Cyclosporine nephrotoxicity in type 1 diabetic patients. A 7-year follow-up study.
(17/6121)
OBJECTIVE: To evaluate kidney function 7 years after the end of treatment with cyclosporine A (CsA) (initial dosage of 9.3 tapered off to 7.0 mg.kg-1.day-1) in young patients (mean age 20 years) with newly diagnosed type 1 diabetes participating in a randomized, double-blind, placebo-controlled CsA trial. RESEARCH DESIGN AND METHODS: In this study, 21 patients received CsA for 12.5 +/- 4.0 months (mean +/- SD) and 19 patients received placebo for 14.4 +/- 3.8 months. The two groups were similar with regard to mean arterial blood pressure (BP), urinary albumin excretion rate (UAER), serum creatinine, and estimated glomerular filtration rate (GFR [Cockcroft and Gault]) at initiation of CsA treatment (baseline). HbA1c (mean +/- SEM) during 7 years of follow-up was also the same: 8.7 +/- 0.4 vs. 8.3 +/- 0.4% in the CsA and placebo groups, respectively. RESULTS: During the 7 years after cessation of study medication, two CsA group patients and one control patient were lost to follow-up. One placebo-treated patient developed IgA nephropathy (biopsy proven) and was excluded. Four CsA-treated patients developed persistently elevated UAER > 30 mg/24 h (n = 3 with microalbuminuria), whereas all the 17 placebo-treated patients had normal UAER (< 30 mg/24 h) after 7 years of follow-up. At the end of follow-up, the CsA group had a more pronounced rise in UAER: 2.5-fold (95% CI 1.4-4.5) higher than baseline value vs. 1.1-fold (0.7-1.7) in the placebo-treated group (P < 0.05). Estimated GFR (ml.min-1.1.73 m-2) declined from baseline to end of follow-up (1994) by 6.3 +/- 6.0 in the former CsA group, whereas it rose by 7.4 +/- 5.0 in the placebo group (P = 0.05). In 1994, 24-h blood pressure was nearly the same: 131/77 +/- 4/2 vs. 127/75 +/- 2/2 mmHg (NS) in the CsA and placebo groups, respectively. Five randomly selected CsA-treated patients had a kidney biopsy performed shortly after the CsA treatment was stopped. Interstitial fibrosis/tubular atrophy and/or arteriolopathy were present in two subjects who both subsequently developed persistent microalbuminuria. CONCLUSIONS: The results of our 7-year follow-up study suggested that short-lasting CsA treatment in young, newly diagnosed type 1 diabetic patients accelerated the rate of progression in UAER and tended to induce a loss in kidney function. Longer term follow-up is mandatory to clarify whether CsA-treated patients are at increased risk of developing clinical nephropathy. (+info)
The subtype 2 of angiotensin II receptors and pressure-natriuresis in adult rat kidneys.
(18/6121)
The present work examined the effects of the subtype 2 of angiotensin II (AT2) receptors on the pressure-natriuresis using a new peptide agonist, and the possible involvement of cyclic guanosine 3', 5' monophosphate (cyclic GMP) in these effects. In adult anaesthetized rats (Inactin, 100 mg kg(-1), i.p.) deprived of endogenous angiotensin II by angiotensin converting enzyme inhibition (quinapril, 10 mg kg(-1), i.v.), T2-(Ang II 4-8)2 (TA), a highly specific AT2 receptor agonist (5, 10 and 30 microg kg(-1) min(-1), i.v.) or its solvent was infused in four groups. Renal functions were studied at renal perfusion pressures (RPP) of 90, 110 and 130 mmHg and urinary cyclic GMP excretion when RPP was at 130 mmHg. The effects of TA (10 microg kg(-1) min(-1)) were reassessed in animals pretreated with PD 123319 (PD, 50 microg kg(-1) min(-1), i.v.), an AT2 receptor antagonist and the action of the same dose of PD alone was also determined. Increases in RPP from 90 to 130 mmHg did not change renal blood flow (RBF) but induced 8 and 15 fold increases in urinary flow and sodium excretion respectively. The 5 microg kg(-1) min(-1) dose of TA was devoid of action. The 10 and 30 microg kg(-1) min(-1) doses did not alter total RBF and glomerular filtration rate, but blunted pressure-diuresis and natriuresis relationships. These effects were abolished by PD. TA decreased urinary cyclic GMP excretion. After pretreatment with PD, this decrease was reversed to an increase which was also observed in animals receiving PD alone. In conclusion, renal AT2 receptors oppose the sodium and water excretion induced by acute increases in blood pressure and this action cannot be directly explained by changes in cyclic GMP. (+info)
Relationship between glomerular hyperfiltration and ACE insertion/deletion polymorphism in type 1 diabetic children and adolescents.
(19/6121)
OBJECTIVE: Glomerular hyperfiltration may predict diabetic nephropathy in type 1 diabetes, and some studies suggest that the ACE D allele is associated with diabetic nephropathy. The aim of this study was to examine a possible relationship between glomerular hyperfiltration and ACE insertion/deletion (I/D) polymorphism in type 1 diabetic children and adolescents. RESEARCH DESIGN AND METHODS: A cross-sectional study was conducted to examine the relationship between glomerular hyperfiltration and ACE (I/D) polymorphism in 76 type 1 diabetic children and adolescents without diabetic nephropathy (mean +/- SD: age 16 +/- 3 years; diabetes duration 7 +/- 4 years; age at diabetes onset 9 +/- 4 years; HbA1c 9.5 +/- 1.9%). Glomerular hyperfiltration (defined as a glomerular filtration rate [GFR] > or = 135 ml.min-1. 1.73 m-2 and by 51Cr-labeled EDTA plasma disappearance technique) and ACE I/D genotypes and plasma levels (enzyme-linked immunosorbent assay [ELISA] method) were determined. RESULTS: Of the patients, 29 (38%) displayed glomerular hyperfiltration. An association between glomerular hyperfiltration and ACE (I/D) polymorphism was observed (chi 2 = 7.09, P = 0.029) because of a reduced proportion of DD genotypes among patients with glomerular hyperfiltration (4 vs. 19; chi 2 = 6.03, P = 0.014) and not because of an excess of the II genotype (5 vs. 9; chi 2 = 0.04, P = 0.83). Age, diabetes duration, age at diabetes onset, and HbA1c were not different according to genotype. Patients with glomerular hyperfiltration had low plasma ACE levels, compared with those with normal glomerular filtration (457 +/- 157 vs. 553 +/- 186 micrograms/l; P = 0.027). CONCLUSIONS: These results suggest an unexpected association between glomerular hyperfiltration and ACE (I/D) polymorphism, characterized by a defect of the DD genotype among type 1 diabetic children and adolescents with glomerular hyperfiltration. (+info)
Validity of rapid estimation of glomerular filtration rate in type 2 diabetic patients with normal renal function.
(20/6121)
BACKGROUND: Rapid estimation of the renal function is widely used in clinical practice. METHODS: The validity of rapid estimation of renal function as well as long-term changes in renal function from the Cockcroft-Gault formula for estimation of creatinine clearance or from serum creatinine measurements was evaluated against the 51Cr-EDTA plasma clearance technique in 36 type 2 diabetic patients with normal renal function followed for 5.2 (2.7-7.5) (mean (range) years. RESULTS: Compared with 51Cr-EDTA plasma clearance the Cockcroft-Gault formula significantly underestimated glomerular filtration rate by 21%. The degree of underestimation was observed over the whole range of glomerular filtration rate studied and increased with increasing levels of isotopically measured glomerular filtration rates. Serum creatinine was not significantly associated with glomerular filtration rate. The average long-term change in renal function was significantly overestimated by the Cockcroft-Gault formula (-2.8+/-2.3 ml/min/year) compared with the measured rate (-1.5+/-2.5 ml/min/year) (P=0.002). The difference in change rate between the two methods was highest when the measured fall rates were small and tended to disappear in patients with faster fall rates. Changes in serum creatinine correlated significantly, but imprecisely, with the rate of decline of measured glomerular filtration rate (r=-0.48, P=0.003). The variability of the estimated fall rate of renal function was unacceptably high for all approaches. CONCLUSION: Valid estimates of glomerular filtration rate as well as the rate of change in glomerular filtration rate cannot be obtained by estimation of creatinine clearance from the Cockcroft-Gault formula or from serum creatinine concentration measurements in type 2 diabetic patients with normal renal function. (+info)
Augmentation of diabetes-associated renal hyperfiltration and nitric oxide production by pregnancy in rats.
(21/6121)
We tested the hypothesis that pregnancy might increase diabetes-associated nitric oxide (NO) production and renal hyperfiltration. Two weeks following i.v. streptozotocin (40 mg/kg), mean arterial pressure (MAP) was not modified by diabetes; glomerular filtration rate (GFR), renal plasma flow (RPF) and filtration fraction (FF) were higher in pregnant than in virgin controls and increased by diabetes to a greater extent in pregnant than in virgin rats. Urinary volume (UV), creatinine, albumin and sodium (UNaV) were significantly increased by diabetes. Diabetes led to an increase in renal, cardiac, aortic and uterine but not in placental NO synthase activities. Infusion of NG-nitro-l-arginine (l-NA) caused a dose-dependent reduction in GFR, RPF, plasma NO2-/NO3-, UV and UNaV; in general, diabetes increased these effects to a greater extent in pregnant than in virgin rats. l-NA increased MAP in all groups of rats but did not alter FF. Diabetes did not alter responses of thoracic aorta rings to vasoconstrictor effects of phenylephrine and the vasorelaxant effects of sodium nitroprusside but increased endothelium-dependent relaxant effects of acetylcholine. In general the effects of diabetes of 7 days duration were similar to those described above for diabetes of 14 days duration. These data suggest that diabetes-associated renal hyperfiltration and NO production are augmented by pregnancy. (+info)
Thyroid hormones modulate zinc transport activity of rat intestinal and renal brush-border membrane.
(22/6121)
Thyroid hormone status influences the Zn2+ and metallothionein levels in intestine, liver, and kidney. To evaluate the impact of thyroid hormones on Zn2+ metabolism, Zn2+ uptake studies were carried out in intestinal and renal brush-border membrane vesicles (BBMV). Steady-state Zn2+ transport in intestinal and renal cortical BBMV was increased in hyperthyroid (Hyper-T) rats and decreased in the hypothyroid (Hypo-T) rats relative to euthyroid (Eu-T) rats. In both the intestinal and renal BBMV, Hyper-T rats showed a significant increase in maximal velocity compared with Eu-T and Hypo-T rats. Apparent Michaelis constant was unaltered in intestinal and renal BBMV prepared from the three groups. Fluorescence anisotropy of diphenyl hexatriene was decreased significantly in intestinal and renal brush-border membrane (BBM) isolated from Hyper-T rats compared with Hypo-T and Eu-T rats. A significant reduction in the microviscosity and transition temperature for Zn2+ uptake in intestinal and renal BBM from Hyper-T rats is in accordance with the increased fluidity of these BBMs. These findings suggest that the increased rate of Zn2+ transport in response to thyroid hormone status could be associated with either an increase in the number of Zn2+ transporters or an increase in the active transporters due to alteration in the membrane fluidity. Thus the thyroid hormone-mediated change in membrane fluidity might play an important role in modulating Zn2+ transport activity of intestinal and renal BBM. (+info)
Excretion of progastrin products in human urine.
(23/6121)
The renal handling of carboxyamidated gastrins, NH2-terminal progastrin fragments, and glycine-extended gastrins was examined in healthy volunteers. The respective urinary clearances after a meal amounted to 0.09 +/- 0.02%, 0.17 +/- 0.04% (P < 0.05), and 0.04 +/- 0.01% (P < 0.01) of the glomerular filtration rate. During intravenous infusion of carboxyamidated gastrin-17, progastrin fragment-(1-35), and glycine-extended gastrin-17, the respective urinary clearances amounted to 0.08 +/- 0.02, 0.46 +/- 0.08, and 0. 02 +/- 0.01%, respectively, of the glomerular filtration rate. The metabolic clearance rate of the three peptides was 24.4 +/- 1.3, 6.0 +/- 0.4, and 8.6 +/- 0.7 ml. kg-1. min-1. A maximum rate for tubular transport or degradation of the peptides could not be determined, nor was a renal plasma threshold recorded. Plasma concentrations and urinary excretion rates correlated for gastrin-17 and progastrin fragment-(1-35) (r = 0.94 and 0.97, P < 0.001), whereas the excretion of glycine-extended gastrin diminished with increasing plasma concentrations. We conclude that renal excretion of progastrin products is negligible compared with renal metabolism and that renal handling of the peptides depends on their molecular structure. Hence, the kidneys exhibited a higher excretion of NH2-terminal progastrin fragments than of carboxyamidated and especially glycine-extended gastrins. (+info)
Neonatal uninephrectomy causes hypertension in adult rats.
(24/6121)
This study was designed to test the hypothesis that a reduced number of nephrons from birth leads to increased arterial pressure in adulthood. Newborn Sprague-Dawley rat pups were uninephrectomized during the first 24 h after birth. In chronically instrumented adult animals (approximately 22 wk), mean arterial pressure on a normal (0.20%)-Na+ diet was higher in uninephrectomized rats (133 +/- 2 mmHg vs. 121 +/- 2 mmHg in controls, P < 0.0001). Body weights were not significantly different, but the total kidney-to-body weight ratio was significantly reduced by 14% in adult uninephrectomized animals (P < 0.05). Glomerular filtration rate was reduced by approximately 30% in uninephrectomized rats (1.84 +/- 0.09 vs. 2.63 +/- 0.14 ml/min, P < 0.0002), and effective renal plasma flow was reduced to a lesser degree (6.37 +/- 0.38 vs. 7.87 +/- 0.51 ml/min, P < 0.03), such that the filtration fraction was also reduced (0.291 +/- 0.007 vs. 0.338 +/- 0.014, P < 0.01). After 7-10 days on a high (3.15%)-Na+ diet, arterial pressure increased more in uninephrectomized animals than in controls (20 +/- 3 vs. 1 +/- 1 mmHg, P < 0.003). Thus surgical removal of 50% of the nephrons, when done during development, caused reduced renal function and a salt-sensitive hypertension in adulthood. These data suggest that a reduced nephron endowment from birth, caused by genetic and/or perinatal environmental factors, could contribute to essential hypertension in adulthood. (+info)