Fas on renal parenchymal cells does not promote autoimmune nephritis in MRL mice.
BACKGROUND: Although Fas on pancreatic islets promotes autoimmune diabetes in mice, the role of Fas expression on kidney parenchymal cells during autoimmune disease is unknown. METHODS: To determine whether Fas on renal parenchymal cells promotes autoimmune renal destruction, we compared apoptosis and pathology in Fas-intact and Fas-deficient kidneys in an autoimmune milieu. For this purpose, we transplanted single, normal kidneys from MRL-++ (Fas-intact) mice (3 months of age) into age-matched, congenic MRL-Faslpr (Fas-deficient) recipients after removal of nephritic kidneys. These Fas-intact kidneys were compared with Fas-deficient nephritic kidneys. RESULTS: There is a progressive increase of FasL on kidney-infiltrating cells and Fas and FasL on renal parenchymal cells in MRL-++ kidneys during engraftment (0, 2, 4-6, and 8 weeks). By comparison, we detected an increase in FasL in MRL-Faslpr kidneys (3 to 5 months of age), whereas Fas was not detectable. The engagement of T cells bearing FasL with Fas expressing tubular epithelial cells (TECs) induced TEC apoptosis in vitro. However, apoptosis and pathology were similar in kidneys (MRL-++, 8 weeks postengraftment vs. MRL-Faslpr, 5 months) with equivalent amounts of FasL-infiltrating cells or FasL TECs, regardless of Fas on renal parenchymal cells. CONCLUSION: The expression of Fas on renal parenchymal cells does not increase apoptosis or promote renal disease in MRL-++ mice. We speculate that the autoimmune milieu evokes mechanisms that mask, counter, or pre-empt Fas-FasL-initiated apoptosis in MRL kidneys. (+info)
Sodium reabsorption and distribution of Na+/K+-ATPase during postischemic injury to the renal allograft.
BACKGROUND: A loss of proximal tubule cell polarity is thought to activate tubuloglomerular feedback, thereby contributing to glomerular filtration rate depression in postischemic acute renal failure (ARF). METHODS: We used immunomicroscopy to evaluate the segmental distribution of Na+/K+-ATPase in tubules of recipients of cadaveric renal allografts. Fractional excretion (FE) of sodium and lithium was determined simultaneously. Observations were made on two occasions: one to three hours after graft reperfusion (day 0) and again on post-transplant day 7. An inulin clearance below or above 25 ml/min on day 7 was used to divide subjects into groups with sustained (N = 15) or recovering (N = 16) ARF, respectively. RESULTS: In sustained ARF, the fractional excretion of sodium (FENa) was 40 +/- 6% and 11 +/- 5%, and the fractional excretion of lithium (FELi) was 76 +/- 5% and 70 +/- 2% on days 0 and 7, respectively. Corresponding findings in recovering ARF were 28 +/- 2% and 6 +/- 2% for the FENa and 77 +/- 4% and 55 +/- 3% (P < 0.05 vs. sustained) for FELi. Na+/K+-ATPase distribution in both groups was mainly basolateral in distal straight and convoluted tubule segments and collecting ducts. However, Na+/K+-ATPase was poorly retained in the basolateral membrane of proximal convoluted and straight tubule segments in sustained and recovering ARF on both days 0 and 7. CONCLUSIONS: We conclude that loss of proximal tubule cell polarity for Na+/K+-ATPase distribution is associated with enhanced delivery of filtered Na+ to the macula densa for seven days after allograft reperfusion. Whether an ensuing activation of tubuloglomerular feedback is an important cause of glomerular filtration rate depression in this form of ARF remains to be determined. (+info)
Effect of MTHFR 677C>T on plasma total homocysteine levels in renal graft recipients.
BACKGROUND: Hyperhomocysteinemia is an established, independent risk factor for vascular disease morbidity and mortality. The 5,10-methylenetetrahydrofolate reductase (MTHFR) gene polymorphism C677T has been shown to result in increased total homocysteine concentrations on the basis of low folate levels caused by a decreased enzyme activity. The effect of this polymorphism on total homocysteine and folate plasma levels in renal transplant patients is unknown. METHODS: We screened 636 kidney graft recipients for the presence of the MTHFR C677T gene polymorphism. The major determinants of total homocysteine and folate plasma concentrations of 63 patients, who were identified to be homozygous for this gene polymorphism compared with heterozygotes (N = 63), and patients with wild-type alleles (N = 63), who were matched for sex, age, glomerular filtration rate (GFR), and body mass index, were identified by analysis of covariance. The variables included sex, age, GFR, body mass index, time since transplantation, folate and vitamin B12 levels, the use of azathioprine, and the MTHFR genotype. To investigate the impact of the kidney donor MTHFR genotype on total homocysteine and folate plasma concentrations, a similar model was applied in 111 kidney graft recipients with stable graft function, in whom the kidney donor C677T MTHFR gene polymorphism was determined. RESULTS: The allele frequency of the C677T polymorphism in the MTHFR gene was 0.313 in the whole study population [wild-type (CC), 301; heterozygous (CT), 272; and homozygous mutant (TT), 63 patients, respectively] and showed no difference in the patient subgroups with various renal diseases. The MTHFR C677T gene polymorphism significantly influenced total homocysteine and folate plasma concentrations in renal transplant recipients (P = 0.0009 and P = 0.0002, respectively). Furthermore, a significant influence of the GFR (P = 0.0001), folate levels (P = 0.0001), age (P = 0.0001), body mass index (P = 0.0001), gender (P = 0.0005), and vitamin B12 levels (P = 0.004) on total homocysteine concentrations was observed. The donor MTHFR gene polymorphism had no influence on total homocysteine and folate levels. Geometric mean total homocysteine levels in patients homozygous for the mutant MTHFR allele were 18.6 micromol/liter compared with 14.6 micromol/liter and 14.9 micromol/liter in patients heterozygous for the MTHFR gene polymorphism and those with wild-type alleles (P < 0.05 for TT vs. CT and CC). Geometric mean folate levels were lower in CT and TT patients (11.2 and 10.2 nmol/liter) compared with CC patients (13.6 nmol/liter, P < 0.05 vs. CT and TT). CONCLUSIONS: This study demonstrates that homozygosity for the C677T polymorphism in the MTHFR gene significantly increases total homocysteine concentrations and lowers folate levels in kidney graft recipients, even in patients with excellent renal function (GFR more than median). These findings have important implications for risk evaluation and vitamin intervention therapy in these patients who carry an increased risk for the development of cardiovascular disease. (+info)
Flow-mediated vasodilation and distensibility of the brachial artery in renal allograft recipients.
BACKGROUND: Alterations of large artery function and structure are frequently observed in renal allograft recipients. However, endothelial function has not yet been assessed in this population. METHODS: Flow-mediated vasodilation is a useful index of endothelial function. We measured the diameter and distensibility of the brachial artery at rest using high-resolution ultrasound and Doppler frequency analysis of vessel wall movements in the M mode. Thereafter, changes in brachial artery diameter were measured during reactive hyperemia (after 4 min of forearm occlusion) in 16 cyclosporine-treated renal allograft recipients and 16 normal controls of similar age and sex ratio. Nitroglycerin-mediated vasodilation was measured to assess endothelium-independent vasodilation. Brachial artery blood pressure was measured using an automatic sphygmomanometer, and brachial artery flow was estimated using pulsed Doppler. RESULTS: Distensibility was reduced in renal allograft recipients (5.31 +/- 0. 74 vs. 9.10 +/- 0.94 x 10-3/kPa, P = 0.003, mean +/- sem), while the brachial artery diameter at rest was higher (4.13 +/- 0.14 vs. 3.25 +/- 0.14 mm, P < 0.001). Flow-mediated vasodilation was significantly reduced in renal allograft recipients (0.13 +/- 0.08 vs. 0.60 +/- 0.08 mm or 3 +/- 2 vs. 19 +/- 3%, both P < 0.001). However, nitroglycerin-mediated vasodilation was similar in renal allograft recipients and controls (0.76 +/- 0.10 vs. 0.77 +/- 0.09 mm, NS, or 19 +/- 3 vs. 22 +/- 2%, NS). There were no significant differences in brachial artery flow at rest and during reactive hyperemia between both groups. The impairments of flow-mediated vasodilation and distensibility in renal allograft recipients remained significant after correction for serum cholesterol, creatinine, parathyroid hormone concentrations, end-diastolic diameter, as well as blood pressure levels, and were also present in eight renal allograft recipients not treated with cyclosporine. Flow-mediated vasodilation was not related to distensibility in either group. CONCLUSIONS: The results show impaired endothelial function and reduced brachial artery distensibility in renal allograft recipients. The impairments of flow-mediated vasodilation and distensibility are not attributable to a diminished brachial artery vasodilator capacity, because endothelium-independent vasodilation was preserved in renal allograft recipients. (+info)
A prospective, randomized trial of tacrolimus/prednisone versus tacrolimus/prednisone/mycophenolate mofetil in renal transplant recipients.
BACKGROUND: Between September 20, 1995 and September 20, 1997, 208 adult patients undergoing renal transplantation were randomized to receive tacrolimus/prednisone (n=106) or tacrolimus/prednisone/mycophenolate mofetil (n=102), with the goal of reducing the incidence of rejection. METHODS: The mean recipient age was 50.7+/-13.7 years. Sixty-three (30.3%) patients were 60 years of age or older at the time of transplantation. The mean donor age was 34.5+/-21.7 years. The mean cold ischemia time was 30.5+/-9.2 hr. The mean follow-up is 15+/-7 months. RESULTS: The overall 1-year actuarial patient survival was 94%; the overall 1-year actuarial graft survival was 87%. When the patient and graft survival data were stratified to recipients under the age of 60 who did not have delayed graft function, the overall 1-year actuarial patient survival was 97%, and the corresponding 1-year actuarial graft survival was 93%. There were no differences between the two groups. The overall incidence of rejection was 36%; in the double-therapy group, it was 44%, whereas in the triple therapy group, it was 27% (P=0.014). The mean serum creatinine was 1.6+/-0.8 mg/dl. A total of 36% of the successfully transplanted patients were taken off prednisone; 32% of the patients were taken off antihypertensive medications. The incidence of delayed graft function was 21%, the incidence of cytomegalovirus was 12.5%, and the initial and final incidences of posttransplant insulin-dependent diabetes mellitus were 7.0% and 2.9%; again, there was no difference between the two groups. CONCLUSIONS: This trial suggests that the combination of tacrolimus, steroids, and mycophenolate mofetil is associated with excellent patient and graft survival and a lower incidence of rejection than the combination of tacrolimus and steroids. (+info)
The spouse as a kidney donor: ethically sound?
A shortage of cadaver donor organs requires transplant units to examine all possible alternatives. Transplantation from living donors accounts for only approximately 10% of kidney transplants in the UK. Recent studies have shown that the results of kidney transplantation between spouses are at least as good as those of well-matched cadaver organs, but very few transplants of this type have been performed in this country so far. As part of the assessment process, the proposed donor and recipient are required to provide written statements about the issues. We reproduce here the personal statements made by one of our patients and his wife: we believe that the statements support our contention that spousal transplantation is ethically justifiable and should be more widely available. We report our early experience in Bristol with seven kidney transplants from spousal donors and we encourage other renal units in this country and elsewhere to consider this method of improving the prospects of kidney transplantation for their patients. (+info)
Incidence of analgesic nephropathy in Berlin since 1983.
BACKGROUND: Phenacetin was removed from the German market in 1986 and was replaced mainly in analgesic compounds by acetaminophen. Our objective was to examine the effect of this measure on the incidence of analgesic nephropathy in light of the changes in other end-stage renal diseases. METHODS: We therefore compared the proportion of renal diseases in all patients starting dialysis treatment during three 18-month periods: 4/1982-9/1983 (n=57); 1/1991-6/1992 (n=81); and 10/1995-3/1997 (n=76). RESULTS: On the one hand, the proportion of end-stage analgesic nephropathy decreased significantly from 30% in 1981-1982 to 21% in 1991-1992 and 12% in 1995-1997 (P=0.01). On the other hand, type II diabetes increased significantly from 7% to 22% (P=0.01) and 29%, (P=0.001). Using the chi2 distribution test to analyze the frequencies of seven diseases at three different time intervals, however, showed that the changes in renal-disease proportions between 1982-1983, 1991-1992 and 1995-1997 were not significantly independent. There was a significant median age increase from 52 years (CI0.95 44-58) in 1982-1983 to 63 (CI0.95 55-67) in 1991-1992 and 63 (CI0.95 60-66) in 1995-1997 (P=0.003) for all patients starting dialysis but not for those with analgesic nephropathy [59 (55-71) vs 64 (53-67) and 61 (50-72); n.s.]. CONCLUSION: The decrease of end-stage analgesic nephropathy since 1983 may be partially due to the removal of phenacetin from the German market in 1986. However, considering the general increase in numbers of dialysis patients, their higher age and the increased incidence of type II diabetes, the decrease in analgesic nephropathy is not a statistically significant independent variable. Altered admittance policies for dialysis treatment have yielded a new pattern of renal-disease proportion which interferes with changes in the incidence of analgesic nephropathy. (+info)
Studies on structural changes of the carotid arteries and the heart in asymptomatic renal transplant recipients.
BACKGROUND: The present study was designed to characterize early structural changes of large arteries in renal transplant recipients with no clinical evidence of cardiovascular disease and normal blood pressure values, and to analyse the relationship between arterial alterations and those of the heart. METHODS: Intima media thickness and atherosclerotic plaques of the carotid arteries as well as left ventricular geometry and function were examined in 35 asymtomatic renal transplant recipients and 29 age- and sex-matched healthy controls by high resolution B-mode ultrasound and by echocardiography. RESULTS: Intima-media thickness of the carotid arteries was significantly higher in renal transplant recipients (1.21+/-0.08 mm) than in healthy controls (0.74+/-0.04 mm) (P<0.001). Atherosclerotic plaques were found in the majority of renal transplant recipients (71% vs 14% in healthy controls, P<0.001). Left ventricular mass index was significantly increased in the group of renal transplant recipients (264+/-13 g, 146+/-7 g/m2) when compared with healthy controls (155+/-8 g, 83+/-4 g/m2) (P<0.001). Multiple regression analysis in renal transplant recipients showed that intima media thickness of the carotid arteries was significantly related to left ventricular mass index (P<0.02), but not to age, blood pressure, body mass index, serum creatinine, cholesterol and lipoprotein (a) levels. In the group of healthy controls, intima-media thickness of the carotid artery was related to age (P<0.002), but not to left ventricular mass index or the other independent variables. CONCLUSIONS: The present study documents pronounced intima-media thickening in asymptomatic renal transplant recipients. Atherosclerotic lesions are present in most renal transplant recipients with no clinical evidence of cardiovascular disease. We observed a parallelism between arterial wall thickening and left ventricular hypertrophy, although blood pressure levels were normal during haemodialysis therapy and after renal transplantation. (+info)