Stuart L. Linas

Urinary Diagnostic Indices in Acute Renal Failure: A Prospective Study

A prospective analysis of the value of urinary diagnostic indices in ascertaining the cause of acute renal failure was undertaken. Our results show that in the setting of acute oliguria a diagnosis of potentially reversible prerenal azotemia is likely with urine osmolality greater than 500 mosm/kg H2O, urine sodium concentration less than 20 meq/litre, urine/plasma urea nitrogen ratio greater than 8, and urine/plasma creatinine ratio greater than 40. Conversely, a urine osmolality less than 350 mosm/kg, urine sodium concentration greater than 40 meq/liter, urine/plasma urea nitrogen ratio less than 3, and urine/plasma creatinine ratio less than 20 suggest acute tubular necrosis. A significant number of oliguric patients will not have urinary indices that fall within these guidelines. In this setting, urine sodium concentration divided by the urine-to-plasma creatinine ratio (the renal failure index) and the fractional excretion of filtered sodium provide a reliable means of differentiating reversible prerenal azotemia from acute tubular necrosis.

Divergent Results Using Clinic and Ambulatory Blood Pressures: Report of a Darusentan-Resistant Hypertension Trial

Patients with resistant hypertension are at increased risk for cardiovascular events. The addition of new treatments to existing therapies will help achieve blood pressure (BP) goals in more resistant hypertension patients. In the current trial, 849 patients with resistant hypertension receiving ≥3 antihypertensive drugs, including a diuretic, at optimized doses were randomized to the selective endothelin A receptor antagonist darusentan, placebo, or the central &agr;-2 agonist guanfacine. The coprimary end points of the study were changes from baseline to week 14 in trough, sitting systolic BP, and diastolic BP measured in the clinic. Decreases from baseline to week 14 in systolic BP for darusentan (−15±14 mm Hg) were greater than for guanfacine (−12±13 mm Hg; P<0.05) but not greater than placebo (−14±14 mm Hg). Darusentan, however, reduced mean 24-hour systolic BP (−9±12 mm Hg) more than placebo (−2±12 mm Hg) or guanfacine (−4±12 mm Hg) after 14 weeks of treatment (P<0.001 for each comparison). The most frequent adverse event associated with darusentan was fluid retention/edema at 28% versus 12% in each of the other groups. More patients withdrew because of adverse events on darusentan as compared with placebo or guanfacine. We conclude that darusentan provided greater reduction in systolic BP in resistant hypertension patients as assessed by ambulatory BP monitoring, in spite of not meeting its coprimary end points. The results of this trial highlight the importance of ambulatory BP monitoring in the design of hypertension clinical studies.

Increased Osmolal Gap in Alcoholic Ketoacidosis and Lactic Acidosis

OBJECTIVE To determine whether an elevated osmolal gap is specific for toxic alcohol ingestion. DESIGN Cross-sectional. SETTING Emergency room and medical and surgical inpatient wards at a university-affiliated hospital. PATIENTS Twenty-three patients with lactic acidosis, 19 with alcoholic ketoacidosis, and 10 randomly selected controls. MEASUREMENTS AND MAIN RESULTS Calculated and measured serum osmolality was determined in all study participants. The osmolal gap was increased in patients with lactic acidosis (17.4 +/- 5.4 mmol/kg) and alcoholic ketoacidosis (26.9 +/- 7.6 mmol/kg) when compared with controls (-1.7 +/- 1.7 mmol/kg, P less than 0.05 for both comparisons). When ethanol was included in the calculation, the osmolal gap remained elevated in the lactic acidosis (10.3 +/- 2.0 mmol/kg) and alcoholic ketoacidosis (11.1 +/- 3.2 mmol/kg) groups (P less than 0.05 for both comparisons). CONCLUSIONS The osmolal gap is often used as a screen for toxic alcohol ingestion. When calculating the osmolal gap, the contribution of ethanol should be considered. An elevated osmolal gap is not specific for toxic alcohol ingestion, as the osmolal gap was elevated in patients with lactic acidosis and alcoholic ketoacidosis. These two conditions should be considered when using the osmolal gap to design therapy (for example, hemodialysis) in the setting of anion gap metabolic acidosis and suspected toxic alcohol ingestion.

Efficacy and safety of darusentan in patients with resistant hypertension: results from a randomized, double-blind, placebo-controlled dose-ranging study.

In this phase 2, randomized, double‐blind, placebo‐controlled forced dose‐titration study, 115 patients with resistant hypertension, receiving background therapy with ≥3 antihypertensive medications including a diuretic at full doses, were randomized 2:1 to increasing doses of darusentan (10, 50, 100, 150, and 300 mg), a selective endothelin receptor antagonist, or matching placebo once daily for 10 weeks. Darusentan treatment decreased mean systolic and diastolic blood pressure levels in a dose‐dependent fashion compared with placebo; the largest reductions were observed at week 10 (300‐mg dose) (systolic, −11.5±3.1 mm Hg [P=.015]; diastolic, −6.3±2.0 mm Hg [P=.002]). Darusentan (300 mg) also decreased mean 24‐hour, daytime, and nighttime ambulatory blood pressures from baseline to week 10. Darusentan was generally well tolerated; mild to moderate edema and headache were the most common adverse events. This study demonstrates a clinical benefit from a new class of antihypertensive agent in patients classified as resistant by the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure guidelines.

On the Mechanism of Polyuria in Potassium Depletion: THE ROLE OF POLYDIPSIA

The association of potassium (K) depletion with polyuria and a concentrating defect is established, but the extent to which these defects could be secondary to an effect of low K on water intake has not been systematically investigated. To determine whether hypokalemia has a primary effect to increase thirst and whether any resultant polyuria and polydipsia contribute to the concentrating defect, we studied three groups of rats kept in metabolic cages for 15 days. The groups were set up as follows: group 1, normal diets and ad lib. fluids (n = 12); group 2, K-deficient diet on ad lib. fluids (n = 12); and group 3, K-deficient diet and fluid intake matched to group 1 (n = 14). Daily urine flow and urinary osmolality of groups 1 and 3 were not significantly different throughout the study. In contrast, as of day 6, group 2 rats consistently had a higher fluid intake (P < 0.0025), higher urine flow (P < 0.001), and lower urinary osmolality (P < 0.001) than the other two groups. These alterations in fluid intake and urine flow preceded a defect in maximal concentrating ability. On day 7, maximal urinary osmolality was 2,599+/-138 msmol/kg in rats on K-deficient intake and 2,567+/-142 msmol/kg in controls. To determine whether this primary polydipsia is itself responsible for the development of the concentrating defect, the three groups of rats were dehydrated on day 15. Despite different levels of fluid intake, maximal urinary osmolality was impaired equally in groups 2 and 3 (1,703 and 1,511 msmol/kg, respectively), as compared to rats in group 1 (2,414 msmol/kg), P < 0.001. We therefore conclude that K depletion stimulates thirst, and the resultant increase in water intake is largely responsible for the observed polyuria. After 15 days of a K-deficient diet, the impaired maximal urinary concentration in hypokalemia, however, was not related to increased water intake, since fluid restriction did not abolish the renal concentrating defect.

Cytoskeleton-dependent endocytosis is required for apical type 1 angiotensin II receptor-mediated phospholipase C activation in cultured rat proximal tubule cells.

Renal proximal tubule sodium reabsorption is enhanced by apical or basolateral angiotensin II (AII). Although AII activates phospholipase C (PLC) in other tissues, AII coupling to PLC on either apical or basolateral surfaces of proximal tubule cells is unclear. To determine if AII causes PLC activation, and the differences between apical and basolateral AII receptor function, receptors were unilaterally activated in rat proximal tubule cells cultured on permeable, collagen-coated supports. Apical AII incubation resulted in concentration- and time-dependent inositol trisphosphate (IP3) formation. Basolateral AII caused greater IP3 responses. Apical AII-induced IP3 generation was inhibited by DuP 753, suggesting that the type 1 AII receptor subtype mediated proximal tubule PLC activation. Apical AII signaling did not result from paracellular ligand leak to basolateral receptors since AII-induced PLC activation occurred when basolateral AII receptors were occupied by Sar-Leu AII or DuP 753. Inhibition of endocytosis with phenylarsine oxide prevented apical (but not basolateral) AII-induced IP3 formation. Cytoskeletal disruption with colchicine or cytochalasin D also prevented apical AII-induced IP3 generation. These results demonstrate that in cultured rat proximal tubule cells, AII is coupled to PLC via type 1 AII receptors and cytoskeleton-dependent endocytosis is required for apical (but not basolateral) AII receptor-mediated PLC activation.

The role of obesity in the pathogenesis of hypertension

The rapid rise in the incidence and prevalence of obesity and the concomitant increase in the incidence and prevalence of hypertension have fueled investigation into the role of obesity in the pathogenesis of hypertension. The genetic background that predisposes obese individuals to hypertension is being elucidated, and the importance of adipose tissue as an endocrine organ in the pathogenesis of hypertension is increasingly being recognized. Visceral adipose tissue is critical in the production of pathologic cytokines that are thought to mediate obesity-induced hypertension. Changes in the types and levels of adipocytokines that result from the accumulation of aberrant adipose tissue directly leads to alterations in systemic vascular resistance, sodium retention and sympathetic nervous system activity. Key changes in adipocytokine levels seen in obesity-induced hypertension include increased leptin and adiponectin levels. Another important mechanism in obesity-induced hypertension is the generation of angiotensin II and direct stimulation of aldosterone production. The increased sympathetic nervous system activity seen in obesity-associated hypertension leads to increased renal sodium retention and increased systemic vascular resistance. Increased systemic vascular resistance can also occur directly in obese individuals through vascular fibrosis and lipid deposition. Obesity should no longer be simply considered as a marker of cardiovascular risk but should be regarded as an important and primary contributor to the pathophysiology of hypertension.

Controversies in renal artery stenosis: a review by the American Society of Nephrology Advisory Group on Hypertension

Renovascular hypertension is a recognized secondary potentially curable cause of hypertension since the work of Harry Goldblatt. Operative treatments for renal artery stenosis (RAS) have been offered for decades and percutaneous interventions have been widely available for 20 years. Stenting has largely obviated recurrence and modern techniques have contributed greatly to the safety of the procedure. Nevertheless, controversy abounds and prospective randomized trials have not successfully documented the value of intervention in patients with atherosclerotic RAS. The patient population has also changed remarkably. Whereas earlier patients with RAS were identified on clinical grounds, RAS is now commonly found serendipitously during angiography for other reasons. Whether or not these patients benefit from ‘drive by’ stenting is unknown. The practice may be hazardous and should be critically examined. A dialog and closer cooperation between cardiologists and nephrologists is warranted and organized programs should be formulated to address this problem.

Role of the renin-angiotensin system in post-transplantation hypertension in patients with multiple kidneys.

To define the role of the renin-angiotensin system in post-transplantation hypertension we studied 12 hypertensive recipients of renal transplants. The patients received saralasin acetate, an angiotensin II antagonist, while on a normal sodium diet and again after seven days of sodium restriction. In six patients with only one kidney, saralasin did not lower blood pressure on either diet; salt depletion did not lower systolic or diastolic blood pressures. In six patients with more than one kidney, salt depletion also did not lower blood pressure; however, salt depletion plus saralasin lowered their systolic pressures from a mean (+/- S.E.M.) of 146 +/- 9 to 128 +/- 8 mm Hg, and mean diastolic pressures fell from 103 +/- 5 to 89 +/- 5 (P less than 0.001). In four of five patients renal-vein renin activity was greater in one or more host kidneys than in the transplant kidney (or kidneys). Although pre-transplant blood pressure was the same in both groups, post-transplantation hypertension is more likely to be angiotensin II-dependent in patients with more than one kidney.

The Osmolal Gap in Renal Failure

Excerpt The osmolal gap may be defined as the difference between the calculated and measured serum osmolalities. The calculated component of this entity may be derived from the following formula (1...