Effect of ACE inhibitors in diabetic and nondiabetic chronic renal disease: a systematic overview of randomized placebo-controlled trials.

Clinical trials have shown the beneficial effects of angiotensin-converting enzyme (ACE) inhibitors in delaying the progression of diabetic renal disease. There is less evidence from primary clinical trials of nondiabetic renal disease. We performed an updated meta-analysis to determine the efficacy of ACE inhibitors in slowing the progression of renal disease over a broad range of functional renal impairment. We included published and unpublished randomized, placebo-controlled, parallel trials with at least 1 year of follow-up available from January 1970 to June 1999. In nine trials of subjects with diabetic nephropathy and microalbuminuria, the relative risk for developing macroalbuminuria was 0.35 (95% confidence interval [CI], 0.24 to 0.53) for individuals treated with an ACE inhibitor compared with placebo. In seven trials of subjects with overt proteinuria and renal insufficiency from a variety of causes (30% diabetes, 70% nondiabetes), the relative risk for doubling of serum creatinine concentration or developing end-stage renal disease was 0.60 (95% CI, 0.49 to 0.73) for individuals treated with an ACE inhibitor compared with placebo. Treatment of individuals with chronic renal insufficiency with ACE inhibitors delays the progression of disease compared with placebo across a spectrum of disease causes and renal dysfunction.

MR findings in diffuse renal parenchymal disease.

This study evaluates the MR appearance of the kidney in diffuse renal parenchymal diseases, using precontrast, and immediate and delayed postgadolinium chelate (Gd), spoiled gradient echo (SGE), and pre- and post-Gd, T1-weighted, fat-suppressed spin-echo MR images to determine if characteristic findings exist for various types of renal disease. One hundred twenty-one patients with renal disease underwent MRI. Underlying diagnoses included: (a) glomerular disease (GD), (b) tubulointerstitial disease (TID), (c) microvascular disease (MVD), (d) ischemic nephropathy (INP), (e) obstructive nephropathy (ON), (f) infectious renal disease (IRD), (g) sickle cell disease (SCD), (h) renal cortical necrosis (CN), and (i) renal insufficiency of unknown etiology (UE). MR examinations of 22 patients with normal kidneys (NK) were evaluated as a control group. The presence of corticomedullary differentiation (CMD) demonstrated strong inverse correlation with serum creatinine concentration (SCr) (r = -.568, P < .001). Mean thickness of the renal cortex was 8.4 and 7.8 mm in patients with NK and Gd, respectively. The mean cortical thickness in patients with MVD, TID/Chemo, INP, and ON was 5.2, 5.6, 5.5, and 4.3 mm, respectively, significantly thinner than the renal cortex in the NK and GD groups (P < .01). Irregularity of the renal cortex was more frequent in MVD (60.9%), IRD (62.5%), ON (55.6%), and TID/other (53.8%) than in GD (3.8%) and NK (0%) (P < .01). Diffuse high SI of the entire medulla on delayed postcontrast images was observed in 25 (20.7%) of the patients with renal disease and none of the NK group. Although no pathognomonic features were found, certain findings were observed that may correlate with the etiology of the kidney disease and, therefore, assist in the differential diagnosis of renal parenchymal disease.

Renal corticomedullary differentiation: observation in patients with differing serum creatinine levels.

PURPOSE: To evaluate renal corticomedullary differentiation (CMD) in patients with differing serum creatinine (sCr) levels. MATERIALS AND METHODS: Ten patients with normal sCr levels (0.9-1.3 mg/dL [80-115 mumol/L]), 14 with mildly elevated levels (1.5-2.9 mg/dL [133-256 mumol/L]), and 15 with elevated levels (> 3.0 mg/dL [265 mumol/L]) were examined with unenhanced T1-weighted fat-suppressed spin-echo (T1FS) and immediate gadolinium-enhanced gradient-echo (Gd-GRE) imaging. RESULTS: Patients with normal sCr levels had CMD on T1FS and Gd-GRE images. Among patients with mildly elevated levels, seven did and seven did not have CMD on T1FS images; all had CMD on Gd-GRE images. Patients with elevated levels had no CMD on T1FS images; 13 had CMD on Gd-GRE images. Two patients with levels above 10.0 mg/dL (884 mumol/L) had no CMD on Gd-GRE images. CONCLUSION: Independent of the cause of elevated sCr level, levels above 3.0 mg/dL result in loss of CMD on T1FS images, while levels above 10.0 mg/dL result in loss of CMD on Gd-GRE images.

Vasopressinase-altered vasopressin elevates arterial pressure in anesthetized rats.

Transient diabetes insipidus of pregnancy (TDIP) is associated with elevated activity of vasopressinase, a plasma enzyme that opens the vasopressin (AVP) ring to produce a linear peptide that we have named vasopressinase-altered vasopressin (VAV). VAV may play a role in the pathogenesis of the arterial hypertension associated with TDIP. We sought to determine if VAV elevates arterial pressure, the potency of VAV relative to that of AVP, and whether the peptide binds to the vascular AVP receptor. AVP was incubated with vasopressinase and VAV was separated from residual AVP by high-pressure liquid chromatography. Intravenous bolus administration of VAV or AVP to ganglionic blocked rats produced dose-dependent increases in arterial pressure, with VAV demonstrating approximately 6000-fold lower potency than AVP. Vasopressin receptor blockade abolished the response to both AVP and VAV. These results suggests that high levels of VAV may contribute to the hypertension seen in TDIP.

Unmasking sensitive alpha 2-adrenoceptor-mediated renal vasoconstriction in conscious rats.

Renal vascular reactivity to intrarenal arterial boluses of norepinephrine (NE), phenylephrine (PHE; alpha 1-agonist), and guanabenz (GBZ; alpha 2-agonist) was assessed in conscious, freely moving, chronically instrumented, normotensive Wistar rats. Dose-response curves (DRCs) were obtained in the absence and cumulative presence of propranolol (PROP; beta-antagonist), corynanthine (CORY; alpha 1-antagonist) and idazoxan (IDX; alpha 2-antagonist) to estimate effective dosages (ED) required for 15 and 75% peak reductions in renal blood flow. The PHE DRC had a short shallow ED15 region, but was primarily linear with a steep slope. The GBZ DRC had a shallow slope. The NE DRC had a prolonged shallow phase in the ED15 region and a steep slope in the ED75 region. PROP had no effect on the DRCs. CORY caused a parallel rightward shift of the PHE DRC and had no effect on the GBZ DRC. After CORY, the shallow ED15 portion of the NE DRC was even more pronounced with a slope now identical to that of the GBZ DRC, whereas the ED75 region of the NE DRC was shifted rightward like the PHE DRC. IDX preferentially antagonized the ED15 regions of the GBZ and NE DRCs. In a second group of rats, the alpha 2-adrenoceptor antagonist, rauwolscine, was administered following base-line DRCs to demonstrate rightward shifts of the NE and GBZ DRCs when PHE DRCs remained unaffected. Therefore, when boluses of NE are injected into the rat kidney, the vasoconstrictive responses are a result of the activation of both alpha 1- and alpha 2-adrenoceptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical pharmacology of carvedilol in normal volunteers.

The mechanism of the vasodilatory action of carvedilol (BM 14190), a new antihypertensive agent, was investigated in normal volunteers. Intra-arterial blood pressure and ECG were monitored continuously. Carvedilol (1 mg/min for 15 minutes) produced a rapid reduction in blood pressure and a transient increase in heart rate. At the end of infusion, systolic and diastolic blood pressure were reduced by 23% (-32.3 mm Hg) and 18% (-13.6 mm Hg), respectively, whereas heart rate was not different from baseline. At the doses used, the hypotensive effect of carvedilol was greater than that of labetalol (36 and 72 mg in 15 minutes). Carvedilol and labetalol antagonized isoproterenol-induced hypotension and tachycardia, at serum levels greater than or equal to 8 and 20 mg/ml, respectively. Both drugs antagonized phenylephrine pressor effects. A similar degree of inhibition (25% of control) of pressor effects was observed for carvedilol and labetalol when their respective serum concentrations were 23 ng/ml and 80 ng/ml. Neither carvedilol nor labetalol had any effect on AII pressor responses. Carvedilol serum levels as high as 150 ng/ml failed to inhibit AII-induced pressor responses. Our results suggest that at the doses used in this study, carvedilol has both alpha 1-and nonselective beta-receptor blocking properties. Moreover, carvedilol is approximately three to five times more potent than labetalol in blocking alpha 1-and beta-receptors and in reducing blood pressure.

Mechanism of the vasodilatory effect of carvedilol in normal volunteers: a comparison with labetalol.

In a single blind parallel design, saline (n = 9), labetalol i.v. (40 mg n = 4, 80 mg n = 3), and carvedilol i.v. (15 mg n = 8) were given to volunteers with blood pressure (BP) recorded intraarterially. The effect of these treatments on the response to challenge doses of angiotensin II (to give a rise in mean BP of 20-25 mm Hg), isoproterenol (to give an increase in heart rate of 30-35 beats/min), and phenylephrine (to give a rise in mean BP of 20-25 mm Hg) were studied. The dose of i.v. carvedilol employed gave a greater fall in BP than the dose of labetalol used. Carvedilol appeared to be about four times more potent than labetalol in inhibiting the tachycardia to isoprenaline. Likewise, from inhibition of the pressor response to phenylephrine, it is concluded that carvedilol is four times more effective at the alpha receptor than labetalol. Neither drug was found to antagonize the pressor effects of angiotensin. Calculation of the half-life of carvedilol gave values of 2.2 to 9 h. The volume of distribution was found to be 1.54 l/kg and the total body clearance was 0.521 l/h/kg.

Cholinergic stimulation of the hypothalamus and natriuresis in rats: role of the renal nerves.

The role of the renal nerves in the natriuresis seen after cholinergic stimulation of the hypothalamus was studied in anesthetized rats treated with injection into the lateral hypothalamus (LH) of 1 microgram of carbamylcholine chloride (carbachol) in 1 microliter of 0.15 M NaCl or NaCl alone. Injection of carbachol exhibited diuresis and natriuresis both in acutely denervated kidneys (P less than 0.01) and in contralateral innervated kidneys (P less than 0.01) without changes in glomerular filtration rate (GFR) or renal plasma flow (RPF) (n = 10). Salt and water excretion was unchanged in 10 rats after injection of NaCl. Micropuncture studies in denervated kidneys showed that, after carbachol injection, tubular fluid-to-plasma inulin concentration ratio [(F/P)In] in the late proximal tubule fell from 1.86 +/- 0.08 to 1.64 +/- 0.07 (P less than 0.01) without changes in single-nephron GFR. In nine other carbachol-treated rats in which renal perfusion pressure was maintained low and constant, diuresis and natriuresis, although attenuated, were again observed both in denervated (P less than 0.01) and in contralateral innervated kidneys (P less than 0.05). In another group of 11 animals, efferent renal nerve activity (ERNA) was recorded before and after LH injection of carbachol and isotonic saline. ERNA was significantly depressed for 30 min, only after carbachol injection. Our results suggest that the renal nerves, although involved, are not essential for the natriuretic response after cholinergic stimulation of LH. By exclusion, other factors, presumably hormones, must contribute to the response.

Effects of chronic renal denervation in conscious restrained rats.

Sodium (Na), calcium (Ca), inorganic phosphate (Pi) and water excretion were measured in nondiuretic (ND) and extracellular fluid (ECF) volume expanded (VE) conscious restrained rats four weeks after denervation or sham-denervation of the left kidney. On the day of the study the animals were lightly anaesthetized with ether and the femoral vessels on one side were catheterized. Urine was collected from both kidneys. The animals were allowed to recover for 3 hours and studied in a restraining chamber. In ND animals isotonic saline containing inulin and para-amino-hippuric acid (PAH) were given at a rate of 0.067 +/- 0.002 (SE) ml/min/kg body weight (BW). In VE animals the infusion rate was 0.24 +/- 0.04 ml/min/kg BW. Kidney catecholamine content was measured after the experiments. Clearances of PAH and of inulin (GFR) were the same in both kidneys. Urine volume (V), sodium excretion (UNa V/GFR), inorganic phosphate excretion (UPi V/GFR) and calcium excretion (UCa V/GFR) were significantly higher in the denervated kidneys. Values in sham denervated kidneys were not greater than those of the right kidney. Denervation was proven by demonstrating absent or very low catecholamine content in the kidneys. The results demonstrate that: chronic renal denervation in rats leads to diuresis and natriuresis even in the conscious state, thus confirming previous results from our laboratory; such changes occur independently of the state of the ECF volume and of renal haemodynamic changes; the increased excretion of Ca++ and Pi after denervation demonstrates that renal nerves affect the reabsorption of these ions either independently or by way of their effect on sodium reabsorption. These data allow us to suggest that a renal tubular dysfunction, which was proved in anaesthetized denervated animals, can also be observed in the conscious state.

Role of renal nerves in maintaining sodium balance in unrestrained conscious rats.

This study was designed to investigate the effects of bilateral renal denervation on sodium and water balance, the renin-angiotensin system, and systemic blood pressure in unrestrained conscious rats maintained on a normal- or low-sodium diet. Renal denervation was proven by chemical and functional tests. Both bilaterally denervated rats (n = 18) and sham-denervated rats (n = 15) maintained positive sodium balance while on a normal sodium intake. Both groups were in negative sodium balance for 1 day after dietary sodium restriction was instituted but were in positive sodium balance for the following 9 days. Systolic blood pressure was higher in sham-denervated (115 +/- 3 mmHg) than in denervated rats (102 +/- 3 mmHg) while on a normal diet (P less than 0.05) and remained so during sodium restriction. Plasma renin concentration (PRC) and plasma aldosterone concentration (PAC) were significantly diminished in the denervated rats during normal sodium intake (P less than 0.05). After dietary sodium restriction, PRC increased in both groups but remained significantly lower in the denervated rats (P less than 0.05). Following dietary sodium restriction, PAC also increased significantly to levels that were similar in both groups of rats. These results demonstrate that awake unrestrained growing rats can maintain positive sodium balance on a low sodium intake even in the absence of the renal nerves. However, efferent renal nerve activity influenced plasma renin activity in these animals.

Study of sodium and potassium excretion after renal denervation and cholinergic stimulation of the lateral hypothalamic area of the rat.

Studies were undertaken to characterize the renal responses to acute unilateral renal denervation and chronic bilateral denervated kidneys after cholinergic stimulation of the anterior part of the lateral hypothalamus. Denervation was produced in anesthetized and conscious nondiuretic rats by application of phenol to the renal artery. Studies were also performed in sham denervated rats. Whole kidney function in anesthetized animals showed a significant increase of fractional sodium excretion (0.7 +/- 0.1 to 1.7 +/- 0.4%, P less than 0.01) both in the denervated and in the innervated kidney (0.09 +/- 0.02 to 1.1 +/- 0.2%, P less than 0.005) after carbachol injection into the LHA, whereas the percentage of filtered potassium excreted increased only in the innervated kidney (11.4 +/- 1.3 to 16.3 +/- 1.1%, P less than 0.01). Similarly, in conscious rats, fractional sodium excretion increased after cholinergic stimulation in animals having denervated kidneys (2.1 +/- 0.1 vs 3.6 +/- 0.2%, P less than 0.005). Fractional potassium excretion also increased both in rats with sham-denervated and denervated kidney. There was an acute elevation in mean arterial blood pressure and glomerular filtration rate (GFR) during the first 20-min after carbachol injection. Sodium excretion was statistically significant during the three 20-min collections of the experimental period. This suggests that the natriuresis is not associated with increased arterial pressure, GFR or renal plasma flow. Our results indicate that natriuresis occurs even in the absence of the renal nerves.

Factors causing natriuresis after hypothalamic injection of a cholinergic drug in rats.

We investigated possible mechanisms for the natriuresis seen after injection of the cholinergic drug carbamylcholine chloride (carbachol) into the lateral hypothalamus of conscious rats. In unrestrained rats injection of 1 microgram of carbachol in 1 microliter of 0.15 M NaCl solution through a permanently implanted cannula produced a significant natriuresis and kaliuresis. Injection of vehicle produced no changes. The same animals were then subjected to bilateral renal denervation (n = 13) or sham denervation (n = 13) and injected with the same solutions 1 wk later. Carbachol injection produced a natriuresis (P less than 0.0001) and a kaliuresis (P less than 0.01) in all animals studied. Both responses were of a magnitude similar to the responses seen before denervation. We studied other rats while awake but restrained, which permitted the performance of clearance studies and blood pressure measurements. Injection of carbachol produced diuresis, natriuresis, and kaliuresis in all rats, with no change in p-aminohippurate clearance and only transient change in inulin clearance. An increase in blood pressure occurred in some but not all rats. The response in rats with bilaterally denervated kidneys (n = 7) was similar to that of rats with innervated kidneys (n = 5). The natriuresis seen after cholinergic stimulation of the hypothalamus in conscious rats is not primarily mediated by inhibition of renal nerve activity and can be dissociated from changes in blood pressure, glomerular filtration rate, and renal plasma flow.

Functional evidence for renorenal reflexes in the rat.

Acute left renal denervation in anesthetized volume-expanded rats produced an ipsilateral diuresis and natriuresis in 19 animals. A simultaneous decrease of glomerular filtration rate, p-aminohippurate clearance, urinary volume (P < 0.002), and percentage of filtered sodium excreted (4.0 +/- 0.6 (SE) vs. 1.9 +/- 0.4%, P < 0.003) occurred in the right innervated kidney in 10 rats. Prior denervation of the right kidney in the other nine rats prevented the renal hemodynamic changes and the fall of urinary volume and of sodium excretion (3.9 +/- 0.6 vs. 4.3 +/- 0.5%) by the right kidney after left renal denervation. Nerve traffic to the right kidney was measured in six other animals after left renal denervation and was found to increase to a mean value 33.8 +/- 6.3% above control levels (P < 0.007) 0-30 min after denervation, with a further significant increase to 66.2 +/- 16.1% above control levels (P < 0.025) 30-60 min after denervation. These results indicate that the functional changes in the right kidney after contralateral renal denervation in volume-expanded rats are caused by a reflex increase in nerve traffic to the right kidney, possibly as a consequence of an interruption of afferent nerve activity originating in the left kidney.