A phase I/II randomized open-label multicenter trial of efalizumab, a humanized anti-CD11a, anti-LFA-1 in renal transplantation.

Leukocyte function associated antigen-1 (LFA-1) has a multifaceted role in the immune response, including adhesion and trafficking of leukocytes, stabilizing the immune synapse of the MHC-TCR complex and providing costimulation signals. Monoclonal antibodies to the CD11a chain of LFA-1 have been seen to result in effective immunosuppression in experimental models. Efalizumab, a humanized IgG1 anti-CD11a, is approved for use in psoriasis and may provide effective immunosuppression in organ transplantation. Thirty-eight patients undergoing their first living donor or deceased renal transplant were randomized to receive efalizumab 0.5 or 2 mg/kg weekly subcutaneously for 12 weeks. Patients were maintained on full dose cyclosporine, mycophenolate mofetil and steroids or half dose cyclosporine, sirolimus and prednisone. At 6 months following transplant patient survival was 97% and graft survival was 95%. Clinical biopsy-proven acute rejection in the first 6 months after transplantation was confirmed in 4 of 38 patients (11%). Three patients (8%) developed post transplant lymphoproliferative disease, all treated with the higher dose efalizumab and full dose cyclosporine. The two doses of efalizumab resulted in comparable saturation and modulation of CD11a. This phase II trial suggests that efalizumab may warrant further investigation in transplantation.

Obesity and outcome following renal transplantation.

Single institution series have demonstrated that obese patients have higher rates of wound infection and delayed graft function (DGF), but similar rates of graft survival. We used UNOS data to determine whether obesity affects outcome following renal transplantation. From the UNOS database, we identified patients who underwent primary kidney-only transplantation between 1997 and 1999. Recipient and donor body mass index (BMI) was categorized as underweight (BMI < 18.5), normal (BMI 18.5-24.9), overweight (BMI 25-29.9), obese (BMI 30-34.9) or morbidly obese (BMI > or = 35). We correlated BMI with intermediate measures of graft outcome and overall graft survival, and created multivariate models to evaluate the independent effect of BMI on graft outcome, adjusting for factors known to affect graft success. The study sample comprised 27,377 recipients. Older age, female sex, African American race and increased comorbidity were associated with obesity (p < 0.001). Compared with normal weight patients, morbid obesity was independently associated with an increased risk of DGF (p < 0.001), prolonged hospitalization (p < 0.001), acute rejection (p = 0.006) and decreased overall graft survival (p = 0.001). Donor BMI did not affect overall graft survival (p > or = 0.07). Recipient obesity is associated with an increased risk of DGF and decreased graft survival following renal transplantation.

Review article: current management of renal dysfunction in the cirrhotic patient.

The United Network for Organ Sharing database revealed that over the last 4-5 years, an average of 1800 patients were removed from the cadaveric waiting list annually because of patients' death and an additional 400-500 were removed from the list because of the severity of their illnesses. The pre-transplant evaluation process, therefore, requires careful and continued assessment of the patient's pulmonary, cardiac and renal function among others. This article describes a systematic approach to the evaluation and management of renal dysfunction complicating the course of advanced liver disease, the pathogenic mechanisms and current recommendations for the treatment of hepatorenal syndrome, and the indications for combined liver-kidney transplantation.

Guidelines for the referral and management of patients eligible for solid organ transplantation.

Members of the Clinical Practice Committee, American Society of Transplantation, have attempted to define referral criteria for solid organ transplantation. Work done by the Clinical Practice Committee does not represent the official position of the American Society of Transplantation. Recipients for solid organ transplantation are growing in numbers, progressively outstripping the availability of organ donors. As there may be discrepancies in referral practice and, therefore, inequity may exist in terms of access to transplantation, there needs to be uniformity about who should be referred to transplant centers so the system is fair for all patients. A review of the literature that is both generic and organ specific has been conducted so referring physicians can understand the criteria that make the patient a suitable potential transplant candidate. The psychosocial milieu that needs to be addressed is part of the transplant evaluation. Early intervention and evaluation appear to play a positive role in maximizing quality of life for the transplant recipient. There is evidence, especially in nephrology, that the majority of patients with progressive failure are referred to transplant centers at a late stage of disease. Evidence-based medicine forms the basis for medical decision-making about accepting the patient as a transplant candidate. The exact criteria for each organ are detailed. These guidelines reflect consensus opinions, synthesized by the authors after extensive literature review and reflecting the experience at their major transplant centers. These guidelines can be distributed by transplant centers to referring physicians, to aid them in understanding who is potentially an acceptable candidate for transplantation. The more familiar physicians are with the exact criteria for specific organ transplantation, the more likely they are to refer patients at an appropriate stage. Individual transplant centers will make final decisions on acceptability for transplantation based on specific patient factors. It is hoped that this overview will assist insurers/payors in reimbursing transplant centers for solid organ transplantation, based on criteria for acceptability by the transplant community. The selection and management of patients with end-stage organ failure are constantly changing, and future advances may make obsolete some of the criteria mentioned in the guidelines. Most importantly, these are intended to be guidelines, not rules.

Cyclosporine and tacrolimus-associated thrombotic microangiopathy.

The development of thrombotic microangiopathy (TMA) associated with the use of cyclosporine has been well documented. Treatments have included discontinuation or reduction of cyclosporine dose with or without concurrent plasma exchange, plasma infusion, anticoagulation, and intravenous immunoglobulin G infusion. However, for recipients of organ transplantation, removing the inciting agent is not without the attendant risk of precipitating acute rejection and graft loss. The last decade has seen the emergence of tacrolimus as a potent immunosuppressive agent with mechanisms of action virtually identical to those of cyclosporine. As a result, switching to tacrolimus has been reported to be a viable therapeutic option in the setting of cyclosporine-induced TMA. With the more widespread application of tacrolimus in organ transplantation, tacrolimus-associated TMA has also been recognized. However, literature regarding the incidence of the recurrence of TMA in patients exposed sequentially to cyclosporine and tacrolimus is limited. We report a case of a living donor renal transplant recipient who developed cyclosporine-induced TMA that responded to the withdrawal of cyclosporine in conjunction with plasmapheresis and fresh frozen plasma replacement therapy. Introduction of tacrolimus as an alternative immunosuppressive agent resulted in the recurrence of TMA and the subsequent loss of the renal allograft. Patients who are switched from cyclosporine to tacrolimus or vice versa should be closely monitored for the signs and symptoms of recurrent TMA.

Renal abnormalities in sickle cell disease.

Renal abnormalities in sickle cell disease. Sickle cell nephropathy is indicated by sickled erythrocytes, with the consequent effects of decreased medullary blood flow, ischemia, microinfarct and papillary necrosis. Impaired urinary concentrating ability, renal acidification, hematuria, and potassium secretion are also found. There may be a causal relationship between an increase in nitric oxide synthesis and experimental sickle cell nephropathy, and some studies have indicated that the progression of sickle cell nephropathy is hemodynamically mediated. Although there are many studies showing that proteinuria, nephrotic syndrome, chronic progressive renal failure, and acute renal failure syndromes are the outcome of this disease, the pathogenic mechanism(s) and potential therapies remain to be elucidated. Survival of patients with sickle cell nephropathy who progress to end-stage renal disease (ESRD) is equal to non-diabetic ESRD patients, and graft survival rates are also similar for those who undergo renal transplantation. This article presents a historical review of the glomerular and tubular disorders associated with sickle cell nephropathy, and reviews therapeutic indications to slow its progression. Further research is needed.

The kidney in liver transplantation.

Early recognition and determination of the cause of renal failure in patients with ESLD can be difficult because of the potential interplay among various factors and the wide array of differential diagnoses. A systematic approach, however, assists clinicians to identify common and potentially reversible causes of ARF. It is crucial to distinguish patients with functional renal failure, such as HRS, from those with advanced irreversible renal disease. Isolated liver transplantation is the treatment of choice for the former, and CLKT may be a therapeutic option for the latter. Because of the ever-increasing shortage of donor organs, CLKT must be used judiciously. Kidney biopsy may resolve diagnostic dilemmas. Management of renal complications post-OLT remains a challenge for the physician caring for transplant patients. Modification of nephrotoxic immunosuppressive regimens to avoid postoperative ARF/CRI has met with variable results. Azathioprine has been used in place of cyclosporine. Therapy with polyclonal antilymphocyte preparations or anti-OKT3 monoclonal antibodies (Orthoclone) should be reserved for patients with delayed graft function and for the treatment of acute rejection. The routine use of these agents as prophylactic therapy is not recommended. Data on the impact of renal insufficiency on patient and allograft outcome are inconsistent. Nonetheless, the authors' literature review suggests that renal failure associated with sepsis and, except for patients with HRS, renal failure requiring dialysis are the most consistent features associated with a worse outcome. The need for preoperative or postoperative dialysis has no adverse effect on survival in patients with HRS. On long-term follow-up, despite a greater percentage of patients reaching ESRD in patients with HRS compared with their non-HRS counterparts, the overall outcome in patients with HRS following OLT is favorable. In patients with HRS requiring prolonged dialysis (i.e., greater than 4 weeks), however, irreversible renal failure may develop, necessitating CLKT. Ideally, timely referral of patients for OLT may avoid this complication and obviate the need for double organ transplantation.

Hemodiabsorption in treatment of hepatic failure.

Conducted at the University of California, Los Angeles, this randomized, prospectively controlled study was designed to measure the effects of a hemodiabsorption device in the treatment of 11 patients with hepatic failure and stage III to IV encephalopathy. The results of 5 days of treatment with the hemodiabsorption device were compared with those of standard intensive care procedures. The BioLogic-DT System, a simple sorbent-based system, demonstrated a slight improvement in the neurologic status of patients, a significant improvement in the physiologic status of patients, and an improved outcome for treated patients as opposed to nontreated patients.

Acute abdomen. How to balance costs and quality care.

The costs of health care have been escalating at such a rapid rate, especially during the past decade, that not only in the United States but throughout the Western World, stringent efforts are being made to control and decrease costs. Physicians, through their orders, are responsible for the major part of escalating costs. Sophisticated modern technology plays a large role in medical expense, and will need to be used very discriminately if costs are to be controlled and decreased. Although modern medical technology frequently enhances diagnosis and management, even physicians experienced with its use will attest to its overutilization. Pediatric surgeons and other physicians at times will substitute technology for the basics of history taking and meticulous physical examination. Controlling and lowering the cost of children's surgical care can be achieved in balance and in concert with the provision of optimal care.

A multicenter trial of FK506 (tacrolimus) therapy in refractory acute renal allograft rejection. A report of the Tacrolimus Kidney Transplantation Rescue Study Group.

A multicenter trial was conducted to evaluate the efficacy and safety of tacrolimus in the treatment of refractory renal allograft rejection. Renal transplant recipients experiencing biopsy-proven recurrent acute allograft rejection were eligible if the current rejection episode was refractory to corticosteroids. A total of 73 patients were enrolled, of whom 59 (81%) had previously received at least one course of antilymphocyte antibody as rejection therapy. One-year follow-up was available in 93% of patients. Median time to tacrolimus rescue therapy was 75 days after transplantation (range, 18-1448 days). Therapeutic responses to tacrolimus included improvement in 78% of patients, stabilization in 11%, and progressive deterioration in 11%. The risk of experiencing progressive deterioration was related to the pretacrolimus serum creatinine level: serum creatinine < or = mg/dl, 3%; 3.1-5 mg/dl, 16% (P < 0.04); > 5 mg/dl, 23% (P < 0.02). Twelve-month (from the time of initiation of tacrolimus therapy) actuarial patient and graft survival rates were 93% and 75%. Graft loss occurred in 19 patients (25%) at a median time of 108 days. Fourteen episodes of recurrent rejection were diagnosed in 10 patients (14%), at a median time of 101 days. Eleven episodes of recurrent rejection were treated (three patients underwent transplant nephrectomy), with resolution achieved in nine patients. Antilymphocyte antibody therapy was not used to treat recurrent rejection. Serum creatinine values improved during tacrolimus therapy: median serum creatinine level before tacrolimus, 3.2 mg/dl; median at 1 year after tacrolimus, 1.8 mg/dl. Twelve infections were documented in 11 patients (15%), including cytomegalovirus infection in three patients (4%). Posttransplant lymphoproliferative disorder was diagnosed in a single patient. Tacrolimus whole blood levels averaged 15.0 +/- 9.9 ng/ml at day 7 of tacrolimus therapy and 9.4 +/- 5.1 ng/ml at 1 year, and were consistent among individual centers. Treatment outcome did not correlate with tacrolimus blood levels. The most commonly observed adverse events were neurological and gastrointestinal. Seventy-four percent of patients received tacrolimus for at least 1 year. Tacrolimus therapy was discontinued in 18% of patients for rejection (11% for progressive, unrelenting rejection, and 7% for recurrent rejection). Tacrolimus therapy was discontinued in 8% of patients due to adverse events. In conclusion, tacrolimus rescue therapy provides (1) prompt, effective reversal of refractory renal allograft rejection, (2) good long-term renal allograft function, (3) a low incidence of recurrent rejection, and (4) an acceptable safety profile in renal allograft recipients experiencing refractory rejection.

The effect of pravastatin on acute rejection after kidney transplantation--a pilot study.

Hyperlipidemia is an important complication of kidney transplantation affecting up to 74% of recipients. HMG-CoA reductase inhibitors are reported to provide safe and effective treatment for this problem. A recent study suggests that pravastatin, an HMG-CoA reductase inhibitor, also decreases the incidence of both clinically severe acute rejection episodes and natural killer cell cytotoxicity after orthotopic heart transplantation. We have performed a prospective randomized pilot study of the effect of pravastatin on these same parameters after cadaveric kidney transplantation. Graft recipients were randomized to receive pravastatin after transplantation or no pravastatin (24 patients in each group) in addition to routine cyclosporine and prednisone immunosuppression. Lipid levels, acute rejection episodes and serial natural killer cell cytotoxicities were followed for 4 months after the transplant. At the end of the study period, pravastatin had successfully controlled mean total cholesterol levels (202.6 +/- 9.3 vs. 236.5 +/- 11.9 mg/dl, P < 0.02), LDL levels (107.9 +/- 6.6 vs.149.6 +/- 10.7 mg/dl, P < 0.002), and triglyceride levels (118.8 +/- 14.2 vs. 157.2 +/- 13.8 mg/dl, P < 0.05). In addition, the pravastatin-treated group experienced a reduction in the incidence of biopsy-proven acute rejection episodes (25% vs. 58%, P = 0.01), the incidence of multiple rejections episodes (P < 0.05), and the use of both pulse methylprednisolone (P = 0.01) and OKT3 (P = 0.02). Mean natural killer cell cytotoxicity was similarly reduced (11.3 +/- 1.6 vs. 20.0 +/- 2.0% lysis of K562 target cells, P < 0.002). These data suggest that pravastatin exerts an additional immunosuppressive effect in kidney transplant recipients treated with cyclosporine-based immunosuppression.

HMGCoA reductase inhibitors and omega-3 fatty acids as adjunctive agents in maintenance immunosuppression after solid organ transplantation.

Omega-3 fatty acids have been shown to play a role in preventing development of both acute and chronic rejection. New evidence also suggests that HMGCoA reductase inhibitors may have an immunomodulatory effect and may decrease the incidence of rejection in both animal and human transplant models. Omega-3 fatty acids and HMGCoA reductase inhibitors may be important adjunctive agents in improving short-and long-term allograft function.

Resection of the inferior vena cava for recurrent Wilms' tumor.

Wilms' tumor is one of the most common solid tumors of childhood. Approximately 500 cases occur annually in the United States, and the overall incidence is 0.8 per 100,000 children per year. Direct involvement of the inferior vena cava occurs in 5% to 10% of cases. The National Wilms' Tumor Study (NWTS), an intergroup cooperative clinical trial, indicates that aggressive primary surgical management combined with chemo-radiation therapy improves (with respect to both survival and recurrence) the long-term prognosis for children who have extrarenal involvement. In addition, aggressive surgical resection may further improve the survival rate for patients with recurrent Wilms' tumor after initial multimodal therapy.

Developments and dilemmas in renal transplantation.

The number of patients waiting for a kidney transplant is about three times greater than the number of transplants performed each year. This article highlights current immunosuppression protocols and the newer immunosuppressive drugs under investigation in a number of multicenter trials. These hold out the promise of reducing the frequency of acute rejection and of prolonging graft survival. They are divided into three groups. The first, like cyclosporine, interferes with the action of interleukin 2. The second, like azathioprine, are antimetabolites; and the third, new monoclonal antibodies. The use of antibody-induction therapy is compared with standard regimens. There are risks related to prednisone withdrawal protocols and inadequate cyclosporine dosing that may lead to accelerated graft loss. Cardiovascular disease is a significant problem in older diabetic patients for whom coronary angiography is recommended. A defined set of risk factors is outlined that predicts which younger diabetic patients should have a cardiovascular evaluation. Chronic liver disease is a growing problem and rational strategies are emerging from studies of patients with biopsy-proven active hepatitis. The presence of hepatic inflammation is associated with progressive liver disease and patients must be made aware of this risk when seeking transplantation. A large number of studies of various prophylactic regimens are starting to provide data on the cost-effective reduction of cytomegalovirus disease in transplant recipients. It is recommended that patients receiving antibody therapy also receive preemptive gangciclovir. The issue of chronic allograft rejection is discussed briefly. The most important predictors of chronic allograft rejection are the frequency of acute rejection, inadequate immunosuppression, and infections.(ABSTRACT TRUNCATED AT 250 WORDS)

Progress in childhood cancer care in Florida. 1970-1992.

Pediatric cancer has been a priority in Florida since 1970. That year physicians established a statewide network of children's tumor programs, the Florida Association of Pediatric Tumor Programs (FAPTP), which has grown from the initial two programs to 10 in 1992 and now maintains a registry with follow-up to monitor incidence and other indicators. State-of-the-art care is provided through affiliation with the Pediatric Oncology Group. The incidence of pediatric cancer in Florida is equivalent to national rates, but the number of children followed in 1991 had grown to approximately 2,000. The number receiving care has increased an average of 13% annually since 1981. Services for these patients should be reviewed on a continuing basis to assure access to specialized programs.

The role of combined liver/kidney transplantation in end-stage hepato-renal disease.

The study describes the indications and results of combined liver/kidney transplantation in eight patients suffering from end-stage hepato-renal diseases. The causes of primary renal failure were hyperoxaluria type I (2/8), diabetic nephropathy (2/8), glomerulonephritis (2/8), congenital pyelonephritis (1/8), and polycystic kidneys (1/8). Only five of these patients were on chronic dialysis prior to transplantation. The indication for kidney transplantation in the other three patients was low GFR (< 20 mL/min) and the anticipation of further deterioration of the renal function after liver transplantation as a result of cyclosporine toxicity. The end-stage liver diseases were chronic active hepatitis (4/8) and alcoholic cirrhosis (2/8). There was no evidence for liver failure in two patients undergoing combined transplants for primary hyperoxaluria. The 1-year patient survival rate is 75 per cent, and at that time, kidney and liver function were found to be within normal range. In conclusion, excellent long-term patient survival, as well as kidney and liver graft function, can be achieved in patients suffering from complex end-stage disease of both organs who undergo combined liver and kidney transplantation.

The electrophysiologic and histologic effects of the Argon Beam Coagulator on peripheral nerves.

The electrophysiologic and histologic effects of the Bard Argon Beam Coagulator (ABC) were investigated in the New Zealand White rabbit. Thirty-four rabbits were divided into three groups. Controls underwent simple femoral exploration and closure. The remaining rabbits' femoral nerves were spot coagulated with either the ABC or standard electrosurgical unit (ESU). Stimulus thresholds were recorded before treatment and again prior to sacrifice at 0, 30, 60, or 120 days. Thresholds were significantly elevated for the ABC and ESU compared to controls (P = .0077 and .0351, respectively). Changes in threshold were greater for the ABC than for the ESU, but were not significant. All ABC- and ESU-treated nerves had significant histologic injury when compared to controls (P < .0002). Although the ABC may be clinically safe, significant injury to rabbit femoral nerves occurs when they are exposed to energy emitted by this instrument.