Pekka Häyry

A blinded, randomized clinical trial of mycophenolate mofetil for the prevention of acute rejection in cadaveric renal transplantation

Mycopehenolate mofetil (MMF) is a powerful immunosuppressant that inhibits the proliferation of T and B lymphocytes by blocking the enzyme inosine monophosphate dehydrogenase. MMF has been shown to prevent acute graft rejection in animal experiments and may have an important role in clinical renal transplantation. We conducted a prospective, double-blind, multi-center trial to compare the efficacy and safety of MMF and azathioprine within standard immunosuppressive regimen for patients receiving a first or second cadaveric renal graft. A total of 503 patients were randomized to groups receiving MMF 3 g (n=164), MMF 2 g (n=173), or azathioprine (AZA) 100-150 mg (n=166) daily. All were treated simultaneously with equivalent doses of cyclosporine and oral corticosteroids and followed for 12 months. The primary endpoint was treatment failure, defined as the occurrence of biopsy-proven graft rejection, graft loss, patient death, or discontinuation of the study drug during the first 6 months after transplantation. Treatment failure occurred in 50.% of patients in the AZA group by 6 months after transplantation, compared with 34.8% in the MMF 3g group (P=0.0045) and 38.2 % in the MMF 2g group (P=0.0287). Biopsy-proven rejection occurred in 15.9% of patients in the MMF 3 g group and 19.7% in the MMF2 g group, compared with 35.5% in the AZA group. Rejection of histologic severity grade II or more developed in 6.1 %, 10.4% and 19.9% of patients in the MMF 3 g, MMF 2 g, and AZA groups, respectively. Patients receiving MMF required less frequent and less intensive treatment for acute rejection: 24.4% of patients on MMF 3 g and 31.0% on MMF 2 g were tested for acute rejection, compared with 47.5% on AZA. Only 4.9% on MMF 3 g and 8.8% on MMF 2 g required antilymphocyte antibodies for treatment of severe or steroid-resistant rejection, compared with 15.4% of the patients on AZA. At 1 year after transplantation, graft survival in the MMF groups was marginally superior to that in the AZA group, although this difference was not statistically significant. Gastrointestinal toxicity and tissue-invasive cytomegalovirus infection were more common in the MMF 3 g group. Noncutaneous malignancies occurred in six patients on MMF 3 g, three patients on MMF 2 g, and four patients on AZA. Lymphoproliferative disorders occurred in two patients per MMF group, compared with one patient receiving AZA. MMF appears to be an important advance in prophylaxis following renal transplantation. It is associated with a significantly lower rate of treatment failure compared with AZA during the first 6 months after renal transplantation and produces a clinically important reduction in the incidence, severity, and treatment of acute graft rejection. These differences persist throughout the first year of follow-up. Clinical benefit was greatest with a dose of MMF 3 g/day, but gastrointestinal effects, invasive cytomegalovirus infection, and malignancies were slightly more common at that dose. The appropriate dose may lie between 2 g and 3 g per day and may require individualization depending on clinical course or other factors.

Antibody-mediated rejection criteria - an addition to the Banff 97 classification of renal allograft rejection.

Antibody‐mediated rejection (AbAR) is increasingly recognized in the renal allograft population, and successful therapeutic regimens have been developed to prevent and treat AbAR, enabling excellent outcomes even in patients highly sensitized to the donor prior to transplant. It has become critical to develop standardized criteria for the pathological diagnosis of AbAR. This article presents international consensus criteria for and classification of AbAR developed based on discussions held at the Sixth Banff Conference on Allograft Pathology in 2001. This classification represents a working formulation, to be revisited as additional data accumulate in this important area of renal transplantation.

The desmoid syndrome. New aspects in the cause, pathogenesis and treatment of the desmoid tumor.

Based on a detailed clinical and laboratory investigation of 89 patients with histologically verified desmoid tumor and the pertinent medical literature, we have reviewed the etiologic factors, clinical characteristics, and results of treatment of this rare disorder. The incidence of the tumor in the Finnish population is low, 2.4 to 4.3 new cases per 10(6) inhabitants per year. The age distribution profile demonstrated four distinct peak periods: the juvenile period, the fertile period, the middle-age period and the old-age period. The juvenile desmoid tumor is an extraabdominal tumor found in young girls, the fertile variety is an abdominal tumor found in women, the middle age variety is also overwhelmingly abdominal but the sex ratio approaches equality, whereas in the old age group, both abdominal and extraabdominal tumors are equally frequent and the sex ratio is equal. In all male patients, the growth rate was low. A low growth rate was also recorded in young girls. A growth rate of twice that speed was seen in fertile women and four times that speed in the middle age group. In the old age group, a low growth rate, equal to that of male patients, was a rule. The fertile female patients with desmoid tumor had a significant predisposition to estrogen dominance and deviation from progesterone dominance. The direct relationship of the growth rate to the level of endogenous estrogen in the female patients and the demonstration of significant amounts of estradiol but not progesterone receptors in the tumor cytosol further suggest that the growth rate of desmoid tumor is regulated by steroid sex hormones. A significant number of patients with an abdominal desmoid tumor had a history of surgical trauma in the region of subsequent tumor growth. A very high number of the patients demonstrated multiple minor malformations of the bony skeleton. An increased frequency of these malformations was also recorded in the families of the patients and the distribution of the malformations among the family members was compatible with an autosomally dominant pattern of inheritance. After operation, the frequency of recurrence was not statistically different, regardless of whether the tumor was completely removed or not. A combination of operation and radiotherapy did not reduce the frequency of recurrences; in fact, it doubled it.(ABSTRACT TRUNCATED AT 400 WORDS)

Chronic Allograft Rejection

The short-term results of organ transplantation have significantly improved during the past few years. However, long-term success has remained on the same level as in the pre-cyclosporine era, with the half-life of a renal transplant being 7 years or more (Cho & Terasaki 1988). Although chronic rejection may not be the sole reason for transplants being lost during subsequent years, there is good recent evidence indicating that it is a leading cause in late graft failure (Kirkman et al. 1982, Mahony & Sheil 1987, Dennis et al. 1989). There are several recent publications (Paul & Solez 1991, Paul & Fellstrom 1992, Foegh 1990, Tilney et al. 1991, Adams & Tilney 1989, Fellstrom et al. 1989a) that give good overviews on different clinical and biological parameters of chronic allograft rejection. In this communication we will primarily concentrate on our own experience.

PHASE-I CLINICAL TRIAL OF MONOCLONAL ANTIBODY IN TREATMENT OF GASTROINTESTINAL TUMOURS

A phase-I clinical trial of a murine monoclonal antibody that specifically suppresses growth of human gastrointestinal tumours in athymic mice was conducted in four patients, who were given 15-200 mg purified antibody. The monoclonal antibody persisted in the circulation for more than a week when more than 15 mg was given. Antibodies against mouse immunoglobulin developed in three of the four patients. In one patient who received autologous mononuclear cells that had been mixed with monoclonal antibody by way of a hepatic-artery catheter, hepatic metastases became smaller and their echogenic characteristics changed, and there was heavier monocyte infiltration in the histological appearance of a resected metastasis.

Morphological and functional characterization of isolated effector cells responsible for human natural killer activity to fetal fibroblasts and to cultured cell line targets.

White cells of human blood (Oldham et al. 1973, Takasugi et al. 1973) and cells recovered from various lymphohematopoietic organs of experimental animals (Herberman et al. 1975a, Kiessling et al. 1975a) display spontaneous cytotoxic activity against various, mostly tumor, target cells in vitro. This cytotoxic activity, taking place in the absence of known presensitization, has been termed natural killer (NK) cytotoxicity. Because the natural killer phenomenon can most readily be demonstrated by using cultured tumor cells as targets, it has been suggested that the phenomenon may be linked to surveillance against cancer (Kiessling et al. 1975c, 1976a, Jondal et al. 1978). Numerous attempts have been made to characterize the effector cells responsible for the NK activity. Fractionation procedures utilizing different surface antigens, surface markers and functional properties of lymphohematopioetic cells have been employed (Herberman et al. 1975b, Kiessling et al. 1975b, Herberman et al. 1977, Kiuchi & Takasugi 1976, Jondal & Pross 1975, Vose & Moore 1977, West et al. 1977, Eremin et al. 1978, Bakacs et al. 1977,

Fractionation, morphological and functional characterization of effector cells responsible for human natural killer activity against cell-line targets

Abstract Human natural killer cells cytotoxic against cell-line target cells (NK-CLT) were isolated and characterized by utilizing adsorption-elution of the effector cells from the K-562 target cells. The cell associated with the cytotoxicity was a large lymphocyte with pale and characteristically granular cytoplasm. Thus, its morphology was identical with that of the large granular lymphocyte (LGL) previously shown to be the principal cytotoxic NK cell against fetal fibroblasts (NK-FF). The association of LGL with natural killer activity was verified with contact analysis from mixtures of unfractionated effector cells and target cells, which revealed that the number of contact of LGL with K-562 was correlated to the level of the individually expressed intensity of natural cytotoxicity. The ANAE-staining distribution of LGL was intensively positive with granular or diffuse staining pattern. In direct surface marker analysis LGL were E-rosette forming but, in contrast to NK-FF, heterogenous in regard to the Fc receptors. During in vitro incubation after elution from the target cells, the cytotoxic activity of LGL increased several fold. Also, the presence of K-562 among unfractionated effector cells caused an augmentation of cytotoxicity. This phenomenon was not observed as a result of effector cell-fetal fibroblast coculturing. Evidence from fetal fibroblast adsorption-elution and aggregated IgG blocking experiments suggested that the LGL with strong expression of Fc receptors were initially cytotoxic “mature” NK-cells, whereas the LGL with a weak expression of Fc receptors were initially noncytotoxic, but contact with K-562 “augmented” or “recruited” them to nonselective cytotoxicity.

Sirolimus‐Based Therapy Following Early Cyclosporine Withdrawal Provides Significantly Improved Renal Histology and Function at 3 Years

Graft function and histology are predictive of renal transplant survival. The Rapamune Maintenance Regimen study demonstrated that early cyclosporine (CsA) withdrawal from a sirolimus (SRL)‐CsA‐steroid (ST) regimen improved renal function and blood pressure. We report the protocol‐mandated biopsy findings from that study. Renal transplant patients (n = 430) receiving SRL‐CsA‐ST were randomized at 3 months after transplantation to remain on SRL‐CsA‐ST, or to have CsA withdrawn (SRL‐ST group). Protocol‐mandated biopsies were performed at engraftment and at 12 and 36 months. Two pathologists blindly evaluated 484 biopsies to obtain the Chronic Allograft Damage Index (CADI) scores. At 36 months among patients with serial biopsies (n = 63), the mean CADI score was significantly lower with SRL‐ST(4.70 vs. 3.20, p = 0.003), as was the mean tubular atrophy score (0.77 vs. 0.32, p < 0.001). All six components of the CADI score were numerically lower in SRL‐ST group; moreover, inflammation and the tubular atrophy scores decreased significantly in the SRL‐ST group between 12 and 36 months. The calculated glomerular filtration rate at 36 months was significantly better in the CsA‐withdrawal group (54.8 vs. 68.2 mL/min, p = 0.009). In conclusion, withdrawing CsA from the SRL‐CsA‐ST regimen resulted in improved renal histology and function.

Histological chronic allograft damage index accurately predicts chronic renal allograft rejection.

Chronic rejection has emerged as a major problem in renal transplantation, and clinical trials for prophylaxis and therapy are underway. Use of graft and patient survival as endpoints in prophylactic studies requires long follow-ups to read the endpoint. There is also an obvious need for a starting point for intervention studies. Previously, we formed a histological chronic allograft damage index (CADI), based on numerical scoring of histological alterations compatible with chronic rejection. Using protocol core needle biopsies of 89 functioning grafts 2 years after transplantation and a follow-up of 6 years, we demonstrate now that (a) the CADI at 2 years correlates significantly (r=0.717, P=0.0001) with transplant function at 6 years, and (b) that the CADI at 2 years reliably (P=0.001) predicts the patients who will proceed to clinical chronic rejection later. As protocol core biopsy is an early predictive parameter for chronic rejection, our results suggest that a protocol core biopsy (at 2 years or possibly even earlier) should be included in all clinical investigative protocols dealing with chronic renal allograft rejection.

Chronic rejection in rat aortic allografts. An experimental model for transplant arteriosclerosis.

Chronic rejection has several histological appearances, depending on the type of organ graft. Common to all of them is transplant arteriosclerosis associated with an ongoing inflammatory response in the transplanted graft. To the contrary of classical atherosclerosis, in which the manifestations are mostly focal, proximal, and asymmetric, transplant arteriosclerosis is generalized, and the intimal thickening is concentric. In this article, we describe an experimental animal model whereby transplant arteriosclerosis may be investigated in the inbred rat. Aortic allografts were transplanted from DA (RTIa) to major histocompatibility complex-incompatible WF (RTIv) rats or, for control, to rats of the DA strain. Transplantation was followed by an acute inflammation episode in the aortic adventitia of the allograft, largely lacking in the syngeneic graft, with a prominence of lymphoid activation markers (Cd25) in the cells of the inflammatory infiltrate. The inflammation episode peaked at 2 months after transplantation, became attenuated, and was followed by a proliferative response of myocytes in the allograft media. An increase in the migration of myocytes to the subendothelial space (presumably through small breaks generated in the internal elastic lamina) was observed thereafter, and myocyte proliferation continued in the intima with some intermingled macrophages. Finally, necrosis and disappearance of myocytes and their replacement by fibrous tissue were observed in the media. These alterations are virtually identical with the vascular lesion of chronically rejecting parenchymal organ transplants in human subjects. We suggest that aortic allografts exchanged between histoincompatible rat strains may be used as an experimental model for transplant arteriosclerosis.