Cyclosporine-induced hypertension and decline in renal function in healthy volunteers

OBJECTIVE: To investigate the effect of cyclosporine A (CsA; Sandimmun Neoral) on systemic and renal hemodynamics, tubular function, and sodium excretion in healthy volunteers. Furthermore, we studied whether CsA enhances the systemic and renal hemodynamic sensitivity to norepinephrine. METHODS: Eighteen healthy volunteers were administered 10 mg/kg CsA or placebo capsules in a double-blind fashion. The mean arterial blood pressure (MAP), renal vascular resistance (RVR), glomerular filtration rate (GFR), and renal clearances of lithium (CLi) and sodium (CNa) were measured for 8 h after ingestion of the capsules. Norepinephrine (2 microg/kg per h) was infused intravenously for 1.5 h into nine subjects. RESULTS: CsA increased the MAP by 17+/-2 mmHg. The GFR decreased by 18+/-2% (P < 0.001) and the RVR increased by 37+/-4% (P< 0.001) after ingestion of CsA. The CsA-induced increase in MAP preceded the CsA-induced fall in GFR. The rise in MAP was followed by an early 35+/-8/0 increase in CNa (P < 0.001). At the end of the 8 h study period, CNa decreased by 25+/-7% (P < 0.001). Using CLi, it was found that the initial natriuresis had been caused by a relative decrease both in proximal and in distal tubular reabsorption of sodium, whereas the late sodium retention was secondary to the CsA-induced fall in GFR. Infusion of norepinephrine increased the MAP, RVR, and filtration fraction, and decreased the renal plasma flow, without CsA having any additional effect. CONCLUSION: It was demonstrated that a single oral dose of CsA caused a rise in blood pressure and transient natriuresis, followed by a fall in GFR and antinatriuresis. Thus, the present study confirms and extends earlier observations that renal dysfunction and sodium retention are not the initiating events in CsA-induced hypertension. The study also affords evidence suggesting that such rises in blood pressure are not mediated by an increased sensitivity to norepinephrine.     

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.     

Influence of angiotensin II blockade during exercise in the heat

The effect of the blockade of the renin angiotensin system (RAS) on thermoregulatory, cardiovascular and renal function during moderate exercise in a hot [mean (SEM) 34.4 (0.1) degrees C] environment was evaluated. Six men and three women cycled at 60% peak oxygen uptake for 45 min following acute administration of a placebo (PLAC) or enalapril (ENAL), an angiotensin converting enzyme inhibitor (ACE-I). Resting mean arterial pressure (MAP) was reduced by ENAL, but the pressor response to exercise was unaffected [delta MAP = 7.8 (1.4)mmHg for both trials (P > 0.05)]. Peak esophageal temperature [T(es) = 38.7 (1.0) degrees C (PLAC) vs 38.4 (0.2) degrees C (ENAL)] and mean skin temperatures [Tsk = 36.5 (0.1) degrees C (PLAC) vs 36.6 (0.1) degrees C (ENAL)] were similar for both drug treatments during the exercise. Both aldosterone and plasma renin activity (PRA) increased five fold above resting values during exercise; however, only the PRA response [16.7 (3.2) ng angiotensin I (Ang I).ml-1.h-1 (ENAL) vs 7.4 (1.2)ng Ang I.ml-1.h-1 (PLAC)] was significantly altered by ENAL treatment (P < 0.05). Urine flow, sodium excretion and glomerular filtration rates, determined from creatinine clearance, were similarly reduced following exercise for both ENAL and PLAC treatments. These results suggest acute administration (5 mg) of ACE-I does not impair thermoregulatory, cardiovascular or renal responses during moderate exercise in the heat.     

Renal hemodynamics during norepinephrine and low-dose dopamine infusions in man

OBJECTIVE: To characterize the effects of pressor doses of norepinephrine and low-dose dopamine (3 micrograms/kg/min) on renal hemodynamics in man, as well as to determine the clinical relevance of combining dopamine with norepinephrine. DESIGN: Prospective, single-blind, randomized study. SETTING: Clinical research unit of a tertiary care hospital. SUBJECTS. Six healthy male volunteers ranging in age between 20 and 28 yrs. INTERVENTIONS: The subjects were assigned randomly to four treatments (1 wk apart) in which renal hemodynamics and electrolyte excretion were assessed. Treatments consisted of 180-min infusions of the following: a) 0.9% sodium chloride (control); b) pressor doses of norepinephrine; c) dopamine at 3 micrograms/kg/min; and d) pressor doses of norepinephrine and dopamine at 3 micrograms/kg/min. Pressor doses of norepinephrine was defined as doses required to increase mean arterial pressure (MAP) by 20 mm Hg. MEASUREMENTS AND MAIN RESULTS: Glomerular filtration rate and renal blood flow were derived from inulin and para-aminohippurate clearances, respectively. Urine output and urine solute excretion were also determined. The mean norepinephrine dose required to increase MAP by 22 +/- 2 mm Hg was 118 +/- 30 ng/kg/min (range 76 to 164). After the addition of dopamine, similar doses of norepinephrine resulted in an MAP increase of 15 +/- 4 mm Hg. Glomerular filtration rate and urine output were comparable under all conditions. The infusion of norepinephrine decreased renal blood flow from 1241 +/- 208 to 922 +/- 143 mL/min/1.73 m2 (p = .03). The addition of dopamine returned renal blood flow to baseline values. The clearance of urine sodium increased significantly with the infusion of dopamine alone (p = .03). All subjects completed the four treatment periods. Adverse events, manifested mostly as palpitations and flushing, were rare and self-limiting. CONCLUSIONS: The addition of dopamine (3 micrograms/kg/min) to pressor doses of norepinephrine normalized renal blood flow in healthy volunteers. These hemodynamic changes were not reflected in urine output and glomerular filtration rate; hence, these monitoring parameters may be unreliable indicators of renal function in the setting of vasopressor therapy. In addition, systemic effects were observed with dopamine (3 micrograms/kg/min), as indicated by a decrease in MAP.     

Free and total insulin-like growth factor I (IGF-I), IGF-binding protein-1 (IGFBP-1), and IGFBP-3 and their relationships to the presence of diabetic retinopathy and glomerular hyperfiltration in insulin-dependent diabetes mellitus

The existing literature on serum insulin-like growth factor I (IGF-I) levels in insulin-dependent diabetes mellitus (IDDM) is conflicting. Free IGF-I may have greater physiological and clinical relevance than total IGF-I. Recently, a validated method has been developed to measure free IGF-I levels in the circulation. Serum free and total IGF-I, IGF-binding protein-1 (IGFBP-1), and IGFBP-3 levels were measured in 56 insulin-treated IDDM patients and 52 healthy sex- and age-matched controls. Diabetic retinopathy was established by direct fundoscopy. In 54 IDDM patients, the glomerular filtration rate (GFR) and effective renal plasma flow were calculated from the clearance rate of [125I]iothalamate and [131I]iodohippurate sodium. Fasting free IGF-I, total IGF-I, and IGFBP-3 levels were significantly lower in IDDM patients than in age- and sex-matched healthy controls (free IGF-I, P < 0.005; total IGF-I, P < 0.001; IGFBP-3, P = 0.001), whereas IGFBP-1 levels were higher (P < 0.001). In IDDM subjects, decreases in free IGF-I, total IGF-I, and IGFBP-3 levels with age were observed (free IGF-I, r = -0.27 and P = 0.05; total IGF-I, r = -0.52 and P < 0.001; IGFBP-3, r = -0.37 and P = 0.005). Free IGF-I was inversely related to fasting glucose in IDDM subjects (r = -0.35; P = 0.01), whereas the relationship between total IGF-I and fasting glucose did not reach significance (r = -0.27; P = 0.06). Age-adjusted free IGF-I levels were significantly higher (P < 0.05) in IDDM subjects with retinopathy than in subjects without retinopathy after adjustment for age. Total IGF-I and IGFBP-3 levels were positively related to GFR (total IGF-I, r = 0.35 and P < 0.05; IGFBP-3, r = 0.28 and P < 0.05). Both of these differences lost significance after adjustment for age. Free IGF-I, total IGF-I, and IGFBP-3 levels were lower and IGFBP-1 levels were higher in insulin-treated IDDM subjects compared to those in age- and sex-matched controls. Free IGF-I, total IGF-I, and IGFBP-3 levels decreased significantly with age in IDDM subjects. Age-adjusted free IGF-I levels in subjects with diabetic retinopathy were higher than those in subjects without diabetic retinopathy. Total IGF-I and IGFBP-3 levels were positively related to GFR in IDDM subjects, but these relations were lost after adjustment for age. Measurement of serum free IGF-I levels in IDDM subjects did not have clear advantages compared to that of total IGF-I, IGFBP-1, and IGFBP-3 levels. Serum IGF-I and IGFBPs reflect their tissue concentrations to a various degree. Consequently, extrapolations concerning the pathogenetic role of the IGF/IGFBP system in the development of diabetic complications at the tissue level remain speculative.     

Impact of gender on the renal response to angiotensin II

BACKGROUND: It is clear that women with renal disease progress to end stage at a slower rate than do men. We hypothesized that this protection may result from gender-mediated differences in responses to angiotensin II (Ang II), which has known hemodynamic effects that are thought to promote renal disease progression. We examined sex differences in renin-angiotensin system (RAS) function by measuring renal hemodynamic function and circulating plasma components of the RAS at baseline and in response to graded infusions of Ang II. METHODS: We studied two groups of normal healthy subjects, 24 men and 24 women, mean age 28 +/- 1 years, ingesting a controlled sodium and protein diet. We examined baseline concentrations of angiotensin converting enzyme, plasma renin activity, Ang II, and aldosterone. Inulin and paraaminohippurate clearance techniques were used to estimate effective renal plasma flow (ERPF) and glomerular filtration rate (GFR) at baseline and in response to graded Ang II infusion (0.5, 1.5, and 2.5 ng/kg/min). RESULTS: Mean baseline values for mean arterial pressure and aldosterone were lower in women, whereas values for plasma Ang II, GFR, ERPF, and filtration fraction (FF) did not differ. In response to Ang II, both groups exhibited a similar increase in mean arterial pressure and a decline in ERPF. GFR was maintained during Ang II infusion only in men, resulting in an augmentation of FF. In women, GFR declined in parallel with ERPF, and the FF response was significantly blunted. 17beta-Estradiol plasma concentrations influenced the ERPF response to Ang II infusion, with higher levels predicting a blunting of the decrease. The GFR response was not affected. CONCLUSIONS: The renal microcirculation in sodium-replete women may respond differently to Ang II than that of men, with the female sex predicting a lesser augmentation of FF and possibly a blunted increase in intraglomerular pressure. The mechanism remains obscure, but these contrasting responses may help to explain gender-mediated differences in renal disease progression.     

Renal functional reserve in subjects with diabetes mellitus

Diabetic nephropathy develops in approximately 35% of patients with insulin-dependent diabetes mellitus (IDDM) and in a similar proportion of patients with non-insulin-dependent diabetes mellitus (NIDDM). However, we remain at present unable to identify the susceptible subset prior to the development of microalbuminuria. Up to 25% of IDDM patients and a variable proportion of NIDDM patients manifest glomerular hyperfiltration in the first few years of diabetes. It has been debated whether this basal hyperfiltration is predictive of future renal disease and whether better prediction can be achieved by the use of the renal haemodynamic response to a protein meal, defined by some authors as renal reserve. The concept of renal functional reserve in patients with diabetes mellitus is complicated by the dependence of the GFR response on basal GFR, the influence of the prevailing metabolic conditions, and because the response differs to different stimuli. We review the factors affecting renal hemodynamics and renal hemodynamic responses in the context of supranormal, normal, and impaired renal function in diabetes. We conclude that although the measurement of renal functional reserve may help clarify important pathophysiological mechanisms, the assessment of basal GFR in clinical practice is all that is required for predictive and monitoring purposes.     

Lack of effect of captopril on glomerular hyperfiltration in normoalbuminuric normotensive insulin-dependent diabetic patients

The aim of the present study was to evaluate the effects of captopril on the glomerular filtration rate (GFR) and urinary albumin excretion rate (UAER) of normoalbuminuric normotensive insulin-dependent diabetes mellitus (IDDM) patients with and without glomerular hyperfiltration. Eleven normoalbuminuric (UAER < 30 micrograms/min) patients (age: 34.3 +/- 4.6 years: diabetes duration: 9.5 +/- 6.4 years) participated in the study. Six patients were considered to be hyperfiltering (GFR > or = 134 ml/min/ 1.73m2). GFR (51Cr-EDTA single injection technique), extracellular volume (ECV; distribution volume of 51Cr-EDTA), UAER (RIA) and metabolic and biochemical parameters were measured at baseline, after 6 weeks on captopril (25 mg p.o. twice daily) and after 6 weeks off captopril. Plasma renin activity (PRA; RIA), plasma aldosterone (RIA) and blood volume (51Cr red cell labeled) were measured at baseline and after 6 weeks on captopril. The baseline clinical and laboratory characteristics of hyperfiltering and normofiltering IDDM patients were similar. GFR did not change during the study (144.1 +/- 28.8; 139.7 +/- 21.8; 132.8 +/- 29.9 ml/min/1.73 m2) either in patients with hyperfiltration (164.6 +/- 20.7; 153.8 +/- 18.3; 148.6 +/- 31.0 ml/min/1.73 m2; n = 6) or without hyperfiltration (119.6 +/- 11.1; 123.2 +/- 11.9; 113.8 +/- 14.4 ml/min/1.73 m2; n = 5). Also, ECV (22.2 +/- 3.6; 21.5 +/- 4.3; 21.5 +/- 3.5 L/1.73 m2), UAER (3.9 [0.4-22.1]; 4.0 [0.2-11.4]; 3.7 [2.0-26.2] micrograms/min), systolic (112 +/- 13; 105 +/- 10; 111 +/- 11 mmHg) and diastolic (76 +/- 12; 72 +/- 9; 73 +/- 12 mmHg) blood pressure did not change. No difference in blood volume (60.8 +/- 10.4; 62.3 +/- 8.4 ml/kg) or plasma aldosterone (10.4 +/- 4.9; 7.7 +/- 3.8 ng/dl) was observed between baseline values and values after captopril use. PRA increased (2.4 [0.4-22.1]; 12.9 [2.2-41.1]ng/ml/h) at the end of 6 weeks on captopril (P = 0.002). Fasting plasma glucose, glycated hemoglobin, fructosamine, plasma cholesterol and potassium, 24 h urinary urea and sodium were similar during the study. These results were unchanged when patients with and without hyperfiltration were analyzed as separate groups. From baseline to the end of 6 weeks on captopril there was no correlation between change in GFR and change in glycated hemoglobin (r = 0.02, P = 0.96), systolic (r = 0.23; P = 0.49) and diastolic (r = -0.32, P = 0.32) blood pressure, urinary urea (r = 0.21; P = 0.53) and UAER (r = -0.16; P = 1.00). In conclusion, captopril has no effect on the GFR and UAER of normoalbuminuric normotensive IDDM patients irrespective of the presence of glomerular hyperfiltration.     

Renal reserve is normal in adults born with unilateral renal agenesis and is not related to hyperfiltration or renal failure

This study was carried out to examine the renal hemodynamic response in adult patients with single kidneys born with unilateral renal agenesis. A group of 21 patients with unilateral renal agenesis were divided into three groups according to their glomerular filtration rate (GFR): 112 +/- 3 ml/min x 1.73 m2 in group A, 68 +/- 3.2 ml/min x 1.73 m2 in group B, and 40.7 +/- 3.3 ml/min x 1.73 m2 in group C. Mean arterial blood pressure was significantly higher in the patients of group C who were also proteinuric. The renal hemodynamic response to an oral protein load (2 g/kg of protein as beefsteak) was normal in all groups and unrelated to hyperfiltration or to renal failure and proteinuria. The study indicates that in patients with renal agenesis, the hemodynamic response to a protein challenge is similar to that of kidney donors, renal transplant recipients and uninephrectomized patients. The paper also demonstrates that the renal response to a protein challenge is inadequate to identify patients with renal agenesis who are at risk of developing renal disease. Finally, in renal agenesis with renal disease, creatinine clearance overestimated the GFR by an average of 32.7%.     

A micropuncture study of the renal response to haemorrhage in rats: assessment of the role of vasopressin

The acute effects of haemorrhage (15 ml (kg body wt)-1) on renal function at whole-kidney and single-nephron levels were studied in Inactin-anaesthetized rats. In order to assess the role of vasopressin in mediating the haemodynamic effects, responses in untreated Long-Evans rats were compared with those in Brattleboro rats (which lack circulating vasopressin) and in Long-Evans rats treated with a V1 receptor antagonist. In time-control animals, there were no significant changes in mean arterial pressure (MAP), excretion rates, glomerular filtration rate (GFR), superficial-nephron GFR (SNGFR) or fluid reabsorption in the superficial proximal tubules during the course of the experiment. Following haemorrhage, the immediate reduction in MAP was followed in each group by partial recovery for 30 min; thereafter, MAP was stable. In untreated Long-Evans rats, haemorrhage was followed by a 26% reduction in GFR (P < 0.001, measured 60-150 min post-haemorrhage) and a larger reduction (45%, P < 0.001) in SNGFR, so that the SNGFR/GFR ratio fell significantly ((27.9 +/- 1.9) x 10(-6), control period; (20.2 +/- 2.2) x 10(-6) post-haemorrhage, P < 0.01). Slightly greater reductions in GFR and SNGFR were seen in Brattleboro rats and V1 antagonist-treated Long-Evans rats, which corresponded to slightly greater haemorrhage-induced reductions in blood pressure in these groups; the falls in the SNGFR/GFR ratio were similar to that in untreated Long-Evans rats. In all three groups of bled rats, fractional reabsorption by the proximal convoluted tubule increased slightly 30-60 min after haemorrhage, but during the subsequent period (60-150 min) returned to values indistinguishable from those during the control period. The results suggest that the renal haemodynamic changes that follow moderate haemorrhage include a preferential reduction in the GFR of superficial nephrons. Vasopressin appears to play no role in this response. Increases in fractional reabsorption in the proximal tubules are seen only during the immediate post-haemorrhage period.     

Progressive albuminuria and glomerulosclerosis in a rat model of chronic renal allograft rejection

A significant proportion of renal allografts fail within several months or years after transplantation, primarily because of chronic rejection. The etiology and pathophysiology of this condition remain unclear. We studied the renal function, morphology, and immunohistology, in parallel, among F344-to-Lewis allografts (n = 23) and isografts (n = 13) over the course of 24 weeks. Only an initial 10-day course of CsA (5 mg/kg/day) was given to both groups to prevent acute rejection. Hypertension did not develop, although awake systolic blood pressure was significantly higher in allografts at the end of the study. Significant differences in urine albumin excretion (UalbV) between isografts and allografts were evident as early as 4 weeks after engraftment but rose dramatically by 20 weeks (3.3 +/- 0.7 vs. 21.2 +/- 3.7 mg/day, respectively, P < .001). This pattern continued until the conclusion of the study (5.0 +/- 1.1 vs. 53.5 +/- 7.6 mg/day, P < .001). Serum creatinine values were only significantly elevated in allografts at 16 weeks, which temporally corresponded to the dramatic increase in UalbV. However, renal blood flow and glomerular filtration rate, measured by paraaminohippurate and inulin clearances, respectively, were significantly lower in allografted organs, at 24 weeks. The frequency of glomerulosclerosis lesions was significantly increased in allografted kidneys at 24 weeks and correlated with UalbV values. Glomerular localization of mononuclear leukocyte subsets were equivalent between allografts and isografts; however, the numbers of interstitial macrophages, CD8+, and pan-T-cells were all significantly greater in allografts at 24 weeks. The infiltration of significantly greater numbers of macrophages and lymphocytes into the tubulointerstitium of the allograft group suggests a mononuclear leukocyte effector cell mediation of the progressive glomerular abnormalities in this model of chronic renal allograft rejection in the rat.     

Dopamine D2 receptors mediate glomerular hyperfiltration due to amino acids

Renal dopamine has been proposed to be involved in the regulation of glomerular filtration rate (GFR). Because inhibition of dopamine D2 receptors abolishes the renal hyperfiltration due to amino acid load, we tested the hypothesis that pharmacological activation of D2-like receptors mimicked this renal response. In anesthetized rats, quinpirole (0.3 microgram . 100 g-1 . min-1), an agonist for receptors of the D2-like family, caused an increase in GFR by 20 +/- 2%, which corresponded to that provoked by infusion of an 10% amino acid solution. The D2 receptor antagonist S(-)-sulpiride that acts both centrally and peripherally completely abolished the renal hemodynamic response to quinpirole and to amino acids whereas domperidone, a peripherally acting D2 receptor antagonist, inhibited this hyperfiltration only in part. Urinary dopamine excretion increased in response to amino acid infusion whether GFR increased or not. We conclude that, in anesthetized rats, dopamine D2 receptors contribute to the amino acid-induced hyperfiltration and that both central and peripheral receptors might be involved, whereas dopamine excreted into the urine does not appear to play a functional role in this renal hemodynamic response.     

Development of traditional careers at new universities. The case of medicine

Furosemide has been reported to produce disproportional changes in blood flow in cortical zones and to inhibit tubuloglomerular feedback (TGF), suggesting that furosemide might alter the intracortical distribution of glomerular filtrate. We have tested this hypothesis by a new method for measuring local and total glomerular filtration rate (GFR) based on proximal tubular accumulation of the basic polypeptide aprotinin (mol wt 6513). Local GFR was calculated in tissue samples dissected from outer cortex (OC), inner cortex (IC) and the corticomedullary border zone (CM) from the plasma clearances of two aprotinin tracers injected i.v. before and after a 3 min i.v. infusion of 25 mg kg-1 furosemide. The mean of five samples from each region was used to determine zonal GFR. Isotonic saline was infused at a rate corresponding to urine flow. Furosemide reduced whole kidney GFR from 1.17 to 1.00 mL min-1 and gave a similar reduction of renal artery blood flow. Urine flow increased from 0.6 to 17% of GFR. Haematocrit (approximately 0.48) and plasma protein concentration (approximately 55 mg mL-1) were maintained while the arterial blood pressure tended to decline (118 +/- 5 mmHg to 108 +/- 6 mmHg, P < 0.05). GFR in OC, IC and CM (1.58, 1.18, 0.42 mL min-1 g-1) fell to 87, 88 and 88% of control after furosemide infusion respectively. The furosemide/control ratio for each sample showed a coefficient of variation of about 3%. We conclude that furosemide produced a modest GFR reduction that was uniform throughout the renal cortex. The homogenous GFR response suggests a similar TGF constriction tone in preglomerular vessels of deep and superficial nephrons.     

Progression of nephropathy in long-term diabetics with proteinuria and effect of initial anti-hypertensive treatment

The rate of progression of nephropathy was studied in 6 young male diabetics with intermittent proteinuria (Albustix) and in 10 young male diabetics with constant proteinuria by measuring glomerular filtration rate (GFR), renal plasma flow (RPF), and urinary albumin excretion by exact techniques. Albumin excretion was elevated in both the recumbent and the erect position in patients with intermittent proteinuria. GFR and RPF were at the same level as in diabetics without proteinuria, and no deterioration in renal function was noted during a mean control period of 32 months. In the patients with constant proteinuria the fall rate during a mean period of 33.6 months for GFR and RPF was 0.91 ml/min/month +/- 0.68 (S.D.) and 4.38 ml/min/month +/- 3.23 (S.D.) respectively. Initial fall rate in GFR correlated well with long-term fall rate, both of which were studied in 7 patients. In the same patients there was a positive correlation between the fall rate in GFR and diastolic blood pressure as well as albumin clearance. In 8 patients with constant proteinuria and mean blood pressure of 159/101 mmHg, antihypertensive treatment was started with propranolol alone or combined with hydralazine and furosemide. During a treatment period of 47 days blood pressure was reduced to 143/93 mmHg, and in the same period urinary albumin excretion was reduced significantly from a mean value of 3547 mug/min to 2414 mug/min (P less than 0.01). Further control studies will clarify whether end-stage of renal insufficiency will be postponed by antihypertensive treatment.     

7-D-ALA]-angiotensin 1-7 blocks renal actions of angiotensin 1-7 in the anesthetized rat

Exogenous angiotensin (Ang) 1-7 affects renal function, but the receptor(s) involved in this response remain(s) to be determined. In an in vitro preparation of proximal tubules, Ang 1-7 was shown to act on Ang II AT1 receptors (minor component), but also on a non-AT1, non-AT2 Ang receptor (major component) to inhibit reabsorption. In brain, Ang 1-7 also exerts effects mediated by a non-AT1, non-AT2 binding site; these effects are inhibited, however, by the angiotensin analog [7-D-Ala]-Ang 1-7. Therefore we tested the effect of Ang II AT1-receptor antagonist losartan and [7-D-Ala]-Ang 1-7 on the renal response to exogenous Ang 1-7 in standard renal-clearance experiments in the anesthetized rat. We found that Ang 1-7 (100 pmol/kg/min, i.a.) increased glomerular filtration rate (GFR), urinary flow rate (UV), and urinary sodium excretion (UNaV) without affecting mean arterial blood pressure (MAP) or urinary potassium excretion (UKV), confirming previous reports. Losartan (10 mg/kg, i.v.) blocked the pressor effect of exogenous Ang II (100 pmol/kg/min, i.a.), but did not significantly affect the renal response to Ang 1-7. Conversely, pretreatment with [7-D-Ala]-Ang 1-7 (5 nmol/kg/min) did not affect the pressor effect of Ang II, but abolished the renal response to Ang 1-7. Application of [7-D-Ala]-Ang 1-7 in the absence of exogenous Ang 1-7 did not alter MAP or GFR, but increased UNaV (by 52%). Our data indicate that similar to the response in brain, the renal response to exogenous Ang 1-7 may be mediated predominantly by a distinct non-AT1 binding site, which is sensitive to blockade by [7-D-Ala]-Ang 1-7. Furthermore, ambient endogenous Ang 1-7 acting on this distinct binding site may not contribute significantly to control of MAP or GFR, but exerts an antinatriuretic influence in the anesthetized rat.     

Proximal tubular basement membrane width in insulin-dependent diabetes mellitus

Although glomerular structure has been studied, careful evaluation of tubular basement membrane (TBM) structure in diabetes in humans has not been done. We measured proximal TBM width, glomerular basement membrane (GBM) width, mesangial fractional volume [Vv(Mes/glom)], mesangial matrix fractional volume [Vv(MM/glom)], and cortical interstitial fractional volume [Vv(Int/cortex)] in 35 insulin-dependent diabetic (IDDM) patients and 20 controls. The patients' mean age was 28 +/- 10 years (X +/- SD) and IDDM duration was 17 +/- 8 years. Twenty-five patients were normoalbuminuric, four microalbuminuric, and six had overt proteinuria. Tubular basement membrane and GBM widths were measured by the orthogonal intercept method and mesangial and interstitial parameters by point counting. The TBM width was 915 +/- 320 nm in IDDM patients and 558 +/- 116 nm in controls (P = 0.0005); the TBM width was also increased in normoalbuminuric patients (849 +/- 297 nm, P = 0.0005). The TBM width was strongly directly related to GBM width (r = 0.67, P < 0.001), Vv(Mes/glom) (r = 0.52, P < 0.01), and Vv(MM/glom) (r = 0.61, P < 0.001), but only weakly to Vv(Int/cortex) (r = 0.29, NS). The TBM width (r = 0.65, P < 0.001) and GBM width (r = 0.65, P < 0.001) were strongly related to hemoglobin A1C (HbA1C), while the Vv(Mes/glom) (r = 0.35, P < 0.05) and Vv(Int/cortex) (r = 0.30, NS) were only weakly related to HbA1C. Thus, increased proximal TBM width is an integral component of early nephropathology in IDDM patients. This study suggests that the metabolic disturbances of diabetes are strong determinants of the constellation of structural abnormalities occurring in human diabetic nephropathy.     

Recombinant human respiratory syncytial virus (RSV) from cDNA and construction of subgroup A and B chimeric RSV

OBJECTIVE: The present study was performed to discriminate between central and peripheral effects of noradrenaline (NA) in normotensive, non-obese, type 2 diabetic patients. METHODS: Study I: In 10 patients and 10 healthy volunteer (HV) cumulative doses of NA were infused intravenously until mean arterial pressure (MAP) rose with 20 mmHg, and subsequently the effects on the forearm blood flow (FBF) was measured. Also, the FBF response to intra-arterial NA (0.025, 0.1, 0.4 micrograms min-1) was measured. Study II: In 13 patients and 14 HV the venous constrictor response to a cumulative local infusion of NA in a dorsal hand vein was determined. RESULTS: In study I the circulating plasma NA concentrations inducing a rise in MAP of 20 mmHg, were lower in the type 2 patients relative to the HV (p < 0.01). The relationship between changes in pressure and changes in heart rate were similar in both groups. Moreover, FBF responsiveness to intra-arterial NA was not different between the two groups. The slopes of the delta MAP/NA regression lines were correlated with basal insulin levels and relative insulin resistance in the healthy volunteers (R = 0.77, p < 0.01, and R = 0.83, p < 0.01), but not in the type 2 diabetic patients. In study II no differences were observed in the dose generating half maximum (ED50) and the maximum (Emax) response to NA between the type 2 patients and the HV. CONCLUSIONS: Non-obese normotensive type 2 patients have an increased pressor response to NA, which is not based upon a defect in skeletal muscle resistance arterioles, peripheral veins, or a defect in the baroreceptor system. Therefore, in type 2 diabetes the noradrenergic responsiveness of other vascular beds, such as the splanchnic or renal, must be enhanced.     

Cohort size rather than follicle-stimulating hormone threshold level determines ovarian sensitivity in polycystic ovary syndrome

BACKGROUND: Hypertension and nephrotoxicity are well-known side-effects of cyclosporine A (CsA). CsA-induced vasoconstriction of the afferent glomerular arteriole probably plays a role in at least the nephrotoxicity. Frequently renal transplant recipients on CsA have to be treated with antihypertensive drugs and for this purpose also beta-blockers are used. Tertatolol is a new beta-blocker with specific vasodilatory properties, and thus might be particularly useful in CsA-treated transplant recipients. METHODS: We studied the systemic and renal haemodynamic effects of atenolol and tertatolol in 12 hypertensive renal transplant recipients on cyclosporine A (CsA). In a cross-over way, all patients were treated with atenolol and tertatolol for 4 weeks each, separated by a wash-out period also of 4 weeks. At the end of each period, the mean arterial pressure (MAP), heart rate, glomerular filtration rate (GFR) and renal plasma flow (RPF) were measured. RESULTS: The mean arterial pressure was lower (P < 0.05) during atenolol (124 +/- 2 mm Hg) and tertatolol (125 +/- 2 mm Hg) treatment compared with washout (132 +/- 4 mm Hg). Also the heart rate was lower (P < 0.01) during atenolol and tertatolol (54 +/- 3 and 55 +/- 2 beats/min respectively) than in the wash-out period (65 +/- 3 beats/min). GFR and RPF were not changed by either beta-blocker. CONCLUSION: In CsA treated renal transplant recipients both atenolol and tertatolol effectively reduced blood pressure. In these patients we found no evidence of a specific vasodilatory effect of tertatolol. Both beta-blockers had no negative influence on renal function. Hence, these cardioprotective agents are an attractive and safe choice for the treatment of hypertension in such patients.     

Enhanced involvement of endothelin in the haemodynamic sequelae of endotoxaemia in conscious, hypertensive, transgenic ((mRen-2)27) rats

1. Age-matched (3-4 months old) male, heterozygous, hypertensive, transgenic ((mRen-2)27) rats (abbreviated to TG rats) and the normotensive control animals (homozygous, Hannover Sprague-Dawley rats (abbreviated to SD rats), were chronically instrumented for the assessment of regional haemodynamic responses to continuous lipopolysaccharide (LPS) infusion (150 microg kg(-1) h(-1), i.v.) 2. The early (1-2 h) hypotension in SD rats (-11+/-3 mmHg; n=7) was significantly less than that in TG rats (-35+/-3 mmHg; n=8), but by 24 h mean arterial blood pressure (MAP) in both strains of rat was not different from the pre-LPS value (SD rats: baseline, 108+/-3 mmHg; 24 h LPS, 112+/-4 mmHg; TG rats: baseline, 171+/-2 mmHg; 24 h LPS, 169+/-3 mmHg). At this stage in the SD rats there was a renal vasodilatation (delta vascular conductance, 29+/-10 [kHz mmHg(-1)]10(3)) but not in TG rats (delta vascular conductance 2+/-3[kHz mmHg(-1)]10(3)). 3. Co-infusion of LPS and the non-selective endothelin receptor antagonist, SB 209670 (600 microg kg(-1) bolus, 600 microg kg(-1) h(-1)) between 24 and 31 h in SD rats caused a fall in MAP of 16+/-2 mmHg accompanied by hindquarters vasodilatation (delta vascular conductance 11+/-3 (kHz mmHg(-1))10(3)). In TG rats, under the same conditions, the fall in MAP was -60+/-6 mmHg, and there were renal, mesenteric and hindquarters vasodilatations (delta vascular conductance, 23+/-5, 32+/-7, and 14+/-4 (kHz mmHg(-1))10(3), respectively). All effects, except the hindquarters vasodilatation, were greater in TG than in SD rats. 4. In TG rats infused with LPS alone for 31 h, between 24 and 31 h the fall in MAP was -17+/-4 mmHg, and the changes in renal, mesenteric and hindquarters vascular conductances were 5+/-3, -4+/-5, and 12+/-4 (kHz mmHg(-1)10(3), respectively. 5. Administration of the angiotensin (AT1)-receptor antagonist, losartan (10 mg kg(-1), i.v.) following co-infusion of LPS and SB 209670 between 24 and 31 h caused similar falls in MAP in SD and TG rats (-12+/-3 and -14+/-4 mmHg, respectively). 6. These results, together with previous findings, are consistent with a relative enhancement of the contribution of endothelin to the maintenance of cardiovascular status in endotoxaemic TG rats, particularly through a mesenteric vasoconstrictor action.     

Renal effects of oral prostaglandin supplementation after ibuprofen in diabetic subjects: a double-blind, placebo-controlled, multicenter trial

Prostaglandins of the E series (PGE) are known to contribute to the maintenance of renal hemodynamics in subjects with chronic renal insufficiency. Agents that block PGE synthesis, nonsteroidal anti-inflammatory agents (NSAID), are widely used by people with renal insufficiency. This study was undertaken in subjects with renal insufficiency secondary to diabetes to evaluate the acute effects of a PGE1 analog, misoprostol, on NSAID-induced changes in RBF, as calculated by para-aminohippurate clearance, and GFR, as calculated by inulin clearance. Sodium excretion was also assessed. Twenty-five fasting subjects with a mean age of 56 +/- 4 yr received 800 mg of ibuprofen orally. A concomitant dose of either a placebo (PL) or 200 micrograms of misoprostol was also given. This was followed in 1 h by either a placebo or an additional 200-micrograms dose of misoprostol. Measurements for the determination of RBF, GFR, blood pressure, and fractional excretion of sodium were performed every 30 min for the next 5 h. The greatest reduction in both GFR (-25 +/- 7 mL/min per 1.73 m2 PL versus -10 +/- 4 mL/min per 1.73 m2, misoprostol delta GFR; P < 0.05) and RBF (-48 +/- 21 mL/min per 1.73 m2 PL versus -15 +/- 8 mL/min per 1.73 m2, M delta RBF; P < 0.05) occurred approximately 2 h after the NSAID dose. No significant differences were noted in blood pressure, fractional excretion of sodium, or other measured parameters between groups during the entire study. Gastrointestinal upset was the most common side effect observed in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)