availability↗
PubMed1997

Should obese patients lose weight before receiving a kidney transplant?

BACKGROUND: The results of renal transplantation in obese recipients have been controversial, with some reports finding increased morbidity prohibitive and others finding increased morbidity acceptable. We attempted to determine whether obese patients in extreme excess of their ideal body weight should undergo transplantation. METHODS: The study population included 127 obese (body mass index >30 kg/m2) patients who were compared with a matched nonobese control group (body mass index <27 kg/m2) of 127 recipients with similar demographics. There were no significant differences between the groups according to donor source, recipient race or sex, retransplants, transplant percent reactive antibodies, cause of renal failure, or hypertension. However, significantly more obese patients had a pretransplant history of angina (11.2% vs. 3.2%, P=0.02) or a previous myocardial infarction (5.6% vs. 0.8%, P=0.04). RESULTS: The mean follow-up was 58.9+/-40 (range 3-170) months. Nonobese patients enjoyed a significantly (P=0.0002) greater patient survival (89% vs. 67%) at 5 years and suffered only about half the number of deaths (25 vs. 46) during the period of observation. Cardiac disease was the leading cause of death (39.1%) in the obese group. Patient death had a major impact on graft survival because there were no differences between the groups when death with graft function was censored from the analysis. There were no significant differences between the groups in delayed graft function, acute rejection, chronic rejection, length of hospital stay, operative blood loss, or mean serum creatinine up to 5 years. However, obese patients experienced significantly (P=0.0001) more complications per patient (3.3 vs. 2.2) and a greater incidence (P=0.0003) of posttransplant diabetes (12% vs. 2%). Similar cyclosporine blood levels were observed in obese recipients even though they were receiving 0.75-2 mg/kg/day less cyclosporine than the nonobese recipients. CONCLUSIONS: Outcome differences in obese renal transplant patients were primarily due to a higher mortality resulting from cardiac events. Obesity seems to have little effect on immunologic events, long-term graft function, or cyclosporine delivery. Aggressive pretransplant screening for ischemic heart disease is essential to identify an especially high-risk subgroup of obese patients. Although it would seem prudent to recommend weight reduction <30 kg/m2 to all patients before transplant, these data suggest that obese patients with a history of cardiac disease should not be transplanted until weight reduction has been accomplished.

Adult↗