Chronic rejection of mouse kidney allografts.
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BACKGROUND: Chronic renal allograft rejection is the leading cause of late graft failure. However, its pathogenesis has not been defined. METHODS: To explore the pathogenesis of chronic rejection, we studied a mouse model of kidney transplantation and examined the effects of altering the expression of donor major histocompatibility complex (MHC) antigens on the development of chronic rejection. RESULTS: We found that long-surviving mouse kidney allografts develop pathological abnormalities that resemble chronic rejection in humans. Furthermore, the absence of MHC class I or class II antigens did not prevent the loss of graft function nor alter the pathological characteristics of chronic rejection. Expression of transforming growth factor-beta (TGF-beta), a pleiotropic cytokine suggested to play a role in chronic rejection, was markedly enhanced in control allografts compared with isografts. However, TGF-beta up-regulation was significantly blunted in MHC-deficient grafts. Nonetheless, these differences in TGF-beta expression did not affect the character of chronic rejection, including intrarenal accumulation of collagens. CONCLUSIONS: Reduced expression of either class I or II direct allorecognition pathways is insufficient to prevent the development of chronic rejection, despite a reduction in the levels of TGF-beta expressed in the allograft. This suggests that the severity of chronic rejection is independent of the level of MHC disparity between donor and recipient and the level of TGF-beta expression within the allograft. (+info)
In chronic nephropathies prolonged ACE inhibition can induce remission: dynamics of time-dependent changes in GFR. Investigators of the GISEN Group. Gruppo Italiano Studi Epidemiologici in Nefrologia.
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The Ramipril Efficacy in Nephropathy Core and Follow-Up Study found that > or =36 mo of continued ramipril therapy decreased substantially the risk of end-stage renal failure (ESRF) in patients with chronic nephropathies and a urinary protein excretion rate > or =3 g/24 h. This study investigates the time-dependent changes in GFR in these patients and in control subjects who were randomized to conventional therapy during the Core period and switched to ramipril during the Follow-Up study. Analyses included 150 patients (continued ramipril: n = 74; switched to ramipril: n = 76) who had at least three GFR measurements (including baseline) during the whole observation period and a subgroup of 43 patients (continued ramipril: n = 26; switched to ramipril: n = 17) who had at least six GFR measurements, including at least three on the Core and at least three on the Follow-Up study. Ramipril (1.25 to 5 mg/d) and conventional therapy were targeted at achieving a diastolic BP below 90 mm Hg. The main efficacy variables were GFR and ESRF (need for dialysis). Analysis was by intention to treat. Throughout the study, the mean +/- SEM rate of GFR decline (deltaGFR) was significantly lower in patients continued on ramipril compared to those switched to ramipril (0.51+/-0.09 versus 0.76+/-0.10 ml/min per 1.73 m2 per mo, P<0.03). In patients on continued ramipril who had at least six GFR measured--but not in control subjects--deltaGFR progressively improved with time and, in the cohort with the longest follow-up, decreased from (in ml/min per 1.73 m2 per mo): 0.16+/-0.12 (at 18 mo) to 0.10+/-0.05 (at 60 mo). This rate was about 10-fold slower compared to patients on conventional therapy during the REIN Core study. Analyses of the individual slopes found that at the end of the follow-up, 10 of 26 patients on continued ramipril therapy had a positive deltaGFR and another 10 patients had an improvement of deltaGFR while on ramipril therapy. DeltaGFR significantly improved in parallel with a significant reduction in proteinuria. Changes in deltaGFR (P = 0.0001) and proteinuria (P = 0.04) were significantly different in the two groups. Baseline characteristics and changes in systolic and diastolic BP and 24-h urine urea and sodium excretion were comparable. The present results offer evidence that in chronic nephropathies, the tendency of GFR to decline with time can be effectively halted, even in patients with remarkably severe disease. (+info)
Resonance in the renal vasculature evoked by activation of the sympathetic nerves.
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We examined the ability of different frequencies in sympathetic nerve activity (SNA) to induce oscillations in renal blood flow (RBF). In anesthetized rabbits the renal nerves were stimulated using modulated sine patterns (base frequency 5 Hz, 5-ms duration pulses) that varied in amplitude between 0 and 10 V at a frequency between 0.04 and 1.0 Hz. The strengths of the induced oscillations in RBF were calculated using spectral analysis. Although faster rhythms in simulated SNA >0.6 Hz contributed to the level of vascular tone, 95% of the power in the frequency response curve was below this frequency, indicating a low-pass filtering/integrating characteristic of the vasculature. Frequencies <0.6 Hz were associated with increasing ability to induce oscillations in RBF. The ability of an SNA rhythm at 0.6 Hz to induce a rhythm in RBF was 21 times less than that at 0.25 Hz. At 0.16 Hz there was a distinct peak in the frequency response curve, indicating the vasculature was more sensitive in this frequency band to sympathetic stimulation. Blockade of endogenous nitric oxide by NG-nitro-L-arginine methyl ester (L-NAME; 20 mg/kg) did not alter resting RBF levels nor was the low-pass filtering/integrating characteristic of the vasculature to nerve stimulation changed (i.e., the curve was not shifted left or right); however, there was a selective increase in the sensitivity to stimulation at 0.16 Hz, i.e., larger oscillations in RBF were evoked. These results indicate an ability of SNA to induce resonant oscillations in the renal vasculature and that there may be active and passive modulators of these responses. Naturally occurring oscillations in SNA <0.6 Hz are likely to contribute to the dynamic control of RBF, ensuring it responds rapidly and with high gain to the stimuli of daily life, while filtering out the faster oscillations ensures stable glomerular filtration. (+info)
A transient increase in renal clearance of phosphate in response to continuous infusion of salmon calcitonin in rats.
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The effects of intravenous carrier-free salmon calcitonin on renal clearances of phosphate, calcium, magnesium, sodium and potassium were studied in male parathyroid-ectomized (PTX) and intact rats. Both natural and synthetic hormone, when infused at constant rates (0.005 approximately 0.5 MRC U/hr), produced a rapid increase (peaking at about 60-90 min) in phosphate clearance. However, the maximal increase was transient in nature in PTX rats. In intact rats, the phosphaturic response was somewhat more pronounced and the decline after the peak was rather modest. When a large amount (4 MRC U) of calcitonin was given in divided doses, the second dose produced a lesser extent of phosphaturia in both intact and PTX rats. The phosphaturic response was accompanied by an increase in sodium and potassium clearances in PTX rats and by an increase in potassium clearance in intact rats. A fall in the apparent clearance values for calcium and magnesium occurred and was maintained throughout the infusion period of hormone in both intact and PTX rats. In conclusion, PTX rats respond to the intravenous administration of salmon calcitonin with a transient phosphaturic response which is accompanied by parallel diuresis of sodium and potassium along with sustained retention of calcium and magnesium by the kidney. (+info)
Favorable effects of glycolate conjugation on the biodistribution of humanized antiTac Fab fragment.
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One of the major limitations of using intact immunoglobulins for targeting tumors is poor penetration into tissues. Although Fab fragments have been used because of their improved kinetics, they have undesirable high renal accumulation. In this study we tested a new approach to block renal accumulation of Fab. METHODS: We conjugated humanized antiTac Fab fragments, which are directed against the interleukin-2 receptor, with glycolate. The biodistribution, pharmacokinetics and catabolism of glycolated Fab (glyco-Fab) were evaluated at two different levels of substitution (heavy and light) compared with nonglycolated Fab in Tac-antigen-positive (ATAC4) and -negative (A431) tumor-bearing nude mice. The mice received coinjections of 125I-labeled glyco-Fab (3 microCi/1 microg) and 131I-labeled nonglycolated Fab (5 microCi/1 microg). In addition, groups of mice receiving these reagents were also coinfused with 50 mg L-lysine. RESULTS: Significantly less glyco-Fab than nonglycolated Fab accumulated in the kidney (21 versus 189 %ID/g; P < 0.001). A higher proportion of glyco-Fab was excreted into the urine in its intact form. The glyco-Fab survived longer in circulation than nonglycolated Fab. The peak tumor accumulation of glyco-Fab was 2.3-fold greater than that of nonglycolated Fab. Furthermore, the ATAC4 tumor-to-normal tissue ratio of glyco-Fab was much higher in all organs than that of nonglycolated Fab. The heavily glyco-Fab accumulated less in the kidney than the lightly glyco-Fab. The coinjected lysine reduced the renal accumulation of both nonglycolated Fab and glyco-Fab. CONCLUSION: Glyco-Fab is a promising agent because of its lower renal accumulation, higher tumor uptake and higher tumor-to-normal tissue ratio. (+info)
Endothelin mediates renal vasodilation and hyperfiltration during pregnancy in chronically instrumented conscious rats.
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Profound vasodilation of the kidneys and other nonreproductive organs transpires during early pregnancy. Because nitric oxide (NO) was found to mediate renal vasodilation and hyperfiltration in conscious pregnant rats, and endogenous endothelin (ET) was suggested to be vasodilatory in the renal circulation of nonpregnant rats, we tested whether endothelin mediates the NO-dependent changes in the renal circulation during pregnancy. Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were measured in conscious pregnant and virgin rats before and during infusion of 30 micrograms/min RES-701-1 (a selective ETB receptor subtype antagonist). Baseline GFR and ERPF were significantly increased by 35% in gravid rats relative to virgin controls. During infusion of RES-701-1, the pregnant rats responded more robustly, showing a greater decline in both GFR and ERPF such that renal function converged in the two groups of rats. ERPF also converged in pregnant and virgin rats during infusion of SB-209760, a nonselective ETA/B receptor subtype antagonist. Combined infusion of Nomega-nitro-L-arginine methyl ester [L-NAME, an NO synthase (NOS) inhibitor] and RES-701-1 reduced GFR and ERPF to levels comparable to those reached with either agent given alone, suggesting inhibition of a common vasodilatory pathway. RES-701-1 and SB-209670 significantly lowered the cGMP content of small renal arteries from gravid and virgin rats in vitro, strengthening the link between the renal endothelial ETB receptor subtype and NO. Importantly, we showed that RES-701-1 is not a direct inhibitor of NOS. We conclude that endothelin mediates the NO-dependent changes in the renal circulation of conscious rats during pregnancy. (+info)
Peripheral atherosclerosis and serum lipoprotein(a) in diabetes.
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OBJECTIVE: Serum lipoprotein(a) [Lp(a)] is strongly associated with atherosclerosis in nondiabetic individuals. To see if atherosclerosis is also associated with serum Lp(a) in both IDDM and NIDDM, we determined the correlation between the toe systolic blood pressure index (TSPI) and serum Lp(a) in tightly controlled diabetic patients without nephropathy. RESEARCH DESIGN AND METHODS: Cross-sectional study of 57 IDDM and 35 NIDDM patients. All patients had been under strict glycemic control for at least 6 months. The main outcome measure was TSPI of both lower extremities. In addition, we measured serum Lp(a) and other serum lipids, serum uric acid, total plasma homocysteine, plasma C-peptide, HbA1c, albumin excretion rate, glomerular filtration rate, BMI, abdominal fat distribution, left ventricular hypertrophy, probabilities for cardiovascular disease (CVD), and routine clinical parameters. RESULTS: TSPI was closely and independently related to serum Lp(a) in IDDM patients: R2 = 0.2999, partial P = 0.0005, and in NIDDM patients: R2 = 0.7326, partial P = 0.0030. TSPI was associated with symptoms of CVD. Median serum Lp(a) concentration was normal in IDDM (45 mg/l [range 10-870]) and NIDDM (72 mg/l [11-803]) patients. CONCLUSIONS: Systemic atherosclerosis measured as the degree of peripheral occlusive arterial disease is strongly associated with serum Lp(a) in both IDDM and NIDDM patients. Serum Lp(a), however, is normal in both types of diabetic patients. Thus, it is indicated that serum Lp(a) should be measured in diabetic patients when assessing their risk profile for atherosclerosis. (+info)
Severity of glomerulopathy predicts long-term urinary albumin excretion rate in patients with type 1 diabetes and microalbuminuria.
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OBJECTIVE: To investigate whether the degree of glomerular structural lesions in young patients with type 1 diabetes and microalbuminuria was associated with urinary albumin excretion rate (AER) 6 years later and whether the AER level was influenced by blood glucose control, blood pressure, or glomerular filtration rate (GFR). RESEARCH DESIGN AND METHODS: There were 17 young adults with type 1 diabetes and microalbuminuria, 8 men and 9 women with mean age 20 years (95% CI: 18-22) and duration of diabetes of 11 years (10-13), who participated in a 6-year prospective study. Kidney biopsies (measurements of basement membrane thickness [BMT] and mesangial and matrix volume fractions) and GFR were performed at baseline. AER and HbA1c were measured at least three times a year and blood pressure once a year. RESULTS: In a multivariate analysis, baseline BMT and mean 6-year HbA1c contributed significantly to AER at the end of the study (R2 = 0.69, P < 0.01). When mesangial volume fraction replaced BMT as the independent variable, this parameter and AER at baseline predicted the AER at 6 years (R2 = 0.55, P < 0.55). Mesangial volume fraction and BMT (in separate analysis) contributed significantly to change in AER during the study. During the study, neither AER (30 micrograms/min [19-40] to 16 micrograms/min [7-90]) nor blood pressure (96 mmHg [92-102] to 95 mmHg [91-98]) changed significantly in the group. However, HbA1c was reduced from 10.3 (9.6-11.0) to 8.4% (7.8-9.1) (P < 0.01). CONCLUSIONS: In young patients with microalbuminuria, the long-term urinary AER was predicted by the degree of glomerular structural changes and associated with blood glucose control, but not with blood pressure or GFR. (+info)