Israel Medical Association Journal

Intractable forms of autoimmune diseases follow a rapid course, with a significantly shortened life expectancy sometimes comparable to that of malignant diseases. Immunoablative therapy, including high dose cytotoxic agents and hematopoietic autologous stem cell rescue, was recently introduced as an aggressive approach to treat autoimmune diseases that have a rapid course and are resistant to conventional therapy. The most frequent indication for this type of treatment is multiple sclerosis, seconded by systemic sclerosis. The results of immunoablative treatment with documented responses in both diseases are encouraging. The data are mature enough to begin comparative randomized studies of immunoablative versus conventional treatment to validate the benefit of the aggressive approach. A randomized trial involving SSc[1] was recently launched (ASTIS) and a trial involving MS[2] is under preparation. Considerably less experience with immunoablative treatment has been gained in systemic lupus erythematosus, rheumatoid arthritis, and other disorders with an autoimmune pathophysiology. Autologous hematopoietic stem cell transplantation in humans offers more long-lasting immunosuppression than reeducation of lymphocytes. In fact, allogeneic transplantation may replace the whole immune system. However, this attractive approach is still associated with considerable morbidity and mortality and is not yet justified for treatment of automimmune diseases. Non-myeloablative allogeneic transplantation and sub-myeloblative high dose cyclophosphamide without stem cell support are alternative approaches that could be explored in pilot studies.

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Background: Leptin is a 16 kDa hormone synthesized by adipocytes and involved in body weight regulation.

Objectives: To determine serum leptin concentrations in heart, liver and kidney transplant recipients.

Methods: We investigated 57 patients: 18 male heart transplant recipients (age 25-69 years) at 1-66 months after transplantation, 6 female and 8 male liver transplant recipients (age 33-70) at 11-73 months after transplantation, and 10 female and 15 male kidney transplant recipients (age 20-61) at 3-138 months after transplantation. All recipients were receiving immunosuppressive therapy, including prednisone 0-20 mg/day, azathioprine 75-125 mg/day, cyclosporin 100-250 mg/day or tacrolimus 2-10 mg/day. The results were compared to those of 10 female and 10 male healthy controls. Morning serum concentrations of leptin were measured with a commercial radioimmunoassay (Linco Research Inc., USA), and serum insulin and cortisol levels were measured by radioimmunoassay.

Results: Patients (both men and women) after heart, liver and kidney transplantation exhibited significantly higher serum concentrations of leptin and leptin/body mass index ratios than controls. Serum leptin concentrations were significantly higher in women than in men and correlated very significantly with BMI[1] in all cases. The multivariate stepwise analyses showed that among parameters including BMI, gender, age, time after transplantation, prednisone dose, hematocrit, serum concentrations of glucose, albumin, creatinine, cortisol and insulin, only BMI, gender, cortisol and insulin were significant independent determinants of serum leptin levels in these patients.

Conclusions: This is the first report showing that, in addition to body mass index and gender, basal cortisol and insulin levels affect the hyperleptinemia in transplant patients. The clinical relevance of hyperleptinemia in these patients will require further investigation.

The future promises good news for the treatment of systemic lupus erythematosus, some of which can already be foreseen. Increased knowledge on genes that participate in the predis­position, pathogenesis, pharmacogenetics of, and protection against this disease may permit intervention at this level. Also, better understanding about the role of sex hormones has allowed trials of weak androgens or prolactin inhibitors. New immunomodulators or i mmunosuppresors may enable more precise treatment at the immunoregulatory level, and greater knowledge on the disturbance of circuits has already provided hints and even allowed trials of anti-interleukin-10 antibodies, an IL-10 decreasing agent, tolerance-induction strategies or intervention at the level of T cell co-stimulation, as well as immune ablation with subsequent stem cell transplantation. Autoantibodies can be removed, controlled by means of anti­idiotypes, which are blocked from reaching their target antigen or uncoupled from the tissues they have reached. All these treatment strategies will gradually become decanted in order to achieve the optimal treatment of SEE, which may turn out to be its cure.

Background: In simultaneous pancreas-kidney transplantation, with both organs coming from the same donor, the addition of a pancreas to the kidney transplant does not jeopardize the kidney allograft outcome despite higher postoperative SPK morbidity. Pancreas allograft outcome has recently improved due to better organ selection and more accurate surgical techniques.

Objective: To demonstrate the positive impact of SPK on kidney allograft outcome versus kidney transplantation alone in insulin-dependent diabetes mellitus patients with end-stage renal failure.

Methods: We performed 39 consecutive SPKs in 14 female and 25 male IDDM patients with renal failure after an average waiting time of 9 months. Multi-organ donor age was 30 years (range 12-53). The kidneys were transplanted in the left retroperitoneal iliac fossa following completion of the pancreas transplantation; kidney cold ischemia time was 16±4 hours. Induction anti-rejection therapy was achieved with polyclonal antithymocytic globulin and methylprednisolone, and maintenance immunosuppression by triple drug therapy (prednisone, cyclosporine or tacrolimus, and azathioprine or mycophenolate mofetil). Infection and rejection were closely monitored.

Results: All kidney allografts produced immediate urinary output following SPK. Two renal grafts had mild function impairment due to acute tubular damage but recovered after a short delay. Three patients died from myocardial infarction, cerebrovascular event and abdominal sepsis on days 1, 32 and 45 respectively (1 year patient survival 92%). An additional kidney allograft was lost due to a renal artery pseudo-aneurysm requiring nephrectomy on day 26. Nineteen patients (49%) had an early rejection of the kidney that was resistant to pulse-steroid therapy in 6. No kidney graft was lost due to rejection. Patients with acute kidney-pancreas rejection episodes suffered from severe infection, which was the main cause of morbidity with a 55% re-admission rate. Complications of the pancreas allograft included graft pancreatitis and sepsis, leading to a poor kidney outcome with sub-optimal kidney function at 1 year. Kidney graft survival at one year was 89% or 95% after censoring the data for patients who died with functioning grafts.

Conclusions: Eligible IDDM patients with advanced diabetic nephropathy should choose SPK over kidney transplantation alone from either a cadaver or a living source.

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SPK= simutaneous pancreas-kidney transplatation

IDDM= insulin-dependent diabetes mellitus