Guy P. Alexandre

Long-Term Effect of HbS Antigenemia on Patient Survival after Renal Transplantation

We studied 121 renal-graft recipients to delineate the effects of HBs antigenemia on patient and graft survival. Grafts had functioned for at least six months; follow-up periods averaged 37 months. Mortality was significantly higher (P less than 0.05) in the HBs Ag-positive (17 deaths among 61 patients) than in the HBs Ag-negative group (eight of 60 patients). Patient and graft survivals, from six months onwards, were significantly lower at four years in the positive (64 and 60 per cent respectively) than in the negative group (87 and 80 per cent respectively). These differences resulted solely from a fivefold increase in mortality from liver disease in the positive group and were unrelated to graft rejection. HBs antigenemia did not improve graft tolerance during the first 24 months in 129 patients in whom repeated HBs Ag determinations had been obtained before operation. We conclude that HBs antigenemia has an unfavorable effect on transplant and patient survival.

Maximal Hydration During Anesthesia Increases Pulmonary Arterial Pressures and Improves Early Function of Human Renal-transplants

The recipients hemodynamic condition during anesthesia for renal transplantation has a major influence on the early diuresis of the graft. The effect of maximal hydration during operation was studied in a series of 120 primary human cadaver kidney transplantations performed under peroperative monitoring of the pulmonary arterial pressures (PAPs). The PAPs levels before and at the time of clamp release were correlated with the frequency of postoperative acute tubular necrosis (ATN). The 120 patients were divided in two groups according to the PAPs levels before release of the vascular clamps: group 1 (22 patients) with a mean PAP (PAP) of ≤ 20 mm Hg and a diastolic PAP (DPAP) of > 15 mm Hg was compared with group 2 (98 patients) with a PAP of > 20 mm Hg and a DPAP of > 15 mm Hg. Both groups were comparable with regard to the donors data and the quantity of peroperative fluids. The frequency of ATN was 36% in group 1 versus only 6% in group 2. This difference is attributed to the different hemodynamic conditions in both groups: at the beginning of the transplant procedure, PAP, DPAP, and central venous pressure (CVP) were higher in group 2; at the time of clamp release, PAP, DPAP, CVP, and systolic blood pressure (SBP) were also higher in group 2. This study emphasizes the importance of the PAPs levels at the time of release of vascular clamps to avoid postoperative ATN of a kidney transplant.

Outcome of thirty patients with Alport's syndrome after renal transplantation.

Graft antiglomerular basement membrane nephritis in patients with Alports syndrome (AS) is a unique complication related to the glomerular basement membrane (GBM) abnormality characteristic of the disease. Its prevalence and clinical significance however remain unknown. We used strict criteria of AS to select 30 patients (26 men, 4 women), aged 17 to 44 years (m: 27) in whom 35 grafts (30 first, 5 second) had been performed at our center between 1968 and 1988. Patient and graft survival were, respectively, 96 and 75% at 5 years, 77 and 42% at 10 years. Graft survival and function, as well as the incidence of rejection episodes in the AS group were not different from those of a control group without AS, matched for age, sex, graft origin, and immunosuppressive regimen. Fifteen grafts were examined by immunofluorescence at least 3 months after TP: linear IgG deposits along GBM were present in 5 cases in the absence of signs of crescentic glomerulonephritis. Circulating anti-GBM antibodies detected in one of these cases 8 months post-TP had disappeared 24 months later. The presence of linear IgG did not seem to influence graft survival and function. We conclude: (1) the overall outcome of TP in AS patients does not differ from a control group without AS; (2) appearance of linear glomerular IgG is frequent but is not necessarily associated with a poor graft out come; (3) the course of de novo graft anti-GBM disease may be benign; and (4) the aggressivity of the disease could be determined by the degree of immunosuppression and/or by the specificity of the anti-GBM antibodies.

Late Urinary-tract Infection After Transplantation - Prevalence, Predisposition and Morbidity

We have evaluated the incidence, prevalence, predisposing factors and evolution of urinary tract infection (UTI) developing late after transplantation in 63 patients whose graft had lasted at least 3 months and whose follow-up averaged 7 years. Beyond 3 months after transplantation incidence of UTI decreases progressively, from 25 to 0%, 50% of the patients remaining free of infection throughout the period of observation. Neither the original kidney disease except perhaps diabetic nephropathy nor the presence of vesicoureteral reflux were predisposing factors. Incidence and prevalence in females were twice that in male. Late UTI did not affect graft or patient survival, or graft function at 5 years. Most UTI were asymptomatic and had a benign course. However, in 3 patients septicemia or graft dysfunction ensued demonstrating the need for continuous monitoring of urine cultures.

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.

Pregnancy After Combined Pancreas-kidney Transplantation

Four successful cases of pregnancy after combined pancreas-kidney transplantation at four different centers are summarized. The techniques used for the pancreas transplantations were duct obstruction in one patient and enteric exocrine diversion in two patients; in all three patients the insulin delivery was to the systemic circulation. In one patient exocrine diversion was to the stomach and the vascular anastomosis to the splenic vessels, thus accomplishing portal insulin delivery. Immunosuppression consisted of cyclosporin and prednisolone in two patients; cyclosporin alone in one patient; and cyclosporin, azathioprine, and prednisolone in one patient. In all a cesarean section was performed, due to deteriorating renal function in two patients, a fall in fetal growth in one patient, and fear of inducing pancreas-graft pancreatitis during normal delivery in one patient. In all four women, perfect metabolic control was retained throughout the pregnancy, and despite the proximity of the pancreas graft to the growing uterus in three of the women, the pancreas grafts did not suffer any damage during the pregnancy. However, in one patient the pancreas graft was lost in acute rejection after delivery. This pancreas had functioned normally for 3 yr before this occasion. Of the offspring, one was completely normal, one had a bilateral cataract, and two were small for date. The latter two subsequently showed normal growth development. At follow-up at 3, 5, 7, and 28 mo, ail kidney grafts and three of the pancreas grafts remained functional. We conclude that after combined pancreas-kidney transplantation, successful conception and pregnancy can be obtained. Despite reduced islet mass (segmental grafts), normal metabolic control can be retained throughout the pregnancy. However, the risks of complications related to kidney- or pancreas-graft function are considerable and must be emphasized in each case in which pregnancy is considered.

Prevention of acute cyclosporine nephrotoxicity by atrial natriuretic factor after ischemia in the rat.

The present experimental study investigates whether the atrial natriuretic factor (ANF) is able to prevent the nephrotoxic effects of cyclosporine infused after 30 min of warm renal ischemia in the rat. At 2 hr after the end of ischemia, the glomerular filtration rate was improved by an ANF infusion: 390 +/- 19 microliters/min/100 g versus 298.3 +/- 31 microliters/min/100 g in ANF and saline-infused rats, respectively (P less than 0.05). Intravenous CsA infusion at a dose of 2.5 mg/kg/day produced a more pronounced fall in GFR when compared with the control: 205.4 +/- 19.7 microliters/min/100 g versus 298.3 +/- 31 microliters/min/100 g in CsA and saline, respectively (P less than 0.05). In contrast, a synthetic rat atriopeptin III (0.5 microgram/kg/min) infusion after ischemia given together with CsA prevented its deleterious effects upon GFR: 316 +/- 22 microliters/min/100 g versus 205.4 +/- 19 microliters/min/100 g in ANF/CsA versus CsA alone (P less than 0.001). Moreover, the natriuretic ANF effects remained unaffected by high plasma CsA peak levels: indeed, other parameters of renal function--urinary flow, urinary sodium concentration and excretion rates, and urinary sodium reabsorption and fractional excretion rates, were significantly increased in ANF alone or CsA/ANF groups. These preliminary results suggest that ANF may be useful in renal transplantation or in the management of patients given large doses of CsA (liver or heart transplant) since, despite nephrotoxic CsA levels (greater than 1500 ng/ml), ANF provides an improved GFR and tubular function after ischemia.

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.

Treatment of renal graft artery stenosis. Comparison between surgical bypass and percutaneous transluminal angioplasty.

In order to compare saphenous bypass (SB) and percutaneous transluminal angioplasty (PTA) as treatment of renal graft artery stenosis (GAS), we have reviewed the results of both procedures in 33 patients treated consecutively by either SB (n = 16) or PTA (n = 17). All patients had become hypertensive within the first year after transplantation despite triple hypotensive drug therapy. SB was performed 17 (range 3-55) and PTA 19 (range 2-96) months after transplantation. SB failed in only 1 patient as a result of vascular thrombosis with graft loss. PTA was technically unsuccessful in 3 patients and was complicated by vascular branch thrombosis in 1 patient. Blood pressure decrease was similar in both groups: from 179/114 before SB to 147/90 (n = 15, P less than .001) at 6 months and 150/93 (n = 14, P less than .005) at 12 months after SB and from 177/110 before PTA to 149/93 (n = 13, P less than .01) at 6 months and 150/95 (n = 10, P less than .02) at 12 months. At 1 year, control of BP was improved in 85% of SB group patients and 74% of PTA group patients. Recurrent stenosis was documented in 3 PTA group patients: subsequently 1 had a successful SB and the 2 others a repeated PTA--successful in 1, unsuccessful in the other. We conclude that both methods are equally effective for BP control but that PTA entails a higher rate of initial failure and a significant rate of restenosis. However, because of technical ease and better tolerance, PTA emerges as the first-choice treatment of GAS, SB remaining indicated when PTA is not feasible or has failed.

From ABO-incompatible human kidney transplantation to xenotransplantation1

Abstract:  The development (in 1981) of a protocol for successful renal allotransplantation across ABO barriers is outlined. From this experience, the concept of ‘adaptation’, subsequently termed ‘accommodation’, was defined. It was then hypothesized that a similar approach might allow pig‐to‐human organ xenotransplantation. This hypothesis was explored in the pig‐to‐baboon renal transplantation model, with graft survival for a maximum of 23 days. Rejection episodes were temporarily reversed, providing encouragement that discordant xenotransplantation would one day prove successful. Finally, the preparation of the thymokidney, developed as a means of inducing xenotolerance, is briefly reviewed.