CLCN5 mutation Ser244Leu is associated with X-linked renal failure without X-linked recessive hypophosphatemic rickets.

This study demonstrates that a missense mutation in the voltage gated chloride channel, CLCN5, can cause X-linked renal failure without X-linked recessive hypophosphatemic rickets. A large kindred (Family A), initially evaluated in 1974 with an inherited syndrome characterized by hypercalciuria, nephrocalcinosis, low molecular weight proteinuria, renal tubular acidosis, and renal failure, was clinically re-evaluated and genetically characterized. Medical histories, physical examinations, blood chemistries, and 24-hour urine collections were obtained from 48 family members. Both female and male family members exhibited hypercalciuria, nephrolithiasis, and low molecular weight proteinuria. However, only men developed renal insufficiency, consistent with an X-linked recessive gene defect. Genetic linkage located the disease locus on the proximal short arm of the X chromosome (Xp11) where a voltage gated chloride channel gene, CLCN5, had previously been mapped. DNA sequence of the CLCN5 gene demonstrated a missense mutation (Ser244Leu) in affected family members. The same missense mutation has previously been shown to cause X-linked recessive hypophosphatemic rickets. No affected member of Family A had evidence of chronic hypophosphatemia, clinically significant rickets, or osteomalacia. We hypothesize that genetic background, environment, diet, or an unidentified modifying gene may account for the differing phenotypes resulting from this shared gene defect.

A prospective evaluation of a simplified captopril test for the detection of renovascular hypertension.

Renovascular hypertension is potentially curable but of low prevalence. A previous retrospective study has demonstrated the use of a potentiated increase in plasma renin activity after captopril administration as a diagnostic test for renovascular hypertension; this requires two blood samples for plasma renin activity determination and three inclusive criteria for a positive test result. We applied this test prospectively to screen 100 hypertensive patients for renovascular hypertension. We evaluated 29 patients with renovascular hypertension; the remainder were diagnosed as having essential hypertension. In our patient population, a postcaptopril plasma renin activity of 5.7 ng of angiotensin per milliliter per hour (ngAl.mL-1.h-1) or greater had a 100% sensitivity and an 80% specificity for renovascular hypertension. An absolute increase in plasma renin activity with captopril of 4.7 ngAl.mL-1.h-1 or greater had a lower sensitivity of 90% and a specificity of 87%, whereas a fractional increase in plasma renin activity after captopril of 150% or higher had the lowest sensitivity of 69% and a specificity of 86%. A subgroup analysis of 38 patients who were receiving diuretic therapy demonstrated that the test sensitivity was unchanged but the specificity was reduced. In conclusion, a single postcaptopril plasma renin activity value of 5.7 ngAl.mL-1.h-1 or greater is a simplified screening test for renovascular hypertension, with excellent sensitivity and acceptable specificity. This test is well tolerated, inexpensive, and easy to perform.

The captopril glomerular filtration rate renogram in renovascular hypertension.

Administration of captopril to animals with two-kidney, one clip, renovascular hypertension (RH) lowers the glomerular filtration rate (GFR) in the clipped kidney. The authors therefore tested the hypothesis that a decrease in GFR after captopril administration would identify patients with RH. Total GFR was measured by the plasma disappearance of Tc-99m-diethylenetriaminepentaacetic acid (DTPA) after bolus injection and single-kidney GFR from renal uptake of DTPA assessed by renography. The authors studied six patients with arteriosclerotic RH who had strongly lateralizing renal vein renin levels and greater than 80% stenosis of the renal artery to that kidney. Results were contrasted with those of six patients with essential hypertension (EH) with a similar mean arterial blood pressure (MABP). Captopril (50 mg orally) increased total GFR (ml/min) in all patients with EH (102 +/- 8 to 120 +/- 12, P less than 0.005). However, GFR decreased in patients with RH (73 +/- 8 to 61 +/- 9, P less than 0.05) after captopril. Although the single-kidney GFR of patients with RH decreased in all six stenotic kidneys (27 +/- 4 to 21 +/- 5, P less than 0.02), it did not change consistently in the contralateral kidneys (45 +/- 8 to 40 +/- 6, N.S.). Clonidine (0.3 mg) also lowered MABP in patients with RH but, unlike captopril, it did not reduce total kidney GFR (75 +/- 10 to 79 +/- 11, N.S.). In conclusion, short-term captopril administration increases GFR in patients with EH, but decreases it in those with RH. This action is unrelated to its depressor response.(ABSTRACT TRUNCATED AT 250 WORDS)

Contrast echocardiography: effects of microbubbles on coronary blood flow and left ventricular hemodynamics.

Contrast echocardiography is currently being used to define and quantitate myocardial perfusion at the time of cardiac catheterization. Limited and conflicting data exist regarding the physiologic effects of microbubble-containing contrast agents. In the present study, coronary blood flow measured using an electromagnetic flow meter, blood pressure, and heart rate responses were studied in six dogs. An ECG-gated power injector was used to deliver 7 to 9 ml of sonicated and nonsonicated solutions (saline, Renografin-76, dextrose 50% and 70%, and sorbitol 70%) through an intra-aortic catheter placed above the aortic cusps. Paired injections of sonicated and nonsonicated agents were compared to determine whether the presence of microbubbles affected the physiologic response to these agents. Simultaneous recordings of two-dimensional cross-sectional images of the left ventricle were obtained. Data are expressed as percentage of change from preinjection control values. Within 10 seconds of an injection, decreases in coronary blood flow occurred in a range from -1 to -10% compared with preinjection control values. Coronary blood flow increased between 10 and 25 seconds postinjection within a range from +11 to +29%. Systemic blood pressures rose during injections and then declined below control values within 10 seconds. The magnitude of the decline in systolic blood pressure ranged from -5. to -18%. Diastolic blood pressure declined in a range from -13 to -33%. Within 20-30 seconds postinjection, systemic blood pressure rose above control values. The magnitude of the systolic and diastolic blood pressure rise ranged from +4 to +11%.(ABSTRACT TRUNCATED AT 250 WORDS)

Diagnostic uses of angiotensin-converting enzyme inhibitors in renovascular hypertension.

The response to angiotensin-converting enzyme inhibitors (ACEIs) can be of considerable help in the diagnosis of human renovascular hypertension (RVH) in three settings. First, a particularly dramatic antihypertensive response or a decline in glomerular filtration rate (GFR), as indexed by a rise in serum creatinine or blood urea nitrogen concentrations, are useful clues to the presence of renovascular hypertension. Second, an exaggerated rise in plasma renin activity (PRA) after short-term captopril administration is a very promising screening test for this condition. Third, ACEI-induced changes in single-kidney hemodynamics (assessed by renography) may be helpful in confirming the diagnosis and offers the prospect of localizing the ischemic kidney.

Pharmacokinetic and pharmacodynamic properties of intravenous fenoldopam, a dopamine1-receptor agonist, in hypertensive patients.

1 The pharmacokinetic properties of intravenous fenoldopam, a selective dopamine1-receptor agonist, were studied in 10 patients with essential hypertension. 2 Reduction in blood pressure was linearly related to the log fenoldopam plasma concentration (r = 0.69) and the log fenoldopam infusion rate (r = 0.71). 3 The mean elimination half-life (+/- s. e. mean) was 9.8 +/- 1.0 min. The total body clearance was 30.3 +/- 2.3 ml kg-1 min-1 and the volume of distribution was 582 +/- 62 ml kg-1. 4 The rapid onset of action, short elimination half-life, linear dose-response relationship, and ease of administration suggest that fenoldopam may have a role where parenteral treatment of hypertension is required.

Augmentation of renal blood flow and sodium excretion in hypertensive patients during blood pressure reduction by intravenous administration of the dopamine1 agonist fenoldopam.

Activation of dopamine1 (DA1) receptors relaxes vascular smooth muscle, especially in the renal vascular bed. Fenoldopam, the first selective DA1-receptor agonist that can be administered to man, was infused intravenously in 17 patients with essential hypertension (mean blood pressure 152/101 mm Hg). It reduced blood pressure in a dose-dependent fashion at doses between 0.025 and 0.5 microgram/kg/min and the antihypertensive effect was sustained during 2 hr infusions. In 10 patients studied during free-water diuresis, fenoldopam increased renal plasma flow by 42%, glomerular filtration rate by 6%, and sodium excretion by 202%, while lowering mean arterial pressure by 12% (all p less than .05). Similar promotion of sodium excretion was observed during blood pressure reduction in six additional patients studied without water loading. Pronounced enhancement of renal function in spite of blood pressure reduction suggests that fenoldopam might have a special role in the treatment of patients with hypertension and renal impairment.

Contrast ultrasonography of the kidney: a new method for evaluation of renal perfusion in vivo.

Assessment of the effects of pharmacologic agents on renal blood flow (RBF) is clinically important in many disease states, including hypertension and congestive heart failure. However, because of the complexities of RBF, quantitation in vivo has been technically difficult. This study demonstrates the utility of ultrasound imaging of the kidney combined with injection of a sonicated radiocontrast solution (Renografin-76) for the assessment of regional renal blood flow. The technique uses a suspension of uniform microbubbles (diameter 4.4 +/- 2.8 micron), which when injected directly into the descending aorta are distinctly visualized by renal ultrasound. Five dogs were studied. Catheters were placed in the descending aorta for injection of sonicated Renografin and in the renal artery for drug infusions. Data were collected before and during intrarenal artery infusions of bradykinin and norepinephrine. Total RBF was measured by electromagnetic flowmeter. Video density time curves were generated for comparable segments of the outer renal cortex and fit to a monoexponential decay curve. This allowed calculation of the mean exponential decay index (t1/2). An increase in t1/2 paralleled decreased renal perfusion (i.e., longer washout of contrast material). The opposite was true for a decrease in t1/2. Bradykinin increased RBF from 134 +/- 26 to 249 +/- 19 ml/min (p less than .01 vs control), and norepinephrine decreased RBF from 130 +/- 25 to 51 +/- 17 ml/min (p less than .01 vs control).(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of DA1 receptor blockade with SCH 23390 on the renal response to electrical stimulation of the renal nerves.

To evaluate the existence of functional renal dopaminergic innervation in the dog, we studied the effects of direct electrical stimulation of the renal nerves (RNS) with and without blockade of the dopamine receptor (DA1) that mediates the vasodilating and natriuretic response to intrarenal infusion of DA. Before infusion of the DA1 receptor antagonist, SCH 23390, RNS at 1 Hz did not change renal blood flow (RBF) but caused decreased urinary sodium excretion (-53 +/- 9%, P less than 0.01) and fractional excretion of sodium (-47 +/- 10%, P less than 0.01). Stimulation at 4 and 12 Hz elicited marked renal vasoconstriction (delta RBF = -37 +/- 12%, P less than 0.05 and -57 +/- 12%, P less than 0.01, respectively). When RNS (1 Hz) was performed during DA1 receptor blockade with SCH 23390, 0.5 microgram . kg-1 . min-1 iv, the responses were not different than those before SCh 23390 infusion (urinary sodium excretion: -54 +/- 7%, P less than 0.01 and fractional excretion of sodium: -46 +/- 5%, P less than 0.01). Renal vasoconstriction was also not influenced by SCH 23390 (delta RBF = -35 +/- 11%, P less than 0.05 during 4 Hz RNS and -58 +/- 12%, P less than 0.01 at 12 Hz RNS). Thus, the present study does not support the concept of functional dopaminergic innervation of the canine kidney.

Blockade of renal effects of dopamine in the dog by the DA1 antagonist SCH 23390.

Dopamine (DA) acts on two receptor subtypes, DA1 and DA2. The purpose of this study was to determine which subtype is involved in the increments in renal blood flow (RBF) and electrolyte excretion produced by DA. Mongrel dogs were anesthetized with pentobarbital sodium. Phenoxybenzamine (10 mg X kg-1 ia) and propranolol (5 mg X kg-1 iv) were administered to exclude effects mediated by alpha- and beta-adrenoceptors. DA was infused into the renal artery before and after administration of either the selective DA1 antagonist SCH 23390 or the selective DA2 antagonist domperidone. With DA alone, RBF increased by 52 +/- 7%, Na+ excretion increased by 35 +/- 8%, and K+ excretion increased by 35 +/- 5%. Infusion of SCH 23390 (0.5 micrograms X kg-1 X min-1) completely blocked DA-induced increase in RBF and electrolyte excretion. Intravenous infusion of domperidone (1 microgram X kg-1 X min-1) did not attenuate the responses to DA. Neither SCH 23390 nor domperidone affected base-line RBF or electrolyte excretion, suggesting that in these experiments endogenous DA was not active. In conclusion, these data indicate that the effects of DA to increase RBF and electrolyte excretion are the result of action on DA1 receptors.