Jean-Paul Squifflet

Minimization of Immunosuppressive Therapy After Renal Transplantation: Results of a Randomized Controlled Trial

Modern immunosuppressive regimens reduce the acute rejection rate by combining a cornerstone immunosuppressant like tacrolimus or cyclosporine with adjunctive agents like corticosteroids, mycophenolate mofetil (MMF) or azathioprine, often associated with untoward side effects.

Current Thinking on the Pathogenesis of Endometriosis

This manuscript is a review of new ideas regarding the pathogenesis of peritoneal endometriosis, ovarian endometriosis, and retroperitoneal adenomyosis. Peritoneal endometriosis, the different aspects of which (black, red and white) represent distinctive steps in the evolutionary process, can be explained by the transplantation theory. Red lesions are the most active and most highly vascularized lesions and are considered to be the first stage of peritoneal endometriosis. The retroperitoneal nodule is an adenomyotic nodule whose histopathogenesis is not related to the implantation of regurgitated endometrial cells but to metaplasia of Müllerian remnants located in the rectovaginal septum. Metaplastic changes of Müllerian rests into adenomyotic glands involving the rectovaginal septum and the retroperitoneal space are responsible for the striking proliferation of the smooth muscle, creating an adenomyomatous appearance similar to that of adenomyosis in the endometrium.

Hazards of laparoscopic adrenalectomy for Conn's adenoma. When enthusiasm turns to tragedy.

Abstract. A 74-year-old man with primary aldosteronism had a small tumor (27 × 23 mm) of his right adrenal gland successfully removed by a transperitoneal laparoscopy. Despite absence of malignancy in the resected tumor and complete relief of all symptoms in the immediate postoperative period, recurrence occurred 6 months later. The tumor behaved as a carcinoma spread in the peritoneal cavity, and the patient eventually died with peritoneal carcinomatosis. We suggest that the laparoscopic technique coupled with pneumoperitoneum may have favored this recurrence.

Diagnosis and imaging of adenomyotic disease of the retroperitoneal space.

This manuscript discusses the diagnosis and imaging of adenomyotic disease of the retroperitoneal space, a pathology that we have defined as retroperitoneal adenomyotic disease (RAD). By prospective analysis, comparing barium enema, magnetic resonance imaging (MRI) and transrectal ultrasonography, we distinguished three types of retroperitoneal adenomyotic lesions. The most frequently encountered types were posterior vaginal fornix lesions, followed by hourglass-shaped or diabolo-like lesions, and then by rectovaginal septum lesions. This anatomical classification based on clinical examination and imaging will allow us in the future to define the most appropriate treatment for each entity.

Unrelated living donor kidney transplantation

Abstract. Since 1966, we have performed 41 renal transplants from unrelated living donors (ULD), 39 of which were “emotionally related”. All donor‐recipient pairs included in the present series were ABO‐compatible. Recipients included 37 with primary and 4 with secondary transplants; 2 of the latter were diabetics. We compared these results to those of 41 recipients of cadaver donor kidneys matched for age, sex, immunosuppressive regimen, rank, and year of transplant, focusing our attention on the subgroups of patients under cyclosporin A (CyA) therapy (n= 24). We found that ULD transplantation was as successful as cadaver transplantation with good HLA matching: at 3 years, graft survival rates were 81% in ULD versus 86% in the control group under CyA. Moreover, grafts from ULD functioned more rapidly (no post‐transplant dialysis and 70% of the patients with serum creatinine below 2 mg/dl within 3 days post‐transplant). Graft tolerance was equivalent in both groups (50% of the patients experienced no rejection). We conclude that despite poor HLA matching, ULD transplantation with CyA as the basic immunosuppressive agent offers good results: benefiting from the quality of living donor kidney grafts, it helps to alleviate the persistent shortage of cadaver donors.

Measurement of the vasoconstrictive substances endothelin, angiotensin II, and thromboxane B2 in cold storage solution can reveal previous renal ischemic insults.

Abstract In a rat model, the left kid ney was subjected to 60 min of normothermic ischemia followed by 15 min of reperfusion, whereas the right kidney, serving as a paired control, was not rendered ischemic. Both kidneys were then perfused in situ with either Euro‐Collins (EC) solution (n=12) or University of Wisconsin (UW) solution (n=6) for 10 min. Each kidney was then harvested and stored at 4°C in its respective solution. After 24 and 48 h of cold storage, the following vasoactive substances were measured in the preservation media: endothelin (ET), angiotensin II (A‐II), thromboxane (B2) (TxB2), and prostaglan‐din I2 (PGI2). After 24 h in EC solution, left kidneys uniformly produced significantly higher concentrations of each vasoactive substance than right kidneys: ET 1.64 ± 0.3 pg/ml vs 0.82 ± 0.1 pg/ml (P 0.009); A‐II 20.8 ± 6.2 pg/ml vs 7.75 + 2.3 pg/ml (P 0.007); TxB2, 100.8 ± 17.7 pg/ml vs 40.1 f 11.7 pg/ml (P 0.04); PGI2, 638.3 ± 41.1 pg/ml vs 318.3 ± 36.4 pg/ml (P 0.001), respectively. At 48 h, a similar pattern of results was obtained as the kidney continued to produce TxB2 and prostacyclins during the 24–48 h period. In the UW solution, basal levels of ET and A‐II were lower than those in EC solution, but similarly increased after initial ischemia. At 24 h, the concentrations produced by the left and right kidneys were as follows: ET 0.66 ± 0.1 pg/ml vs 0.48 ± 0.1 pg/ml (P 0.14); A‐II 10.36 f 3.7 pg/ml vs 2.14 ± 0.7 pg/ml (P 0.006); TxB2 178 ± 53 pg/ml vs 52 ± 23.1 pg/ml (P 0.001); and PGI2 448.3 ± 49 pg/ml vs 323 ± 44.3 pg/ml (P 0.01), respectively. After 48 h, the range of concentrations of each substance was similar to that obtained after 24 h. In further studies, the concentrations of ET and A‐II were measured in solution previously used to preserve human kidneys (n=7). The mean concentration of ET and A‐II in these samples was 3.82 ± 1.14 pg/ml and 21.3 ± 9.2 pg/ml, respectively, whereas in control media both substances were below the limits of detection. These results demonstrate that vaso‐constrictive substances can be measured in the preservation media after a kidney has been stored cold and that higher concentrations are found when the organ has been subjected to prior normothermic ischemia. The measurement of these vasoactive substances before transplantation may reveal that the kidney has been subjected to previous ischemic events. Moreover, these vasoactive substances could be involved in the early recovery of renal function after kidney transplantation.

Utility of xenografts: Lack of correlation between PRA and natural antibodies to swine

Abstract: Among the patients that might potentially benefit from the availability of xenografts are those in kidney failure who demonstrate high levels of antibody reactivity to panels of typing lymphocytes. Such individuals with high PRA (panel reactive antibody) are unlikely to receive a renal allograft because they are highly sensitized to the vast majority of potential donors. In addition, all humans have demonstrable levels of natural antibodies reactive to distantly related species such as the pig. If there were a correlation between PRA and levels of natural antibodies, then such patients would also be at greater risk for hyperacute rejection of xenografts. We have therefore examined, in a blinded fashion, the porcine lymphocyte reactivity of sera from PRA positive donors. Subsets of the 105 sera tested were grouped by PRA level and analyzed for levels of natural antibodies detectable by a complement‐dependent cytotoxicity assay on porcine lymphocytes. There was no significant difference in the range of titers of natural antibodies between subsets. Thus, there was no demonstrable correlation between levels of PRA and levels of natural antibodies to porcine lymphocytes.

The History of Transplantation at the Catholic University of Louvain-Belgium 1963-2003.

In 1962, Professor G. P. J. ALEXANDRE obtained a fellowship for a year of surgical research to be spent in the laboratory of the Harvard Medical School in Boston, under the direction of Professor Joseph MURRAY, in the Department of Surgery of the Peter Bent Brigham Hospital directed by Professor Francis D. MOORE. His initial U.S. contact in Boston was with Professor Roy CALNE who was packing to return to England, in whom he put his trust to look at the surviving dogs from his experiments. The dogs were receiving the BW 57322 – the actual Azathioprine (AZA) – as well as other drug combinations including Azaserine and Actinomycin D. The later drug combination was considered good enough to be used in clinical practice (Fig. 1). Therefore, Professor G. P. J. ALEXANDRE returned to Belgium with both drugs in his luggage and this good news to complete his surgical training. Since no chronic dialysis apparatus was available in the Department of Surgery at Saint Pierre Hospital in Louvain (Fig. 2), the first candidates for renal transplantation were maintained on peritoneal dialysis, performed by medical students on a voluntary basis, in 24-hour rotation. On June 3, 1963, a patient was brought in the Emergency Department with a head injury and a profound coma. Despite active resuscitation and vasopressive drugs administration, the patient presented all the signs of what MOLLARET had previously described and named ‘coma dépassé’. Professor Jean MORELLE, who was the Chief of the Department of Surgery and also The History of Transplantation at the Catholic University of Louvain Belgium 1963-2003

Atrial natriuretic factor: a protective role after acute renal ischemia? Is there room for it in kidney transplantation?

Abstract. Because of the deleterious effects of acute tubular necrosis (ATN) after kidney transplantation, the search for new and effective means of protecting the kidneys from ischemic or nephrotoxic injuries continues. The beneficial effects of hyperhydration with mannitol or furosemide infusions in renal allograft recipients have now been well documented. The recent discovery by De Bold and coworkers that hypervolemia (by atrial distension) induces the release of atrial natriuretic factor (ANF) suggests an important physiopathological, and perhaps therapeutic, role for this natriuretic peptide in kidney transplantation. In addition to providing an overview of the current knowledge about ANF and its effects on both intact and ischemically injured kidneys, the physiological role of ANF in various situations, similar to those found in kidney transplantation, is analyzed. The effects of ANF on arachidonic acid metabolites and on the nephrotoxic side effects of cyclosporin are also reported. If the results of the preliminary experimental studies appear to be effective, further prospective clinical trials must be carried out to confirm them.

Prevention of rejection with BTI-322 after renal transplantation (results at 9 months).

Abstract BTI-322, a rat IgG2b, anti-CD2 monoclonal antibody that binds to all human T and natural killer (NK) cells,1 was first administered to renal allograft recipients either on a compassionate-use basis or for treatment of the first episode of acute renal allograft rejection.2 In all cases, the drug was well tolerated, with no evidence of undesirable side effects; significant clinical benefit was shown in each case with a minimally effective dose of 5 mg/d. Moreover, in vitro data showed that BTI-322 can induce antigen-specific hyporesponsiveness. Therefore, we conducted a randomized study to evaluate the efficacy of BTI-322 in preventing first renal allograft rejection.