Lack of benefit of early protocol biopsies in renal transplant patients receiving TAC and MMF: a randomized study.

We conducted a randomized, multicenter study to determine whether treatment of subclinical rejection with increased corticosteroids resulted in beneficial outcomes in renal transplant patients receiving tacrolimus (TAC), mycophenolate mofetil (MMF) and prednisone. One hundred and twenty-one patients were randomized to biopsies at 0,1,2,3 and 6 months (Biopsy arm), and 119 to biopsies at 0 and 6 months only (Control arm). The primary endpoint of the study was the prevalence of the sum of the interstitial and tubular scores (ci + ct)> 2 (Banff) at 6 months. Secondary endpoints included clinical and subclinical rejection and renal function. At 6 months, 34.8% of the Biopsy and 20.5% of the Control arm patients had a ci + ct score >or= 2 (p = 0.07). Between months 0 and 6, clinical rejection episodes were 12 in 10 Biopsy arm patients and 8 in 8 Control arm patients (p = 0.44). Overall prevalence of subclinical rejection in the Biopsy arm was 4.6%. Creatinine clearance at 6 months was 72.9 +/- 21.7 in the Biopsy and 68.90 mL/min +/- 18.35 mL/min in the Control arm patients (p = 0.18). In conclusion, we found no benefit to the procurement of early protocol biopsies in renal transplant patients receiving TAC, MMF and prednisone, at least in the short term. This is likely due to their low prevalence of subclinical rejection.

HDL cholesterol and TaqIB cholesteryl ester transfer protein gene polymorphism in renal transplant recipients.

Decreased serum levels of high-density lipoprotein cholesterol (HDL-C) are a well-known risk factor for coronary heart disease (CHD) in the general population and have been suggested as one of the best predictor of CHD after renal transplantation. However, very heterogeneous HDL-C levels have been reported in renal transplant recipients. In this patient population, serum HDL-C levels are determined by complex interactions between hormonal, environmental (such as a high amount of abdominal adipose tissue), and genetic factors and drugs (particularly glucocorticoids). We, therefore, evaluated the effects of the cholesteryl ester transfer protein (CETP) gene TaqIB polymorphism as well as of abdominal obesity on HDL-C levels in 78 male renal transplant recipients who were receiving azathioprine and/or ciclosporin A in combination with prednisone as immunosuppression. The patients were classified into genotypic groups according to the presence or absence of the restriction site (B1 allele or B2 allele, respectively). The distribution of CETP genotypes was similar to that previously described in the general population. Overall, HDL-C levels were 19 and 26% higher in B1B2 and B2B2 patients as compared with B1B1 homozygotes (p < 0.05), even after control for other lipid measurements. Patients with abdominal obesity (waist girth >/=93 cm) showed reduced HDL-C levels as compared with lean (waist girth <93 cm) patients (1.20 +/- 0.28 vs. 1.42 +/- 0.41 mmol/l, respectively, p < 0.01). Moreover, the HDL-C levels were markedly affected by the CETP TaqIB polymorphism in lean patients (+28 and +41% in B1B2 and B2B2 as compared with B1B1 patients, p < 0.05), but no significant difference was observed among obese patients. Significantly lower total cholesterol:HDL-C ratios were obtained in lean B2B2 homozygotes, suggesting that these patients could be less susceptible to atherosclerosis than lean B1B1 homozygotes. In addition, patients with the B1B1 genotype had more documented CHD as compared with patients carrying at least one B2 allele, supporting the protective effect of the B2 allele against CHD. In conclusion, considerable variation in HDL-C levels appears to be explained by the CETP TaqIB gene polymorphism in male renal transplant recipients, but this potential protective gene effect appears strongly reduced by concomitant abdominal obesity.

Monitoring of cytomegalovirus infections by the CD8+CD38+ T-cell subset in kidney transplant recipients.

BACKGROUND: The CD8+CD38+ T-cell subset can predict progression to acquired immune deficiency syndrome among human immunodeficiency virus-positive subjects. This T-cell subset usually increases during other active viral infections (cytomegalovirus [CMV], Epstein Barr virus). We report on its usefulness in the early detection of CMV infection in kidney transplant recipients. METHODS: Quantitation of CD8+CD38+ T cells was monitored by dual-color flow cytometry analysis on 77 patients during the posttransplantation period. Seventeen of the 52 patients at risk for CMV disease (33%) had primary infection or reactivation and three patients had herpes simplex virus infection only. RESULTS: In every patient with CMV disease, high values for the CD8+CD38+ subset were detected with a 90% positive predictive value for the primary infections. Elevated values were observed at the very first clinical signs of the viral disease or within the few preceeding days. Acute rejection episodes did not provoke false-positive results. CONCLUSION: This immunologic marker is sensitive and easily obtainable on a daily basis. It may help to direct therapy during rejection or serve as a tool for early detection of clinical viral diseases.

Prospective evaluation of pretransplant blood transfusions in cadaver kidney recipients.

BACKGROUND: A beneficial effect of pretransplant transfusions on graft survival was demonstrated in the early 1970s. In the mid-1980s, however, retrospective studies showed that transfusions had lost their graft-protective effect in the cyclosporine era. During the last 10 years, deliberate transfusion pretreatment of transplant patients has been discontinued. METHODS: Within a collaborative project of 14 transplant centers, prospective recipients of cadaver kidney grafts were randomized to receive either three pretransplant transfusions or transplants without transfusions. RESULTS; The graft survival rate was significantly higher in the 205 transfusion recipients than in the 218 patients who did not receive transfusions (at 1 year: 90+/-2% vs. 82+/-3%, P=0.020; at 5 years: 79+/-3% vs. 70+/-4%, P=0.025). Cox regression analysis showed that this effect was independent of age, gender, underlying disease, prophylaxis with antilymphocyte antibodies, and preformed lymphocytotoxins. CONCLUSIONS; Transfusion pretreatment improves the outcome of cadaver kidney transplants even with the use of modern immunosuppressive regimens.

[Development of organ transplantation in Quebec from 1985 to January 1990]. / Evolution de la transplantation d'organes au Québec de 1985 à janvier 1990.

In Québec, the first organ transplantations have been realized in 1958. Several kidney transplant programs started at that time. Cardiac, liver, pancreas and lungs programs followed and reached a full development in the eighties when Cyclosporin became available. Today, there are 4 university transplant programs in Québec (McGill, Montréal, Laval and Sherbrooke) with a total of 7 kidney, 4 liver, 4 heart, 2 pancreas and 2 lungs centers. More than 2,900 transplantations have been realized. Since 1970, organ procurement and distribution is organized by a central agency called Québec-Transplant (previously Métro-transplantation). Organ donation is done on a voluntary basis as every where in North America. More than 90% of the organs comes from cadaveric donors and more than 90% of the relatives accept organ donation. 50% of the donors have deceased from head trauma and 50% from cerebral hemorrhage. In 1989, multi-organ harvesting has been realized in 64% of the donors. Despite efforts and progresses, the number of patients awaiting an organ transplant is steadily growing and outlast the number of available organs. It is hoped that maximal utilisation of the donors and growing exchanges at a national and international level will help to solve this crucial problem.

Improved renal allograft function and survival following nonspecific blood transfusions. I. Induction of soluble suppressor factors inhibiting the mitogenic response.

A small number of blood transfusions (1-3) seems sufficient to improve the cadaveric renal allograft outcome, probably via induction of some nonspecific suppressive activity. This activity was assessed by the concanavalin A (Con A) enhancement method; when present, the response of freshly isolated patients' cells to a submitogenic dose of Con A was lowered, leading to a Con A ratio greater than 5, significantly (P less than 0.0001) higher than the one observed in normal controls or untransfused uremic patients. The correlation between this suppressive activity and graft outcome was determined. Thirty-five patients were studied over a 12-month period for graft function (creatinine level) and survival. Both parameters were significantly improved in the group of patients whose Con A ratio was greater than 5 after transfusions. A soluble suppressor factor, or factors, released into the supernatant of patients' lymphocytes cultured for 48 hr, seems responsible for this suppressive activity. Moreover this process is nonspecific, since it suppresses mitogenic response of cells isolated from normal untransfused volunteers, and could be observed when peripheral blood mononuclear cells were used, but not with purified adherent or nonadherent cells. Addition of indomethacin to the cells during the elaboration of the supernatant abolished this activity. However, amounts of PGE2 secreted into the supernatant during the 48 hr of culture could not be correlated with this suppressive activity. These findings suggest that induction of nonspecific immunosuppression by a few blood transfusions could predict a better kidney graft outcome.

Blood transfusions in renal dialysis patients. Effect on cellular immune response.

The effect of blood transfusions, given in low number (less than 5), on the immune response of renal dialysis patients was studied. A significantly lowered response of lymphocytes to mitogen stimulation was observed in patients after as few as one, two or three transfusions, depending on the patient. This led to an increased delta 48/delta 0 ratio reflected by the enhanced response of the cells following delayed addition of suboptimal dose of mitogen. There was no modification of the ratio of helper/inducer to suppressor/cytotoxic T cells subsets (OKT4/OKT8). The use of such simple in vitro tests in a strict protocol of transfusions could allow an adequate follow-up thereby limiting the risks of sensitization. These results demonstrate that important phenomena affecting patients' immune response are turned on following even a low number of transfusions in the majority of uremic patients. This could probably be related to the beneficial effects of blood transfusions on the kidney allograft survival already described.

Kidney graft survival: role of blood transfusions and lymphocytotoxic antibodies.

In 121 primary cadaver kidney grafts, a significant increase in graft survival has been observed in recipients transfused prior to transplantation, whatever the number of units received or the time of administration. This beneficial effect of blood transfusion was shown to be independent of the recipient's sex, blood group, HLA-A, B match grade and dialysis time. In longitudinal screenings, the incidence of post-transplant antibodies did not differ according to transfusion status of recipient. However, the graft survival was significantly improved in transfused patients without antibody or with an IgM anti-B (cold) antibody (95% survival at 4 years) as compared to nontransfused with the same characteristics. Patients with IgG anti-B (warm), anti-T or anti-PBL antibodies IgG/IgM shared a uniformly poor graft prognosis whether or not they had been transfused.

Influence of HLA-A and HLA-B cross-reactive antigen matching on kidney graft survival.

The presence of cross-reactive (CR) antigens of the HLA-A and B specificities between donor and recipient carries a better graft outcome than an HLA match not taking it into account. This influence of CR antigens has been observed in the case of cadaver kidneys matched only for none or one HLA antigen. If two or more antigens are matched this effect is not seen anymore. This improved graft survival could not be explained on the basis of the number of transfusion nor the incidence of cytotoxic antibodies.

Renin responsiveness to furosemide in the homotransplanted kidney.

Plasma renin activity (PRA) was measured after repetitive furosemide stimulations in 16 normotensive homotransplanted patients who previously had bilateral nephrectomies. The percentage PRA response to furosemide was very low (34%) in the immediate period after transplantation, but increased progressively with time to a level after one year (111%) which was not statistically different from age and sex matched control subjects. A significant correlation was found between the percentage PRA increase and the number of weeks after transplantation (r = 0.48, P less than 0.01). These data indicate that the juxtaglomerular cell responsiveness to furosemide is quantitatively time dependent after transplantation, and it is a factor that should be considered in the evaluation of renin-angiotensin system in such patients.

Characterization of lymphocytotoxic antibodies in renal transplantation.

Anti-B cell, anti-T cell, and antiperipheral blood lymphocyte antibodies were investigated in the sera from 115 cadaveric kidney graft recipients pre- and post-transplantation. These antibodies were characterized: optimal temperature for cytotoxicity (4 C or 22 C), immunoglobulin class (IgG or IgM), and reactivity after platelet absorption, and thereafter defined according to their influence on the graft survival. Patients with IgM anti-B cell antibodies, reacting mostly at 4 C, the activity of which could not be removed by platelet absorption, have a prognosis of the graft as good as those with no antibody, i.e., the graft function (serum creatinine and severity of rejection) at 3 years was comparable between those two groups. However, when the anti-B cell antibodies unabsorbable on platelets are of IgG class and detected at 4 C and 22 C, the graft outcome is poorer (P less than 0.025 at 3 months). A similar prognosis is observed in patients with antiperipheral blood lymphocyte antibodies of IgG or IgM class, absorbable or not on platelets (P less than 0.05). Lymphocytotoxic antibodies of the IgG class are always associated with a poor graft outcome. On another hand, the cold anti-B cell antibodies of the IgM class are not associated with graft failure but no enhancing effect could be seen.

Renal revascularization as treatment for malignant hypertension.

Twelve patients critically ill with accelerated or malignant hypertension caused by atheromatous renal artery disease were treated by renal revascularization because an intensive program of medical treatment had failed. Seven patients had unilateral stenosis, five patients had bilateral lesions. This aggressive approach was beneficial to all the patients; there was no operative mortality and morbidity was minimal. Blood pressure was adequately controlled in all 12 patients. After a mean follow-up of 42 months, renal function was improved or stable in 10 patients but had deteriorated slightly in 2. Interestingly, one patient who had a higher renin activity in his contralateral nonstenotic kidney was much improved by correction of only the stenosis. The authors recommend early surgical intervention in severe renal artery lesions in cases of accelerated or malignant hypertension refractory to vigorous medical treatment or with rapidly progressive renal failure. An occluded renal artery can be revascularized if the kidney has no gross evidence of infarction, has viable glomeruli and if distal arteries and their intrarenal branches are intact. Reduction of blood pressure and stabilization or restoration of renal function can be expected.

Restrictive antibiotherapy after renal transplantation.

Forty-two patients were followed up after 44 renal transplantations in an effort to evaluate possible benefits from the following protocol: systematic microbiologic and clinical surveillance, early and aggressive research for the cause of suspected infections, refusal to use prophylactic antibiotherapy, and selection of treatment according to the established cause of the infection. During 18,030 days of follow-up 124 infections were recorded, of which 110 were bacterial, 11 viral and 3 protozoal. Eighty originated in the urinary tract, 17 in skin wounds and 10 in the lower respiratory tract. Septicemia occurred three times, and one death due to infection was recorded. In the treatment of bacterial infections patients received antibiotics for 2486 days. Ampicillin (given for 816 days) and "minor" drugs such as sulfonamides and urinary antiseptics (given for 1036 days) were used 74.5% of the time, whereas gentamicin was used only 2.6% of the time (64 days). Combined antibacterial therapy was needed 1.2% of the time (29 days). A restrictive policy regarding anti-biotherapy seems to be beneficial to renal transplant recipients.

E1Cold cytotoxic antibodies in kidney graft recipients. / Les lymphocytotoxines froides chez les receveurs de greffe rénale

Serial serum samples from 39 renal allograft recipients were screened for cold and warm cytotoxic antibodies before and after grafting. In the group of patients who developed antibodies only after grafting, 6 had cytotoxins reactive at 37 degree C and 5 had cytotoxins reactive at 15 degree. At one year, all the patients with cold alloantibodies has functioning grafts, but none of the patients with warm antibodies had kept their graft. In three patients with cold antibodies, the cytotoxins reacted with a subpopulation of cells enriched in B lymphocytes but not with T cells eluted from nylon wool columns. This suggests that certain kinds of antibodies which appear in the blood after grafting may have enhancing properties.