Sodium-lithium countertransport activity and insulin resistance in normotensive IDDM patients.

In insulin-dependent diabetes (IDDM), an overactivity of sodium-lithium countertransport (Na+/Li+ CT) has been associated with the risk of nephropathy and hypertension, two conditions of insulin resistance. We investigated the sensitivity to insulin with a hyperinsulinemic (approximately 719 pM [approximately 100 microU/ml]) euglycemic clamp in two groups of normotensive nonproteinuric IDDM patients; 12 (10 men, 2 women) had high Na+/Li+ CT activity (mean 0.47, range 0.42-0.68 mmol/L red blood cells [RBC]/h, group 1) and 12 (9 men, 3 women) had normal Na+/Li+ CT activity (mean 0.24, range 0.12-0.31 mmol/L RBC/h, group 2). The two groups were similar in age (mean +/- SE 36 +/- 2 vs. 33 +/- 1 yr), duration of diabetes (19 +/- 3 vs. 18 +/- 2 yr), body mass index (26 +/- 0.8 vs. 24 +/- 0.6 kg/m2), arterial blood pressure (systolic/diastolic 121 +/- 4/79 +/- 2 vs. 122 +/- 3/77 +/- 2 mmHg), and glycemic control (HbA1 8.5 +/- 0.4 vs. 8.0 +/- 0.4%). Albumin excretion rate (AER) ranged between 4.7 and 148 (geometric mean 14) micrograms/min in group 1 and between 2.7 and 93 (geometric mean 11) micrograms/min in group 2. There were four microalbuminuric patients (AER greater than 30 micrograms/min) in each group. Whole-body glucose uptake was significantly reduced on average in group 1 compared with group 2 (41.6 +/- 2.2 mumol.kg-1.min-1 [7.48 +/- 0.4 mg.kg-1.min-1] vs. 49.6 +/- 2.2 mumol.kg-1.min-1 [8.93 +/- 0.4 mg.kg-1.min-1, P = 0.03), but some overlap existed between the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Increased sodium-lithium countertransport activity in red cells of IgA nephropathy patients.

The aim of this work was to analyze Na,Li countertransport activity in the erythrocytes from patients with IgA nephropathy, in relationship with their blood pressure status and lipid profile. Forty-nine patients (32 males, 17 females) with biopsy-proven IgA nephropathy and without significant impairment of renal function (serum creatinine less than or equal to 1.4 mg/dl) and 36 normal subjects (21 males, 15 females) were evaluated. Twenty-nine patients with IgA nephropathy were normotensive and 20 hypertensive (diastolic pressure greater than or equal to 95 mm Hg or treated by antihypertensive drugs). Na,Li countertransport was significantly higher in red cells from hypertensive than from normotensive patients (P = 0.002) and normal subjects (P = 0.0001), (values respectively 309 +/- 17; 241 +/- 12 and 211 +/- 11 mumol/liter RBC/hr); normotensive patients with IgA nephropathy did not differ from controls regarding the Na,Li countertransport rate. A multiple stepwise logistic regression analysis with blood pressure status as the dependent variable and Na,Li countertransport activity, age, serum creatinine, proteinuria, cholesterol, triglycerides, plasma potassium and time from onset as independent variables, indicated an independent significant association for Na,Li countertransport (P = 0.002) proteinuria (P = 0.006), plasma potassium (P = 0.006) and age (P = 0.029). Other tested variables were not independently related to blood pressure status. Hyperlipidemic patients (plasma total cholesterol concentration greater than 200 mg/dl and/or plasma triglycerides greater than 172 mg/dl) had an erythrocyte Na,Li countertransport activity significantly higher than normolipidemic (P = 0.005) and controls (P = 0.001) (values respectively 295 +/- 14; 226 +/- 12 and 211 +/- 11 mumol/liter RBC/hr).(ABSTRACT TRUNCATED AT 250 WORDS)     

Sodium transport in red blood cells from dialyzed uremic patients

Studies on red blood cell (RBC) sodium (Na) transport in chronic renal failure have described abnormalities in the ouabain-sensitive Na, K pump. We now report Na transport in RBC using cation flux methodology, measuring both the ouabain-sensitive Na, K pump and the ouabain-insensitive Na, K cotransport (CoT) and Na, lithium (Li) countertransport (CTT) in 28 subjects on hemodialysis, eight subjects on chronic ambulatory peritoneal dialysis (CAPD) and 29 control subjects. Intracellular cation content and passive permeability of Na were also examined. Mean Na efflux through the ouabain-sensitive Na, K pump was not reduced in dialysis patients when compared to normal subjects, whether measured in fresh cells (1.41 +/- 0.05 vs. 1.30 +/- 0.03 mmole/liter RBC/hr; P less than 0.05) or in Na-loaded cells (7.10 +/- 0.24 vs. 6.90 +/- 0.22; NS). There was, however, a marked and uniform suppression of the CoT pathway in Na-loaded cells from dialysis patients versus controls (0.14 +/- 0.02 vs. 0.41 +/- 0.05 mmole/liter RBC/hr; P less than 0.001). Mean CTT activity, as measured by Li efflux, was not different between dialysis and normal subjects. Uremic and normal RBC had similar intracellular Na or K content as well as passive permeability for either ion. This indicates that intracellular cationic homeostasis is maintained, perhaps secondary to balanced changes in cationic flux activity through these transport pathways.     

Effects of L-carnitine on sodium transport in erythrocytes from dialyzed uremic patients

Red blood cell (RBC) sodium transport systems were studied by cation flux methodology, measuring both the ouabain-sensitive Na-K pump and the ouabain-insensitive Na-K cotransport (CoT), as well as the Na-lithium (Li) countertransport (CTT), in eight patients on chronic hemodialysis and a control group of eight normal individuals. Intracellular sodium content and passive Na permeability were also determined. The effect of L-carnitine on RBC sodium transport in the uremic group was evaluated by supplementation with oral (1 g/day) and i.v. (1 g post-hemodialysis) L-carnitine for 60 days. Mean Na efflux through the ouabain-sensitive Na-K pump was 30.7% lower in uremic patients than in controls (3.49 +/- 1.52 vs. 5.04 +/- 0.72 mmol/liter RBCxhr; P less than 0.025). Intracellular Na content was higher in uremic patients (11.57 +/- 3.38 vs. 8.86 +/- 0.88 mEq/liter RBC; P less than 0.05), but no differences were found in Na-K CoT, Na-Li CTT or passive Na permeability. L-carnitine treatment increased the ouabain-sensitive Na efflux in uremic patients (4.76 +/- 1.6 vs. 3.49 +/- 1.52 mmol/liter RBCxhr; P less than 0.05), with no change in CoT, CTT, intracellular Na content or passive Na permeability. We conclude that L-carnitine deficiency may play a major role in uremic Na-K pump disfunction.     

Red cell Na+/Li+ countertransport in non-insulin-dependent diabetics with diabetic nephropathy

Genetic predisposition to essential hypertension, as indicated by increased maximal velocity of Na+/Li+ countertransport in red cells, has been suggested as a marker for the risk of developing diabetic nephropathy. To evaluate the validity of this concept in non-insulin-dependent diabetics, we measured the maximal velocity of Na+/Li+ countertransport in red cells in 18 male diabetics suffering from proteinuria due to biopsy proven diabetic glomerulosclerosis (GFR: 51 [range 27 to 146] ml/min/1.73 m2), 17 male diabetics with normoalbuminuria, and in 18 sex-, age-, and body mass index-matched healthy control subjects. Na+/Li+ countertransport was identical in patients with and without diabetic nephropathy, 0.43 (0.24 to 0.92) versus 0.44 (0.20 to 0.83) mmol/(liter cells x hr), but was elevated compared to control subjects, 0.32 (0.09 to 0.73; P less than 0.05). Arterial blood pressure was elevated in patients with nephropathy (162/92 +/- 21/9 mm Hg) compared to normoalbuminuric patients (132/82 +/- 15/7) and control subjects (133/83 +/- 14/7 mm Hg; P less than 0.001). Our study does not support the hypothesis that the risk of diabetic nephropathy in non-insulin-dependent diabetes is associated with a genetic predisposition to hypertension. Diabetes per se seems to enhance Na+/Li+ countertransport activity.     

Clustering of risk factors in hypertensive insulin-dependent diabetics with high sodium-lithium countertransport.

Diabetic nephropathy is more common in patients with a positive family history of hypertension and with elevated red blood cell sodium-lithium countertransport, a marker of risk for essential hypertension. To evaluate whether there is a relationship between this cation transport system and indicators of risk of renal and cardiovascular complications in diabetic patients before the development of clinical proteinuria, we studied 31 type 1 (insulin-dependent) diabetic patients with arterial hypertension, without clinical proteinuria and 12 normotensive normoalbuminuric diabetic patients. Sodium-lithium countertransport activity was significantly higher in hypertensive patients (0.43 +/- 0.03 mmol/l RBC x hr) than in normotensive patients (0.23 +/- 0.03; P less than 0.001). To better explore the nature of the association between this transport system and arterial hypertension, hypertensive patients were divided in two groups, with high (greater than 0.41 mmol/l RBC x hr) or normal (less than 0.41) sodium-lithium countertransport activity. The two groups of hypertensive diabetics were similar in age, sex, body mass index and blood pressure levels.(ABSTRACT TRUNCATED AT 250 WORDS)     

Urinary albumin excretion rate and glomerular filtration rate in the prediction of diabetic nephropathy; a long-term follow-up study of childhood onset type-1 diabetic patients.

BACKGROUND: Predictors of diabetic nephropathy are only partly known. The role of glomerular hyperfiltration is much discussed. We have studied the cumulative incidence of micro and macroalbuminuria and the predictive value of glomerular filtration rate (GFR) and screening value of albumin excretion rate (AER) in type-1 diabetes. METHODS: A cohort of diabetic children was followed up at a mean duration of 29+/-3 years. All 75 children treated in one hospital with diabetes duration > or =8 years were prospectively followed for 8 years examining GFR, AER, blood pressure and HbA1c. After another 8-10 years, 60 of them were traced for endpoint follow-up. RESULTS: Seven patients (12%) developed macroalbuminuria, i.e. persistent overnight AER>200 mg/min, 12 (20%) developed persistent microalbuminuria (AER 15-200 mg/min) and 17 (28%) transient microalbuminuria (>15 mg/min on two consecutive occasions, normalized at endpoint). One baseline screening value of 24-h AER>15 mg/min predicted 93% of patients with persistent micro or macroalbuminuria. The negative predictive value was 78%. Six of seven macroalbuminuric and 10 of 12 microalbuminuric patients had a baseline GFR above the normal limit of the method (> or =125 ml/min/1.73 m(2)). When adjusted for diabetes duration, increased GFR predicted macro or microalbuminuria (odds ratios=5.44, P=0.04). The positive predictive value for having an increased baseline GFR was 53%.The negative predictive value was 77%. Stratification for HbA1c did not change the effect of an increased GFR. CONCLUSIONS: At a mean diabetes duration of 29 years the cumulative incidence of macroalbuminuria was 12%; however, another 20% had persistent microalbuminuria. A screening value of 24-h AER >15 mg/min was a strong predictor, whereas increased GFR was a weaker but significant predictor for micro and macroalbuminuria.     

Erythrocyte Na,K pump activity and arterial hypertension in uremic dialyzed patients

We have evaluated in 26 uremic patients [21 on hemodialysis, 5 on continuous ambulatory peritoneal dialysis (CAPD)], 11 normotensive, and 15 hypertensive (MAP greater than 110 mm Hg) patients the following properties: a) erythrocyte (RBC) Na concentration [Nai] and ouabain-sensitive and -resistant Na effluxes; b) the effect of uremic sera on ouabain-sensitive Na efflux in normal RBC; c) serum digoxin-like immunoreactivity; d) cardiac index and total peripheral resistance. In 19 healthy subjects a) and c) were also evaluated. RBC Na,K pump activity was lower in uremic patients than in normal subjects (P less than 0.0005), and lower in hypertensive (P less than 0.02) than in normotensive patients. Serum from uremic patients inhibited ouabain-sensitive Na efflux in normal RBC, the inhibition being correlated with both the rate constant for ouabain-sensitive Na efflux (r = -0.67; P less than 0.005) and [Nai] (r = 0.43; P less than 0.05) of RBC of patients from whom the serum was obtained. Inhibition of ouabain-sensitive Na efflux was significantly higher with serum from hypertensive than from normotensive patients (P less than 0.05). Serum digoxin-like immunoreactivity was present in all uremic patients (0.402 +/- 0.054 ng/ml in normotensive and 0.428 +/- 0.040 ng/ml in hypertensive, P = ns), while it was not detectable in normal subjects. Hypertensive patients had peripheral resistance significantly higher than normotensive (P less than 0.05), while cardiac index was similar in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Urinary albumin, transferrin and iron excretion in diabetic patients.

The present study was undertaken to determine urinary and serum iron, transferrin and albumin levels in diabetic patients with varying amounts of proteinuria. A highly significant correlation was found between urinary albumin and transferrin excretion over a wide range of urinary albumin excretion (0.005 to 18 g/g creatinine) (r = 0.972). The urine/serum ratio of transferrin and albumin were identical, documenting a similar glomerular leak and tubule handling for these two proteins. In contrast to the above correlation between transferrin and albumin, there was no correlation between iron and either of these proteins until nephrotic range proteinuria had occurred, and even at that time the correlation was much weaker than that found between the proteins (r = 0.680). Urinary iron excretion increased early in the course of diabetic renal disease, being increased in 3 of 11 patients without proteinuria and in 8 of 10 patients with mild proteinuria. All patients with nephrotic range proteinuria had markedly increased urinary iron excretion (150 +/- 166 micrograms/g creatinine vs. 6.4 +/- 0.7 micrograms/g creatinine in controls) and decreased serum iron levels (592 +/- 189 micrograms/liter vs. 979 +/- 394 micrograms/liter in the control group). The iron/transferrin ratio in urine was consistently greater than the iron/transferrin ratio in plasma at all stages of proteinuria. In patients with both subnephrotic and nephrotic range proteinuria, approximately 35 to 40 micrograms Fe/g creatinine was present in the urine with an excess of transferrin. In conclusion, urinary iron excretion is increased early in the course of diabetic renal disease.(ABSTRACT TRUNCATED AT 250 WORDS)     

Prognostic significance of microalbuminuria in insulin-dependent diabetes mellitus: a twenty-three year follow-up study.

A cohort of 63 Type 1 insulin-dependent diabetic patients were first characterized for overnight urinary albumin excretion rate (AER) in 1967. In 1981, seven out of eight (87%) patients with initial AER greater than or equal to 30 less than or equal to 140 micrograms/min (microalbuminuria) developed clinical proteinuria compared to only 2 out of 55 (4%) patients with initial AER less than 30 micrograms/min. The same cohort of patients was reassessed in 1990 after a total follow-up period of 23 years. The aim was to investigate the role of microalbuminuria in the prediction of total/cardiovascular mortality and the development of renal failure, in addition to clinical proteinuria. The initially microalbuminuric patients had a significantly higher risk of developing not only clinical proteinuria (relative risk 9.3, 95% C.I. 1.36 to 3.10, P less than 0.05), but also of dying from a cardiovascular cause (relative risk 2.94, 95% C.I. 1.18 to 7.34, P less than 0.05). The rate of progression to renal failure was higher but not significantly so in the microalbuminuric (2 of 8) compared to the normoalbuminuric (4 of 53) group (relative risk 3.31, 95% C.I. 0.72 to 15.24, NS). In insulin-dependent diabetic patients microalbuminuria is a powerful predictor of clinically overt diabetic renal disease as well as cardiovascular mortality.     

The role of disease duration and hypertension in albumin excretion of type I diabetes mellitus.

The objective of this study was to examine the relationship between blood pressure, albumin excretion, and renal function in patients with type I diabetes mellitus. The study design was as follows: nonselected consecutive patients with type I diabetes mellitus were divided into three groups by level of albumin excretion rate (AER): less than 20 micrograms/min, 20 to 200 micrograms/min, and greater than 200 micrograms/min. The setting for the study was an outpatient diabetic clinic in a tertiary referral center. There were 166 patients studied: 53% men, 47% women, 86% white, 17% treated for hypertension. Seventy-six percent had an AER less than 20 micrograms/min, 18% had an AER of 20 to 200 micrograms/min, and 6% had an AER of greater than 200 micrograms/min. Glycosylated hemoglobin did not differ between groups. AER was increased with age and disease duration (P less than 0.005 by analysis of variance) after 10 yr of disease. Serum creatinine (P less than 0.005) and systolic (P less than 0.005) and diastolic (P less than 0.01) blood pressures were also increased with AER. Serum creatinine and blood pressure were found to be increased in parallel after 10 yr of disease, but both remained within the normal range overall. A comparison of individual blood pressures in patients not taking antihypertensive drugs (N = 138) with age-related blood pressures of nondiabetic subjects revealed increased systolic and diastolic blood pressures at all ages. Group comparison demonstrated a significant link between increased AER and serum creatinine (declining renal function) and increased blood pressure after a latent period of 10 yr. Blood pressure appears to be increased from the earliest age in diabetes compared with healthy populations.(ABSTRACT TRUNCATED AT 250 WORDS)     

Serum and urinary high density lipoproteins in glomerular disease with proteinuria

The serum lipoprotein concentrations, including high-density lipoprotein (HDL) subfractions and apolipoproteins Al and B were measured in 21 patients (14 male and seven female) with nephrotic range proteinuria (greater than 3g/24hr), well maintained renal function (creatinine clearance greater than 35 mliter/min/1.73m2) and biopsy-proven primary glomerular disease. In these, and in a further five patients (creatinine clearance greater than 15 mliter/min/1.73m2), urinary apolipoprotein Al output was determined. Total HDL cholesterol was similar in patients and controls, but in male patients, HDL2 was low (0.54 +/- 0.10 mmole/liter, mean +/- SEM) compared to controls (0.75 +/- 0.04 mmole/liter, P less than HDL3 was high (0.81 +/- 0.07 in patients and 0.63 +/- 0.02 mmole/liter in controls, P less than 0.01). In women, there was a similar tendency for HDL2 to be lower in patients (0.68 +/- 0.18 mmole/liter) than in controls (0.85 +/- 0.10 mmole/liter). Multiple regression analysis revealed that major determinants of the urinary apolipoprotein Al output were the urinary protein output and selectivity index (multiple r = 0.85). Furthermore, some patients lost apolipoprotein Al into their urine at rates indicating increased production of apolipoprotein Al in the nephrotic syndrome. The serum HDL subfraction concentrations in the nephrotic syndrome could be explained by a combination of increased HDL production and increased urinary loss of low molecular wt HDL.     

Hemodialysis and red cell cation transport in uremia: role of membrane free fatty acids

Active and facilitated cation transport in erythrocytes of uremic patients may be improved acutely by hemodialysis, although the mechanisms remain unknown. As nonesterified fatty acids (NEFA) can affect Na+ pump activity in vitro, changes in plasma and red cell membrane NEFA content following a single hemodialysis procedure were examined and compared with acute changes in erythrocyte cation flux rates in 34 hemodialysis patients. In nonsodium-loaded cells, small changes in Na+ pump flux with dialysis did correlate with changes in intracellular Na+ content (r = 0.59; N = 17; P less than 0.01). On average, neither maximal Na+ pump activity nor Na+/Li+ counter-transport flux improved with dialysis, but Na+/K+/Cl- cotransport rates rose 25% post-dialysis (P less than 0.02). Plasma NEFA levels rose 87% following hemodialysis but erythrocyte membrane NEFA content declined by 23% (P less than 0.001). Importantly, 24 of the 34 subjects studied had a decrease in erythrocyte membrane NEFA content of greater than 10%, and in these patients, the fall in membrane NEFA correlated with an increase in ouabain-sensitive Na+ efflux (r = 0.564; P less than 0.01). The effects of hemodialysis on both erythrocyte NEFA content and Na+ pump flux could be reproduced by incubating pre-dialysis cells in fatty acid-free albumin. We conclude that acute changes in membrane NEFA may modulate active cation transport in uremic erythrocytes.     

Neurological and neuropathological sequelae of correction of chronic hyponatremia

The effect of correction of chronic hyponatremia at different rates was studied in 91 rats maintained at a plasma [Na+] of 112 +/- 1 mmol/liter for 19 +/- 1 days. Hyponatremia was corrected into normal ranges (140 to 145 mmol/liter) using three different methods. Rats corrected by water restriction achieved normal plasma [Na+] by 2.1 +/- 0.2 day and had a maximal (4 hr) correction rate of 1.0 +/- 0.1 mmol/liter.hr; rats corrected by water diuresis achieved normal plasma [Na+] by 1.6 +/- 0.1 day and had a maximal correction rate of 2.8 +/- 0.2 mmol/liter.hr; rats corrected by hypertonic saline infusion achieved normal plasma [Na+] by 5.4 +/- 0.3 hr and had a maximal correction rate of 5.7 +/- 0.4 mmol/liter.hr. A fourth control group was not corrected. No demyelinative lesions were found in the brains from the uncorrected rats, whereas the occurrence of such lesions in the brains of the corrected rats was highly correlated with the maximal rate of increase in plasma [Na+] (r = 0.68, P less than 0.001), and to a lesser degree with the magnitude of the increase in plasma [Na+] over the first 24 hours of correction (r = 0.41, P less than 0.001). Brain myelinolysis was first observed in animals whose maximal (4 hr) rate of correction exceeded 1.75 mmol/liter.hr, and the incidence of demyelination increased progressively in rats with more rapid rates of correction. Similarly, myelinolysis was first observed in rats whose magnitude of correction at 24 hours exceeded 16 mmol/liter and also increased in rats with larger 24 hour magnitudes of correction.(ABSTRACT TRUNCATED AT 250 WORDS)     

Mechanism of impaired natriuretic response to furosemide during prolonged therapy

The mechanism of the diuretic braking phenomenon was studied in nine male hypertensive patients by assessing the diurnal pattern of renal sodium (Na) excretion during furosemide therapy, and the response to a test dose of furosemide (10 to 15 mg hr-1 i.v.) infused alone and with chlorothiazide (500 mg bolus i.v.). Patients were studied after one month of twice-daily administration of: placebo (P): chlorothiazide 500 mg (C); furosemide 40 mg (F); furosemide with spironolactone (100 mg b.i.d.) for the last 36 hours (F + S; N = 6). During F therapy, furosemide-induced natriuresis was followed by six hour periods of decreased UNaV. Diuretic therapy with F or C for one month reduced BP, but did not alter body weight, plasma volume (PV), glomerular filtration rate or PAH clearance. After P, the test infusion of furosemide increased fractional Na excretion (FENa) by +10.5 +/- 0.7%; this increment was reduced after therapy with F (+8.9 +/- 0.7%; P less than 0.05), C (+8.5 +/- 1.0%; P less than 0.01), or F + S (+8.9 +/- 0.9%; P less than 0.05). Renal furosemide excretion was greater (P less than 0.05) after F and C treatments (133 +/- 10 micrograms.min-1 and 130 +/- 13 micrograms.min-1, respectively) compared with P (94 +/- 9 micrograms.min-1). After P, a test dose of chlorothiazide given during furosemide infusion increased FENa further (+7.5 +/- 1.2%); this increment was greater after therapy with F (+10.1 +/- 1.4%; P less than 0.01) and F + S (+11.3 +/- 0.8%; P less than 0.05) but not after C (+6.3 +/- 1.5%; P greater than 0.1).(ABSTRACT TRUNCATED AT 250 WORDS)     

Myocardial protection by lidocaine during cardioplegia

This study was undertaken to examine the effects of lidocaine (L) (400 mg/liter) in a normokalemic crystalloid (S) (K +: 5 meq/liter, Na+: 120 meq/liter) and in a hyperkalemic crystalloid cardioplegic solution (K) (K+: 25 meq/liter, Na+: 120 meq/liter) during 90 min of hypothermic (28 degrees C) aortic occlusion followed by 45 min of reperfusion (R). Four groups of dogs were studied: group 1 (S), n = 6; group 2 (S + L), n = 6; group 3 (K), n = 6; group 4 (K + L), n = 6. Left ventricular (LV) function was defined as percentage changes in center of mass between pre- and postarrest function curves. Regional myocardial flow was measured with 9 mu radioactive microspheres and myocardial metabolism monitored by lactate and oxygen utilization. Ventricular biopsies were obtained for measurement of myocardial ATP, creatine phosphate, and water content. Percent recovery of LV function curves at the end of (R) was 59.2 +/- 3.9% in group 1, 85.0 +/- 4.3% in group 2, 71.5 +/- 4.9% in group 3, and 87.0 +/- 4.5 in group 4 (group 1 vs group 2, P less than 0.01; group 3 vs group 4, P less than 0.05). Metabolic recovery was evaluated at 5, 20, and 45 min of (R). Only group 3 (K) demonstrated persistent lactate production at 5 min of (R) (P less than 0.01). The hyperkalemic groups failed to return to control levels of oxygen utilization after 5 min of (R) (group 3, P less than 0.05; group 4, P less than 0.05). LV endocardial/epicardial myocardial blood flow ratio demonstrated greater increase in hyperkalemic groups (group 3, P less than 0.01; group 4, P less than 0.01) at 5 min of (R). ATP was significantly decreased in groups 1, 3 and 4, but not in group 2 at the end of ischemia (group 1, P less than 0.01; group 3, P less than 0.01; group 4, P less than 0.05) and after 45 min of (R) (group 1, P less than 0.05; group 3, P less than 0.01; group 4, P less than 0.01). These results demonstrate that lidocaine has a myocardial protective effect which is superior to standard hyperkalemic cardioplegia. Moreover, lidocaine has an additive salutary effect during potassium cardioplegia. Persistent metabolic derangements post reflow in the hyperkalemic groups suggest deleterious effects of hyperkalemia on subendocardial protection.     

Captopril acutely lowers albuminuria in normotensive patients with diabetic nephropathy.

Angiotensin-converting enzyme (ACE) inhibitors decrease albuminuria in patients with diabetic nephropathy. To study the change in albuminuria in relation to changes in systemic and renal hemodynamics, nine normotensive patients with type 1 (insulin-dependent) diabetes mellitus and persistent proteinuria were given a single oral dose of 25 mg of the ACE inhibitor captopril. Blood pressure, glomerular filtration rate (GFR), effective renal plasma flow (ERPF), and albumin excretion rate (AER) were measured in two periods of 40 minutes before and in four periods of 40 minutes after administration of captopril. A constant water diuresis was maintained. Blood pressure did not decrease significantly (130/79 +/- 4/3 v 124/74 +/- 4/3 mm Hg; mean +/- SEM), median AER decreased from 403 (interquartile range [IQR], 812) micrograms/min to 333 (707) micrograms/min (P < 0.01). GFR did not change (123 +/- 13 v 117 +/- 14 mL/min), but ERPF increased significantly from 609 +/- 56 to 714 +/- 55 mL/min (P < 0.01). Consequently, the filtration fraction (FF; quotient of GFR and ERPF) decreased from 0.20 +/- 0.014 to 0.17 +/- 0.014 (P < 0.01). A strong correlation was found between the decrease of AER and the decrease of FF (rs = 0.75; P < 0.02). No correlation was found between the decrease in AER and changes in GFR or blood pressure. In the normotensive patient with diabetic nephropathy, captopril causes an acute reduction of AER, which is probably mediated by a lowering of the intraglomerular pressure.     

Renal transplantation and red blood cell sodium transport: role of prednisone treatment.

This study assesses the role of prednisone and endogenous digoxin-like immunoreactivity (EDLI) in the increased Na+ pump activity in renal allograft patients. Red blood cell (RBC) Na+ transport activities and plasma concentrations of EDLI were measured in ten controls and ten renal allograft recipients (5 hypertensive) while undergoing treatment with cyclosporin, prednisone, and azathioprine, and also after prednisone withdrawal. As compared to controls, prednisone-treated patients showed an increased Na+ pump activity (0.323/h vs 0.571, P less than 0.05) and decreased RBC Na+ concentration (6.69 mM vs 4.99, P less than 0.05). They also showed a decrease in the activity of cotransport, countertransport, and passive Na+ efflux (0.02/h vs 0.005, P less than 0.05; 207 mumol/l vs 35, P less than 0.05; 0.02/h vs 0.005 respectively, P less than 0.05). After prednisone withdrawal, normotensive and hypertensive patients showed RBC Na+ transport system activities and RBC Na+ concentration similar to those of controls. EDLI was not detected in controls or in patients. We conclude that prednisone treatment increased the Na+ pump activity, and decreased the RBC Na+ concentration. Moreover, it induced a decrease in the activity of secondary RBC Na+ transport systems. This study provides no evidence for a modulatory role of EDLI in the RBC Na+ pump activity. Neither parameters can be presumed to be a marker of hypertension in these patients.     

The early natural history of nephropathy in Type 1 Diabetes: III. Predictors of 5-year urinary albumin excretion rate patterns in initially normoalbuminuric patients

Predictors of albumin excretion rate (AER) abnormalities could provide earlier indicators of diabetic nephropathy risk. Data from the Natural History Study, a prospective 5-year observation of renal structure and function in young type 1 diabetic patients, were examined for predictors of AER patterns in normoalbuminuric type 1 diabetic patients. Included were 170 patients (96 females) (aged 16.7 +/- 5.9 years, duration of diabetes 8.0 +/- 4.3 years) with normal blood pressure, normoalbuminuria (AER <20 microg/min), and eight or more follow-up visits over 5 years. AER, blood pressure, and HbA1c (A1C) were determined quarterly and glomerular filtration rate (GFR) annually. Persistent microalbuminuria (PMA) was defined as 20-200 microg/min in two of three consecutive values within 6-12 months. Four different AER patterns were identified. Group 1 (n = 99): all values <20 microg/min. Group 2 (n = 49): intermittent levels >20 microg/min but not meeting microalbuminuria criteria. Group 3 (n = 14): PMA during follow-up but normoalbuminuria at study exit. Group 4 (n = 8): microalbuminuria at study exit. Group 4 (497 +/- 95 nm, P < 0.01) and group 3 (464 +/- 113 nm, P = 0.03) patients had greater baseline glomerular basement membrane (GBM) width versus group 1 (418 +/- 67 nm). Baseline GFR in group 4 (163 +/- 37 ml.min(-1). 1.73 m(-2)) was higher than group 1 (143 +/- 28 ml.min(-1) . 1.73 m(-2), P = 0.04). A1C was higher in group 2 (9.0 +/- 1.2%) than group 1 (8.4 +/- 1.1%, P = 0.008). Thus, greater increases in GBM width and GFR were predictors of PMA. Since 64% of the patients that developed microalbuminuria reverted to normoalbuminuria, the risk of diabetic nephropathy as defined by current microalbuminuria criteria is unclear.