Jean-Louis Bosmans

Mycophenolate mofetil versus azathioprine for prevention of acute rejection in renal transplantation (MYSS): a randomised trial

BACKGROUND Mycophenolate mofetil has replaced azathioprine in immunosuppression regimens worldwide to prevent graft rejection. However, evidence that its antirejection activity is better than that of azathioprine has been provided only by registration trials with an old formulation of ciclosporin and steroid. We aimed to compare the antirejection activity of these two drugs with a new formulation of ciclosporin. METHODS The mycophenolate steroids sparing multicentre, prospective, randomised, parallel-group trial compared acute rejections and adverse events in recipients of cadaver-kidney transplants over 6-month treatment with mycophenolate mofetil or azathioprine along with ciclosporin microemulsion (Neoral) and steroids (phase A), and over 15 more months without steroids (phase B). The primary endpoint was occurrence of acute rejection episodes. Analysis was by intention to treat. FINDINGS 168 patients per group entered phase A. 56 (34%) assigned mycophenolate mofetil and 58 (35%) assigned azathioprine had clinical rejections (risk reduction [RR] on mycophenolate mofetil compared with azathioprine 13.7% [95% CI -25.7% to 40.7%], p=0.44). 88 patients in the mycophenolate mofetil group and 89 in the azathioprine group entered phase B. 14 (16%) taking mycophenolate mofetil and 11 (12%) taking azathioprine had clinical rejections (RR -16.2%, [-157.5% to 47.5%], p=0.71). Average per-patient costs of mycophenolate mofetil treatment greatly exceeded those of azathioprine (phase A 2665 Euros [SD 586] vs Euros 184 [62]; phase B 5095 Euros [2658] vs 322 Euros [170], p<0.0001 for both). INTERPRETATION In recipients of cadaver kidney-transplants given ciclosporin microemulsion, mycophenolate mofetil offers no advantages over azathioprine in preventing acute rejections and is about 15 times more expensive. Standard immunosuppression regimens for transplantation should perhaps include azathioprine rather than mycophenolate mofetil, at least for kidney grafts.

Fibrous intimal thickening at implantation as a risk factor for the outcome of cadaveric renal allografts.

BACKGROUND During the past decade, the donor age of cadaveric renal allografts steadily increased. Because cerebrovascular injury is the main cause of death in this donor population, an increased prevalence of atherosclerotic lesions in the retrieved grafts could be anticipated. In a prospective study, we investigated the predictive value of morphologic lesions at implantation for the functional and morphologic outcome of cadaveric renal allografts at 1 1/2 years. METHODS In 50 consecutive adult recipients of a cadaveric renal allograft, under cyclosporine-based regimen, implantation biopsies and subsequent protocol biopsies at 18 months were performed, and morphometrically analyzed for the extent of glomerulosclerosis, interstitial fibrosis, and atherosclerosis. Risk factors were assessed at implantation and during the subsequent observation period of 18 months. Endpoints for this study were: the 24-hr creatinine clearance (normalized for body surface area) and the fractional interstitial volume at 1 1/2 years. RESULTS In multivariate analysis, fibrous intimal thickening at implantation (FIT) was the main determinant of the functional and morphologic outcome at 1 1/2 years. FIT represented a relative risk of 4.55 for interstitial fibrosis (95% CI=1.855-11.138), and 1.89 for impaired renal function (95% CI=1.185-3.007) at 1 1/2 years. FIT adversely affected fractional interstitial volume at 1 1/2 years (34.3 vs. 27.7%, P=0.004), as well as renal function (54 vs. 68 ml/min/1.73 m2, P=0.028). CONCLUSIONS Fibrous intimal thickening at implantation is a determinant risk factor for the functional and morphologic outcome of cadaveric renal allografts at 1 1/2 years.

Cell-Free DNA: An Upcoming Biomarker in Transplantation.

After organ transplantation, donor‐derived cell‐free DNA (ddcfDNA) can be detected in the recipients blood and urine. Different ddcfDNA quantification techniques have been investigated but a major breakthrough was made with the introduction of digital droplet PCR and massive parallel sequencing creating the opportunity to increase the understanding of ddcfDNA kinetics after transplantation. The observations of increased levels of ddcfDNA during acute rejection and even weeks to months before histologic features of graft rejection point to a possible role of ddcfDNA as an early, noninvasive rejection marker. In this review, we summarize published research on ddcfDNA in the transplantation field thereby elaborating on its clinical utility.

Renal Abnormalities in Psoriatic Patients: A Review

Numerous systemic diseases affect both skin and kidneys: autoimmune diseases (e.g. lupus, vasculitis), hematologic abnormalities, genetic disorders and others have been described (table 1). Although psoriasis is considered an immunomediated disease, it is assumed to affect the skin and joints exclusively. Psoriasis [1] is a common chronic inflammatory disorder of the skin, which affects more than 2% of people with European ancestry. Its clinical signs and severity vary among individuals and over time. Four distinct pathological alterations characterize this disorder: inflammation, hyperproliferation of the epidermis, altered maturation of the epidermis (resulting in scaling), and vascular alterations (which add to redness). In lesioned skin, polymorphonuclear leukocytes migrate from dermal vessels into the epidermis where they may form spongiform (so-called Kogoj) pustules and subcorneal (so-called Munro) microabcesses. Lesional psoriasis is also rich in activated CD4+ and CD8+ T cells, which release proinflammatory cytokines and lymphokines that stimulate keratinocyte proliferation and induce abnormal epidermal maturation. The superficial dermal plexuses in lesioned skin become lengthened, and dilated capillary loops are more characteristic of venous rather than arterial capillaries. These vascular abnormalities may persist even after treatment and clinical normalization of the epidermis. Persistence of vascular abnormalities is associated with a more rapid recurrence of the disease. Table 1. Diseases with cutaneous and renal manifestations

Magnesium loss in cyclosporine-treated patients is related to renal epidermal growth factor downregulation

BACKGROUND Cyclosporine (CsA) treatment is associated with hypomagnesaemia due to a renal Mg(2+) leak. In animal studies a role for the Mg(2+) channel TRPM6 localized in the distal convoluted tubule and stimulated by epidermal growth factor (EGF) is suggested. We hypothesize that CsA-induced hypomagnesaemia is due to a renal magnesium leak, also in patients, resulting from a downregulation of the renal EGF production, thereby inhibiting the activation of TRPM6. METHODS Renal transplant patients treated with CsA (n = 55) and 35 chronic kidney disease (CKD) patients were included. At three time points, with an interval of at least 1 month, blood and urine samples were taken to determine creatinine, Mg(2+), sodium and EGF. RESULTS Serum Mg(2+) was significantly lower in the CsA group versus the CKD group with significantly more CsA-treated patients developing hypomagnesaemia. Although the fractional excretion (FE) Mg(2+) did not differ significantly between the two groups, subanalysis of the patients with hypomagnesaemia showed a significantly higher FE Mg(2+) in CsA-treated patients compared with CKD patients (P = 0.05). The urinary EGF excretion was significantly decreased in the CsA group and was a predictor of the FE Mg(2+) in the two groups. Serum sodium was significantly decreased in the CsA group simultaneously with an increased FE Na(+). CONCLUSIONS In CsA-treated patients, the association of a low urinary EGF excretion and a decreased renal Mg(2+) reabsorption is in accordance with in vitro and animal studies. In the whole study population, log urinary EGF excretion is an independent predictor of the FE Mg(2+), supporting the role of EGF in magnesium reabsorption.

Simultaneous Kidney-Parathyroid Allotransplantation From a Single Donor After 20 Years of Tetany: A Case Report

Persistent hypocalcemia after total parathyroidectomy and autotransplantation is rare and occasionally has been treated using allotransplantation of parathyroid tissue. We present the case of a 32-year-old woman with terminal renal failure who at age 5 years underwent a first renal transplantation from a brain-dead donor. The graft was lost as a result of acute rejection. Tertiary hypoparathyroidism developed, which was treated with total parathyroidectomy and implantation in the forearm of a standardized amount of parathyroid tissue. The graft failed, and hypoparathyroidism developed. Despite a second implantation of cryopreserved autologous tissue, severe hypocalcemia persisted with a tendency for tetany. Although the patient was highly dependent on high-dose vitamin D(3) (tacalcitol) and calcium supplements, regular paresthesias and tetany developed. At age 9 years, the patient underwent a second renal transplant from a living related donor (her mother). After 18 years, the graft was lost as a result of chronic cyclosporine toxicity and angiosclerosis. Four years later, the patient underwent combined kidney and parathyroid transplantation from a local brain-dead donor. Preservation of the parathyroid glands was in University of Wisconsin solution, with cold ischemia time of 14 hours. Directly after the renal transplantation, parathyroid transplantation was performed, with implantation in the forearm of the total amount of donor parathyroid tissue. Postoperatively, there was recovery of parathyroid function, and the patient was able to discontinue vitamin D and calcium supplements after more than 20 years.

Effect of immunosuppression on damage, leukocyte infiltration, and regeneration after servere warm ischemia/reperfusion renal injury

BACKGROUND Post-ischemia/reperfusion (I/R) damage, accompanied by leukocyte infiltration, is unavoidable in renal transplantation, as is the need for immunosuppressive treatment. Influence of immunosuppressive treatment on post-I/R renal damage, nonalloimmune cellular infiltration, and regeneration is not well studied. METHODS Uninephrectomized inbred LEW rats were submitted to warm renal ischemia of 45 minutes/60 minutes, and received different immunosuppressive regimens: cyclosporine (CsA) 10 mg/kg/day subcutaneously in the neck daily, or mycophenolate mofetil (MMF) 20 mg/kg/day by daily oral gavage. Control animals underwent sham operation (unilateral nephrectomy) with immunosuppressive treatment or ischemia with vehicle administration. In addition the effect of MMF/mycophenolic acid (MPA) on renal tubule cell proliferation in culture was studied with bromodeoxyuridine incorporation. RESULTS The post-I/R interstitial cellular infiltration/proliferation consisted mainly of mononuclear leukocytes [first monocytes/macrophages (Mo/MPhi) followed by CD4+ cells]. This mononuclear cell infiltration became apparent 24 hours after injury at the time of acute tubular necrosis, and was most prominent during the phase of regeneration. Severe I/R combined with CsA aggravated morphologic damage and dysfunction, without effect on tubular cell proliferation and tubular regeneration. Early leukocyte infiltration was qualitatively and quantitatively comparable to control animals, yet decreased moderately later in time. In contrast, MMF in combination with severe I/R did not influence initial morphologic damage and dysfunction. Although the initial leukocyte infiltration was comparable to control animals, the subsequent mononuclear cell accumulation, especially CD4 T cells decreased dramatically during MMF treatment. This was concomitant with a decrease of tubular cell proliferation and hence tubular regeneration. Increasing MPA concentrations in renal tubular cell culture caused a significant decrease in total cell number, and an almost arrest of bromodeoxyuridine incorporation, as measurement of cell proliferation. CONCLUSION Immunosuppressive treatment with CsA or MMF affected significantly and in a different manner post-I/R renal morphologic damage, interstitial leukocyte, accumulation and regeneration.