Effect of intensive treatment on diabetic nephropathy in patients with type I diabetes

We evaluated the long-term effect of an intensive treatment of diabetic nephropathy (anti-hypertensive drugs, low protein diet, multiple insulin injections to achieve a good metabolic control) on glomerular filtration rate (GFR) and albumin excretion rate (AER). Fourteen type I diabetic patients (mean age 45 +/- 9.5 years, mean duration of diabetes 23.5 +/- 7.3 years, 8 males/6 females) with glomerular filtration rate < 70 ml/min-1/1.73 m2 and albumin excretion rate > 30 micrograms/min were treated intensively for 36 months. This intensive treatment consisted of multiple insulin injections, antihypertensive therapy with ACE inhibitors and a low-protein diet (0.8 g/kg body wt/day.) Renal function was evaluated as GFR and AER. HbA1c mean value decreased significantly from 8.7 +/- 0.8% to 6.5 +/- 0.5% (P < 0.0002). GFR rose from 58 +/- 12 ml/min-1/1.73 m2 to 84 +/- 11 ml/min-1/1.73 m2 (P < 0.0008). AER decreased from 208 micrograms/min (range: 73 to 500) to 63.8 micrograms/min (range 15 to 180; P < 0.05). Systolic and diastolic blood pressure decreased respectively from 144 +/- 26 mm Hg to 120 +/- 15 mm Hg and from 89 +/- 9 mm Hg to 75 +/- 8 mm Hg (P < 0.01). We obtained a rise of GFR and a reduction of proteinuria after three years of this treatment. We suggest that this intensive treatment in all patients with early stage diabetic nephropathy may be effective in slowing the progression to renal failure.     

Effect of triethylenepentaminehexaacetic acid on the renal damage in cadmium-treated Syrian hamsters

Cadmium (Cd)-induced nephropathy was treated by triethylenepentaminehexaacetic acid (TTHA) in male Syrian hamsters. Hamsters injected three times a week with 3 mg/kg body wt CdCl2 showed proteinuria, urinary N-acetyl-beta-D-inglucosaminidase (NAG), and fractional excretion of sodium (FENa) when compared to saline-injected control. Cd-treated hamsters injected ip with TTHA 10 mg/kg body wt five times a week showed reduction of renal damage, including reductions in urinary protein (from 6.7 +/- 2.2 to 4.3 +/- 0.5 mg/d) and NAG (0.17 +/- 0.06 to 0.04 +/- 0.02 U/d). Urinary excretion of Cd was significantly increased (from 87 +/- 51.3 to 3052 +/- 1485 mg/L) by TTHA administration. Cd concentration in renal cortical tissue was slightly reduced (26.4 +/- 3.0 to 21.8 +/- 2.7 mg/g. protein). Excretion of malondialdehyde (MDA) was increased only in Cd-injected hamsters (to 2.1 +/- 1.6 nM/L), and elevated MDA in renal cortical tissue was not reduced by the administration of TTHA (1041 +/- 105 vs 1104 +/- 358 nM/g protein). Glutathione (GSH) concentration in the renal cortex was significantly elevated after Cd administration and further increased after TTHA administration (5.5 +/- 2.1 to 9.8 +/- 2.0 micrograms/50 mg protein). There were no marked effects on creatinine clearance (Ccr) and hematocrit. Moreover, renal morphological changes were improved significantly by treatment with TTHA. We demonstrated the efficacy of TTHA in the treatment of Cd-induced nephropathy in hamsters. Although the precise mechanism of the TTHA effects on Cd-induced nephropathy has not been elucidated, it might involve GSH reducing the elevated MDA concentration in renal tissue.     

Proteinuria is still useful for the screening and diagnosis of overt diabetic nephropathy

OBJECTIVE: To assess the performance of urinary total protein measurements in timed 24-h urine collection (24-h UP) and in a diurnal random urine specimen (RUS) for the screening and diagnosis of overt diabetic nephropathy. RESEARCH DESIGN AND METHODS: A total of 167 diabetic patients (20 type 1 and 147 type 2 diabetic patients; 78 women and 89 men), aged 20-84 years, collected 217 timed 24-h urine specimens. Albumin was measured by immunoturbidimetry, total protein by sulfosalicylic acid technique, and creatinine by Jaffe's method. According to the timed 24-h urinary albumin excretion rate (UAER), samples were divided into three groups: normoalbuminuric (NORMO) (UAER < 20 micrograms/min; n = 84), microalbuminuric (MICRO) (UAER 20-200 micrograms/min; n = 78), and macroalbuminuric (MACRO) (UAER > or = 200 micrograms/min; n = 55). Eighty-six patients also collected 105 RUSs (NORMO, n = 47; MICRO, n = 37; MACRO, n = 21), and urinary protein concentration (UPC) and urinary protein-to-creatinine ratio (UPCR) were measured. The receiver operating characteristics (ROC) curve approach was used to analyze the performance of the diagnostic tests. RESULTS: Spearman's coefficient of correlation of 24-h UAER versus 24-h UP was 0.95 (P < 0.001), and of 24-h UAER versus UPC and UPCR were 0.77 and 0.72, respectively (P < 0.001). The calculated areas (+/- SEM) under the ROC curve for the diagnosis of over diabetic nephropathy were 0.9987 +/- 0.001 for 24-h UP, 0.9926 +/- 0.006 for UPC, and 0.9751 +/- 0.014 for UPCR. In the ROC curves, the first points with 100% sensitivity were 541 mg (95.7% specificity) for 24-h UP, 431 mg/l (92.9% specificity) for UPC, and 0.2 (76.2% specificity) for UPCR. CONCLUSIONS: Measurements of proteinuria presented almost perfect accuracy for the screening and diagnosis of overt diabetic nephropathy. Protein measurement in spot urine is a reliable and simple method for the screening and diagnosis of overt diabetic nephropathy.     

High prevalence of risk factors for cardiovascular disease in parents of IDDM patients with albuminuria

Life expectancy is shorter in the subset of insulin-dependent diabetic (IDDM) patients who are susceptible to kidney disease. Familial factors may be important. In this study the prevalence of cardiovascular disease mortality and morbidity and of risk factors for cardiovascular disease was compared in the parents of 31 IDDM patients with elevated albumin excretion rate (AER > 45 microg/min; group A) with that of parents of 31 insulin-dependent diabetic patients with normoalbuminuria (AER < 20 microg/min; group B). The two diabetic patient groups were matched for age and duration of disease. Information on deceased parents was obtained from death certificates and clinical records and morbidity for cardiovascular disease was ascertained using the World Health Organization questionnaire and Minnesota coded ECG. Hyperlipidaemia was defined as serum cholesterol higher than 6 mmol/l and/or plasma triglycerides higher than 2.3 mmol/l and/or lipid lowering therapy; arterial hypertension as systolic blood pressure higher than 140 mmHg and/or diastolic blood pressure higher than 90 mmHg and/or antihypertensive treatment. The percentage of dead parents was similar in the two groups (26 vs 20% for parents of group A vs group B, respectively), but the parents of the diabetic patients with elevated AER had died at a younger age (58 +/- 10 vs 70 +/- 14 years; p < 0.05). Parents of diabetic patients with nephropathy had a more than three times greater frequency of combined mortality and morbidity for cardiovascular disease than that of the parents of diabetic patients without nephropathy (26 vs 8%; odds ratio 3.96, 95% CI 1.3 to 12.2; p < 0.02). Living parents of group A had a higher prevalence of arterial hypertension (42 vs 14% p < 0.01) and hyperlipidaemia (49 vs 26% p < 0.05) as well as higher levels of lipoprotein (a) [median (range) 27.2 (1-107) vs 15.6 (0.2-98) mg/dl; p < 0.05]. They also had reduced insulin sensitivity [insulin tolerance test: median (range) K(itt) index: 3.7 (0.7-6.2) vs 4.8 (0.7-6.7)% per min; p < 0.05]. In the families of IDDM patients with elevated AER there was a higher frequency of risk factors for cardiovascular disease as well as a predisposition to cardiovascular disease events. This may help explain, in part, the high prevalence of cardiovascular disease mortality and morbidity in those IDDM patients who develop nephropathy.     

Steroid therapy during the early stage of progressive IgA nephropathy. A 10-year follow-up study

This study was undertaken to clarify the effect of corticosteroids on the long-term clinical course of the early stage of progressive IgA nephropathy. The early stage of progressive IgA nephropathy was defined as having moderate proteinuria between 1 and 2 g/day, creatinine clearance values of 70 ml/min or more, and a histological severity score of 7 or more. The number of patients who fulfilled these three conditions during 12 years from 1972 and then were continuously followed up for 10 years or more in our renal unit was 46. Twenty of them received steroid treatment for an average period of 18 months, and the remaining 26 patients had no steroid treatment. The initial data of proteinuria, creatinine clearance values, frequency of hypertensive cases, and histological scores of 7 or more were not different between the two groups: 1.4 +/- 0.4 vs. 1.3 +/- 0.3 g/day, 85 +/- 14 vs. 88 +/- 13 ml/min, 25 vs. 38%, and 10.7 +/- 2.5 vs. 11.0 +/- 3.0, respectively. During the follow-up period of 10 years, the renal survival rate was significantly different between the two groups (100 vs. 84% 5 years after starting therapy and 80 vs. 34% 10 years later; p < 0.001). The final creatinine clearance values were significantly different between the two groups (54 +/- 35 vs. 20 +/- 29 ml/min; p < 0.005). On the other hand, the patient groups with mild histological changes or decreased renal function due to moderate proteinuria showed no significant differences in the final outcome. These results indicate that corticosteroids are beneficial in stabilizing the renal function for a long time during the early stage of progressive IgA nephropathy, although this study was not a randomized one.     

Association of angiotensinogen gene T235 variant with progression of immunoglobin A nephropathy in Caucasian patients

Genetic variability in the renin-angiotensin system may modify renal responses to injury and disease progression. We examined whether the M235T polymorphism of the angiotensinogen (AGT) gene, the insertion/deletion polymorphism of the angiotensin-converting enzyme (ACE) gene, and the A1166--> C polymorphism of the angiotensin II type 1 receptor gene may be associated with disease progression in 168 Caucasian patients with IgA nephropathy. All patients had serial measurements of their creatinine clearance, proteinuria, and blood pressure (mean+/-SD) with a follow-up of 6.1+/-4.7 yr. The genotype frequencies for each gene were consistent with Hardy-Weinberg equilibrium, and were similar to those of 100 Caucasian control subjects. We examined two primary outcomes: (a) the rate of deterioration of Ccr, and (b) the maximal level of proteinuria. We found that patients with the AGT MT (n = 79) and TT (n = 29) genotypes had a faster rate of deterioration of Ccr than those with the MM (n = 60) genotype (i.e., median values, -6.6 and -6.2 vs. -3. 0 ml/min/yr, respectively; P = 0.01 by Kruskal-Wallis test). Similarly, patients with AGT MT and TT genotypes had higher maximal values of proteinuria than those with the MM genotype (i.e., median values, 2.5 and 3.5 vs. 2.0 g/d, respectively; P < 0.02 by Kruskal-Wallis test). Neither the ACE insertion/deletion nor angiotensin II type I A1166--> C gene polymorphism was associated with disease progression or proteinuria in univariate analysis. Multivariant analysis, however, detected an interaction between the AGT and ACE gene polymorphisms with the presence of ACE/DD polymorphism adversely affecting disease progression only in patients with the AGT/MM genotype (P = 0.008). Neither of these gene polymorphisms was associated with systemic hypertension. Our results suggest that polymorphisms at the AGT and ACE gene loci are important markers for predicting progression to chronic renal failure in Caucasian patients with IgA nephropathy.     

The use of the Micral-Test strip to identify the presence of microalbuminuria in people with insulin dependent diabetes mellitus (IDDM) participating in the EUCLID study

In IDDM, microalbuminuria (urinary albumin excretion rate (AER) of 20-200 micrograms/min) is a predictor of persistent proteinuria and diabetic nephropathy. Early intervention may prevent or reduce the rate of progression of renal complications. The Micral-Test strip can be used to establish a semi-quantitative estimate of AER. We assessed the field performance of the Micral-Test strip in detecting microalbuminuria in the EUCLID study, an European wide, 18 centre study of 530 IDDM participants, aged 20 to 59 years. People with macroalbuminuria were excluded. On entry, all participants had albumin concentrations from two overnight urine collections measured by a central laboratory, and the corresponding Micral-Test performed on the two collections locally. a cut off of > or = mg/l albumin from the first Micral-Test, to detect a centrally measured albumin concentration > or = 20 mg/l, yielded 29 (5.8%) false negative results and 58 (11.6%) false positive results (sensitivity 70%, specificity 87%). The mean AER, from two collections, was compared with the corresponding 'pooled' Micral-Test results (mean of the two readings). Receiver Operating Characteristic (ROC) curves were used to assess if there was a suitable 'pooled' Micral-Test result for screening microalbuminuria. A 'pooled' Micral-Test result (> or = 15 mg/l) was used to detect mean AER > or = 20 micrograms/min (sensitivity 78%, specificity 77%). This 'pooled cut-off' had already been used for screening on to the study and led to an over-estimate (154 vs. 77) of the true number of microalbuminuric participants on the study. In conclusion, our findings suggest that the Micral-Test strip is not an effective screening tool for microalbuminuria, using the 'pooled' result from two measurements did not improve the sensitivity of the test.     

Immune response to glycated and oxidized LDL in IDDM patients with and without renal disease

OBJECTIVE: To study autoantibodies to oxidized and glycated LDL in IDDM patients with and without diabetic nephropathy and in nephropathy-related macroangiopathy RESEARCH DESIGN AND METHODS: The study included 101 IDDM patients with a long duration of diabetes and 54 healthy subjects. Patients were divided into two groups according to their median urinary albumin excretion rate (AER); the normoalbuminuric group had AER <20 microg/min and the albuminuric group >200 microg/min. The groups were matched for age and BMI, and the two diabetic groups were matched for duration of diabetes and glycemic control. Antibodies against oxidized LDL (using malondialdehyde-modified LDL as the antigen) and against glycated LDL were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: The mean antibody levels against glycated LDL were higher in IDDM patients (0.305 +/- 0.399) than in healthy subjects (0.166 +/- 0.22 optical density [OD]; P = 0.019), but levels did not differ significantly between normoalbuminuric and albuminuric IDDM patients (0.258 +/- 0.354 vs. 0.388 +/- 0.459, respectively). Among the three groups, antibody levels to oxidized LDL did not differ. IDDM patients showed an inverse correlation between antibodies to oxidized LDL and HbA1 (r = -0.211, P = 0.04). The antibody levels to glycated and oxidized LDL did not differ among albuminuric IDDM patients with or without clinical macroangiopathy. CONCLUSIONS: Antibodies to glycated and oxidized LDL do not seem to associate with diabetic nephropathy or nephropathy-related macroangiopathy.     

Enhanced renal vitamin-K-dependent gamma-glutamyl carboxylase activity in experimental rat urolithiasis

OBJECTIVE: To investigate the role of glycemic control and blood pressure in the development and progression of nephropathy and to suggest goals for glycemic control and blood pressure for the prevention of nephropathy in elderly Japanese NIDDM patients. RESEARCH DESIGN AND METHODS: A total of 123 age- and diabetes duration-matched elderly Japanese NIDDM patients (aged 60-75 years; 74 normoalbuminuric and 49 microalbuminuric) were retrospectively studied for 6 years. RESULTS: The group that developed microalbuminuria from normoalbuminuria (group NM: n = 24) showed a higher 6-year mean HbA1c than the group that remained normoalbuminuric (group NN: n = 50; 9.0 +/- 0.8 vs. 8.1 +/- 0.8%, P < 0.01) in spite of no significant difference in 6-year mean blood pressure (MBP). On the other hand, the group that progressed from microalbuminuria to overt proteinuria (group MP: n = 26) showed a higher 6-year MBP than the group that remained microalbuminuric (group MM: n = 23; 106 +/- 5 vs. 95 +/- 6 mmHg, P < 0.01) in spite of no significant difference in 6-year mean HbA1c. The cutoff level of HbA1c separating group NN from group NM was 8.5% (normal range < or = 6.5%), and that of MBP separating group MM from group MP was 100 mmHg. CONCLUSIONS: Glycemic control is a more potent factor than blood pressure level on the development of microalbuminuria. However, as far as the progression of microalbuminuria to overt proteinuria is concerned, hypertension is the most crucial factor in elderly NIDDM patients. Suggested goals for glycemic control and blood pressure level for the prevention of nephropathy in elderly Japanese patients are an HbA1c of < or = 8.5% (equivalent to 7.8% in the current measurement of stable HbA1c; normal range < or = 5.8%) and an MBP of < or = 100 mmHg.     

Interobserver variability in recognizing arousal in respiratory sleep disorders

BACKGROUND: The study was designed to investigate the influence of haemodialysis on the pharmacokinetics of the non-ionic contrast medium iopentol and the outcome of radiocontrast nephropathy in patients at risk undergoing angiography. METHODS: We prospectively studied 30 patients with reduced renal function (mean serum creatinine concentration (+/- SEM), 2.4 +/- 0.16 mg/dl (212 +/- 14 mumol/l)). Patients were randomly assigned to receive either a haemodialysis procedure for 3 h, started as soon as possible (63 +/- 6 min) after administration of contrast medium, or a conservative treatment. Serum concentrations of iopentol and creatinine were followed for up to 14 days. RESULTS: The extracorporal plasma clearance of contrast medium was 71 +/- 2.5 ml/min. The fraction of the dose eliminated was 32 +/- 3%. The rate of radiocontrast nephropathy (defined as serum creatinine increase of > or = 0.5 mg/dl (44 mumol/l) within 48 h) after administration of contrast medium was similar in both groups (53 and 40% in group 1 (haemodialysis) and group 2 (conservative treatment) respectively). The course of absolute changes in serum creatinine over the whole observation period was not different in both groups. CONCLUSIONS: The data indicate that haemodialysis eliminates contrast medium effectively, but it may not influence the incidence or outcome of contrast induced nephropathy.     

Protection afforded by a novel K channel opener (Y-26763), against glycerol-induced acute renal failure (ARF) in rats

Y-26763, a benzopyran derivative, is a newly developed ATp-sensitive K channel opener and has been reported to protect against ischemic acute renal failure (ARF). We examined the effects of Y-26763 on glycerol-induced myoglobinuric ARF in the rats. ARf was induced in 28 adult male Sprague-Dawley rats by hind-limb intramuscular injection of 50% glycerol (5 ml/kg) after 18 hrs of water deprivation. Y-26763, 7 micrograms/kg (GY group, n = 10) of vehicle (G group, n = 12) was given intravenously 15 min before glycerol injection. Glibenclamide (20 mg/kg), a K channel blocker was given prior to Y-26763 injection to see of the effects was due to the K-channel opener (GYG group, n = 6). Animals were sacrificed 24 or 96 hrs after glycerol injection. Y-26763 partially, but significantly, restored renal dysfunction 24 hrs after ARF. Pcr (mg/dl) and Ccr (ml/min), respectively were as follows: G group, 5.7 +/- 0.4, 0.015 +/- 0.006; GY group, 4.1 +/- 0.4, 0.061 +/- 0.027 (p < 0.05). These favorable effects were antagonized by glibenclamide (Pcr in GYG group, 5.4 +/- 0.3 mg/dl, p < 0.05). Renal calcium content was not statistically significant (3.5 +/- 1.2 vs. 3.4 +/- 1.2 micrograms/mg dry weight). Histological examinations revealed that extensive tubular necrosis and cast formation seen in the G group were reduced in the GY group. At the recovery phase, 96 hrs after glycerol injection, Y-26763 accelerated the recovery from ARF as shown in Pcr (mg/dl) and Ccr (ml/min): 4.3 +/- 0.2, 0.05 +/- 0.01 in the G group, 2.8 +/- 0.2, 0.13 +/- 0.02) in the GY group (p < 0.01). In conclusion, Y-26763 partially protected against glycerol-induced ARF.     

Effects of natriuretic peptide receptor inhibition on remnant kidney function in rats

To identify the contribution of natriuretic peptide (NP) activity to the adaptative increases in glomerular filtration rate (GFR), effective renal plasma flow rate (ERPF) and fractional sodium excretion (FENa) observed in the remnant kidney, we investigated the acute effects of administering HS-142-1 (HS), a potent NP receptor antagonist, in 5/6th nephrectomized (NPX) rats. In addition to normal sodium intake, high or low sodium intakes were used to stimulate or suppress, respectively, endogenous NP activity in NPX rats. In rats three days after NPX on high sodium, HS (20 mg/kg bolus i.v.) reduced GFR from 0.55 +/- 0.05 to 0.35 +/- 0.04 ml/min; ERPF from 1.83 +/- 0.19 to 1.53 +/- 0.16 ml/min; and FENa from 7.1 +/- 1.1 to 1.6 +/- 0.4%, without affecting MAP. Similar changes of lesser magnitude were observed in NPX rats on normal sodium intake. By contrast, GFR, ERPF, FENa and MAP were unchanged following HS in NPX rats on low sodium intake, suggesting that the magnitude of responses to HS is dependent upon the expected levels of activity of NP. We conclude that in anesthetized rats, natriuretic peptides contribute to the compensatory increases in GFR, ERPF and FENa observed in the remnant kidney under normal and salt-replete conditions.     

An increase in renal dopamine production after the administration of radiographic contrast agents

Renal vasoconstriction and anti-natriuresis conditioned by radiographic contrast agents (CA) may be antagonised by the administration of exogenous dopamine. However, the influence of CA on the activity of renal synthesis of dopamine has not been studied. This study assessed the daily urinary excretion of dopamine, its precursor. L-3, 4-dihydroxyphenylaline (L-DOPA), and its metabolites (acid 3, 4-dihydroxyphenylacetic, DOPAC; homovanillic acid, HVA) 24 hours before and 48 hours following administration of a non ionic and hyposmolar (lopromide) CA in patients (n = 10; average age 61.3 +/- 4.3 years) submitted to coronary angiography. Urinary excretion of noradrenalin, a marker of sympathetic activity, was also assessed during the same period. The deputation of creatinine (Ccr) and the urinary excretion of sodium (UNa+) lowered after the administration of the CA (Ccr, 79.2 +/- 10.2 vs 72.2 +/- 9.6 ml/min/1.73 m2, p < 0.05; UNa+, 112.8 +/- 9.6 vs 61.7 +/- 25.1 mmol/24 h, p < 0.05). On the contrary, the urinary excretion of potassium increased in the period of 24 h following the administration of the AC (31.7 +/- 5.2 vs 103.8 +/- 10.8 mmol/24 h, p < 0.05). There was an increase in the urinary excretion of dopamine as well as noradrelalin during the 24 hour period following the administration of the CA (dopamine, 1260.2 +/- 196.8 vs 1571.5 +/- 170.2 mmol/24 h p < 0.5; noradrenalin, 186 +/- 36.6 mmol/24 h, p < 0.05). On the contrary, the urinary excretion of L-DOPA lowered after the administration of the CA (115.4 +/- 25.5 vs 80.5 +/- 13.2 mmol/24 h, p < 0.05). These results conditioned an increase in the dopamine/L-DOPA ratio in the urine, after the administration of the CA (12.2 +/- 1.5 vs 22.2 +/- 4.5 mmol/24 h, p < 0.05). In conclusion, the administration of CA is accompanied by an increase in the renal production of dopamine which, in these conditions, may act as a compensatory natriuretic hormone.     

Angiotensinogen polymorphism M235T, hypertension, and nephropathy in insulin-dependent diabetes

The allele 235T (a threonine in place of a methionine at position 235) of angiotensinogen has been found to be associated with a predisposition to essential hypertension. We investigated whether this allele also confers increased susceptibility to nephropathy in patients with insulin-dependent diabetes mellitus (IDDM). A group of 380 patients who had had IDDM for 15 to 20 years were genotyped at the angiotensinogen 235 locus. Included were 75 patients with normoalbuminuria (albumin excretion rate < 30 micrograms/min), two series of patients with microalbuminuria (n = 30 and n = 136), and two series with overt proteinuria (n = 41 and n = 98). Allele 235T frequency was higher among cases with microalbuminuria (0.41 in the two series combined) or overt proteinuria (0.40) than in the normoalbuminuria group (0.36). However, this difference was not statistically significant with this sample size (chi 2 = 1.2, P = NS with 2 df). Under a recessive model, allele 235T homozygotes had a 1.6-fold risk of developing nephropathy relative to carriers of other genotypes, but this value was not significantly different from 1(95% CI = 0.8 to 3.5). The strength of the association did not improve after stratification by degree of glycemic control. With respect to the hypertension in these IDDM patients, no association with allele 235T was found. Allele 235T frequencies in normotensive and hypertensive individuals were 0.363 and 0.353, respectively, among normoalbuminuric IDDM individuals (chi 2 = 0.01, P = NS) and 0.411 and 0.414 among microalbuminuric IDDM subjects (chi 2 = 0.0, P = NS). We conclude that the angiotensinogen polymorphism M235T might influence susceptibility to nephropathy in insulin-dependent diabetes, but its effect, if any, is rather small and independent of hypertension.     

Enhanced recovery from acute renal failure by the postischemic infusin of adenine nucleotides and magnesium chloride in rats

Although a number of manipulations prior to or during the initiation phase of an acute renal injury will modify the degree of functional impairment, agents administered after the acute insult usually have been ineffective. In the present study, adenine nucleotides (AMP, ADP, or ATP) combined with magnesium chloride were infused after an ischemic renal injury. Twenty-four hours later: (1) rats that received no infusion or one of the components of the mixture alone had reduced CIn (355 +/- 40 microliter/min/100 g of body wt vs. 977 +/- 40 control value), decreased RBF (3550 +/- 205 microliter/min/100 g of body wt vs. 5095 +/- 171 control value), elevated FENa (0.65 +/- 0.10% vs. 0.17 +/- 0.04 control value), and diminished UOsm (862 +/- 110 mOsm/kg vs. 1425 +/- 132 control value); (2) rats given dopamine or phenoxybenzamine maintained low CIn (365 +/- 50) despite improved RBF (4678 +/- 222); (3) rats infused with either AMP, ADP, or ATP combined with magnesium chloride had markedly improved CIn (594 +/- 44, P < 0.01), increased RBF (4269 +/- 223, P < 0.01); normalized FENa (0.18 +/- 0.07%, P < 0.01), and improved UOsm (1201 +/- 106 mOsm/kg, P < 0.05). In animals given no infusion or only magnesium chloride, ultrastructural studies demonstrated focal cellular necrosis and marked generalized tubular cell and mitochondrial swelling, whereas rats infused with ATP and magnesium chloride had fewer ultrastructural changes with better preservation of cellular morphology. Rats treated with ATP and magnesium chloride had improved CIn despite ischemic periods of 30, 45, and 60- min; and the degree of improvement was directly related to the quantity of ATP and magnesium chloride administered. The cellular content of exogenously administered ATP was 2.5 times greater in previously ischemic kidneys than in nonischemic kidneys. The data indicate that adenine nucleotides combined with magnesium chloride when infused after the initiation of acute renal failure significantly improve both CIn and tubular function and suggest that these agents effectively enhance recovery following an ischemc renal insult.     

Hemorheology, plasma protein composition and von Willebrand factor in type I diabetic nephropathy

Patients with IDDM, especially those with albuminuria are at high risk for macrovascular and microvascular complications. Besides the major classic risk factors altered hemorheology may also play a role. Plasma viscosity, erythrocyte aggregation and erythrocyte deformability are the major determinants of blood flow in the microcirculation. Therefore, these hemorheological parameters and plasma protein composition were evaluated in 58 IDDM-patients with none (N0), incipient (N1: albuminuria 30-300 mg/day) and overt clinical nephropathy (N2: albuminuria > 300 mg/day). As an estimate of endothelial injury plasma levels of von Willebrand Factor (vWF) were investigated. Patients with incipient and clinical nephropathy exhibited increasing blood levels of fibrinogen (N0 = 2.47 +/- 0.09, N1 = 2.71 +/- 0.15, N2 = 3.49 +/- 0.24 g/l, p < 0.001), alpha 2-macroglobulin (N0 = 257 +/- 11, N1 = 251 +/- 21, N2 = 382 +/- 43 mg/100 ml, p < 0.01) and haptoglobin (N0 = 174 +/- 16, N1 = 216 +/- 39, N2 = 278 +/- 36 mg/100 ml, p < 0.05), whereas serum albumin concentration decreased (N0 = 5.1 +/- 0.1, N1 = 4.7 +/- 0.1, N2 = 4.1 +/- 0.2 g/100 ml, p < 0.001). In the same patients erythrocyte aggregation (N0 = 10.0 +/- 0.4, N1 = 12.1 +/- 0.5, N2 = 12.9 +/- 0.6, p < 0.001), plasma viscosity (N0 = 1.34 +/- 0.01, N1 = 1.38 +/- 0.02, N2 = 1.40 +/- 0.02 mPas, p < 0.05) and erythrocyte rigidity (N0 = 0.05 +/- 0.01, N1 = 0.15 +/- 0.05, N2 = 0.09 +/- 0.02, p < 0.05) were increased, predominantly in those with overt clinical nephropathy. Erythrocyte aggregation was positively correlated with plasma concentrations of fibrinogen (r = 0.65, p < 0.001) and alpha 2-macroglobulin (r = 0.35, p < 0.05), but negatively with plasma albumin concentration (r = -0.49, p < 0.001). Plasma viscosity was positively correlated with plasma concentrations of fibrinogen (r = 0.46, p < 0.001) and haptoglobin (r = 0.46, p < 0.001). Von Willebrand Factor levels were higher in patients with overt clinical nephropathy (N0 = 126 +/- 8, N1 = 136 +/- 12, N2 = 163 +/- 14%, p < 0.09, PN0-N2 < 0.05). A significant correlation between vWF and the rheological determinants could not be detected. These data demonstrate that blood rheology is profoundly altered in patients with IDDM and nephropathy. Elevated levels of vWF may indicate endothelial damage, and changes in plasma viscosity as well as erythrocyte aggregability seem to be the result of altered plasma protein composition due to proteinuria. These abnormalities in hemorheology may be an aggravating factor promoting microvascular and macrovascular damage in patients with type I diabetes mellitus and nephropathy.     

Reduced neuromuscular blocking potency of atracurium in patients with purulent intrathoracic diseases

OBJECTIVE: Based on personal observations the neuromuscular blocking potency of atracurium was supposed to be diminished in purulent intrathoracic diseases. This hypothesis was tested in a prospective clinical trial. METHODS: 52 adult patients undergoing general anaesthesia (methohexitone, sufentanil, flunitrazepam, N2O, enflurane) for elective thoracic surgery were investigated. After the intubation dose of 0.6 mg/kg atracurium was applied continuously to maintain a 90% suppression of the evoked compound electromyogram. According to the intraoperatively established diagnosis patients were allocated to three categories: 1) non-malignant tumor as the control group (n = 15), 2) lung cancer (n = 22), 3) purulent intrathoracic process without tumor (n = 15). The groups were compared regarding onset time, DUR 10% and maintenance dose of atracurium. RESULTS: Patients with lung cancer did not differ significantly from the controls regarding efficiency of atracurium. In contrast, patients with a purulent intrathoracic process showed a significantly longer onset time (6.3 +/- 2.5 vs. 2.9 +/- 0.8 min, p < 0.001), and a significantly shorter DUR 10% (23 +/- 6 vs. 36 +/- 10 min, p < 0.001) compared to the control group. Mean infusion rate of atracurium to maintain a 90% suppression of the evoked compound electromyogram was significantly higher in patients with a purulent process compared to the controls (10.5 +/- 3.2 vs. 6.0 +/- 1.2 micrograms/kg.min, p < 0.001). CONCLUSION: Our results support the hypothesis that patients with a purulent intrathoracic disease show a clear reduction in neuromuscular blocking potency of atracurium.     

Antiviral activities of Nepalese medicinal plants

The aim of this cross-sectional study was to establish the prevalence of renal involvement and to identify associations with its most important possible risk factors in a group of patients with Type II diabetes mellitus, representative of the population living in Catalonia. One thousand two hundred and three patients (47% males, mean age: 61 +/- 6 years, diabetes duration 9 +/- 6 years) were studied. Overnight urine samples were collected to determine urinary albumin excretion (UAE). If UAE was > 15 micrograms/min, a new 24-h urine collection for UAE measurement to establish the existence of microalbuminuria (20-200 micrograms/min) or macroalbuminuria (> 200 micrograms/min) was obtained. Clinic and metabolic evaluations were also performed. The prevalence (%) of microalbuminuria, macroalbuminuria and hypertension were, respectively, 23. 1, 5.4 and 42. In comparison with normoalbuminurics, patients with microalbuminuria were predominately male (P < 0.03), with a significantly higher systolic (P < 0.001) and diastolic (P < 0.001) blood pressure and body mass index (P < 0.001). The prevalence of smokers (former + current) was higher in patients with microalbuminuria (43 vs 32%, P < 0.025). Moreover, patients with nephropathy had more prevalence of retinopathy (P < 0.001), neuropathy (P < 0.001), peripheral angiopathy (P < 0.001) and coronary disease (P < 0.001). The prevalence of microalbuminuria in Type II diabetes in Catalonia is similar to that observed in other european countries. The existence of microalbuminuria is associated with several diabetic complications, as well as tobacco consumption and obesity.     

Urinary protein excretion rate is the best independent predictor of ESRF in non-diabetic proteinuric chronic nephropathies. "Gruppo Italiano di Studi Epidemiologici in Nefrologia" (GISEN)

We investigated the predictors of the rate of glomerular filtration rate decline (delta GFR) and progression to end-stage renal failure (ESRF) in the 352 patients with proteinuric non-diabetic chronic nephropathies [urinary protein excretion rate (UProt) > or = 1 g/24 hr, creatinine clearance 20 to 70 ml/min/1.73 m2] enrolled in the Ramipril Efficacy In Nephropathy (REIN) study. Overall the GFR declined linearly by 0.46 +/- 0.05 ml/min/1.73 m2/month (mean rate +/- SEM) over a median follow-up of 23 months (range 3 to 64 months), and progression to ESRF was 17.3%. Using multivariate analysis, higher UProt and mean arterial pressure (MAP) independently correlated with a faster delta GFR (P = 0.0001 and P = 0.0002, respectively) and progression to ESRF (P = 0.0001 and P = 0.003, respectively). Mean UProt and systolic blood pressure during follow-up were the only time-dependent covariates that significantly correlated with delta GFR (P = 0.005 and P = 0.003, respectively) and ESRF (P = 0.006 and P = 0.0001, respectively). After stratification for baseline UProt, patients in the lowest tertile (UProt < 1.9 g/24 hr) had the slowest delta GFR (0.16 +/- 0.07 ml/min/1.73 m2/month) and progression to ESRF (4.3%) as compared with patients in the middle tertile (UProt 2.0 to 3.8 g/24hr; delta GFR, 0.55 +/- 0.09 ml/min/1.73 m2/month, P = 0.0002; ESRF, 15.3%, P = 0.0001) and in the highest tertile (UProt 3.9 to 18.8 g/24 hr; delta GFR, 0.70 +/- 0.11 ml/min/1.73 m2/month, P = 0.0001; ESRF, 32.5%, P = 0.0001). Both delta GFR (P = 0.01) and progression to ESRF (P = 0.01) significantly differed even between the middle and the highest tertiles. On the contrary, stratification in tertiles of baseline MAP failed to segregate subgroups of patients into different risk levels. Patients with the highest proteinuria and blood pressure were those with the fastest progression (delta GFR, 0.91 +/- 0.23; ESRF 34.7%). Of interest, at each level of baseline MAP, a higher proteinuria was associated with a faster delta GFR and progression to ESRF. On the other hand, at each level of proteinuria, a faster delta GFR was associated with MAP only in the highest tertile (> 112 mm Hg) and the risk of ESRF was independent of the MAP. Thus, in chronic nephropathies proteinuria is the best independent predictor of both disease progression and ESRF. Arterial hypertension may contribute to the acceleration of renal injury associated with enhanced traffic of plasma proteins. Antihypertensive drugs that most effectively limit protein traffic at comparable levels of blood pressure are those that most effectively slow disease progression and delay or prevent ESRF in proteinuric chronic nephropathies.     

Cortisol and catecholamine kinetics during continuous hemodiafiltration in patients with multiple organ dysfunction syndrome

OBJECTIVE: To assess the influence of continuous hemodiafiltration (CHDF) on cortisol and catecholamine kinetics in multiple organ dysfunction syndrome. DESIGN: Consecutive clinical study. SETTING: General intensive care unit of a university hospital. PATIENTS: Ten adult patients with multiple organ dysfunction syndrome requiring CHDF. MEASUREMENTS AND RESULTS: A total of 40 samples were collected during CHDF for cortisol and catecholamine assays. The clearances for cortisol, epinephrine, norepinephrine and dopamine were 2.5 +/- 1.7 ml/min, 26.3 +/- 2.7 ml/min, 16.7 +/- 4.2 ml/min and 26.3 +/- 2.6 ml/min (Mean +/_ SE), and their daily extractions were 1.8 +/- 0.2 mg/day, 11.4 +/- 4.8 micrograms/day, 1.0 +/- 0.1 micrograms and 2.3 +/- 0.3 micrograms/day, respectively. There were no significant changes in blood cortisol and catecholamine levels during CHDF conducted for 48 h. CONCLUSIONS: The cortisol and catecholamine losses during CHDF were small and unlikely to lead to hemodynamic disturbances.