Recent advances in the management of hypertension in the elderly.

Important new advances have occurred in our understanding and approach to management of high blood pressure in the elderly. New clinical trials have re-emphasized the risk of development of cardiovascular and cerebrovascular complications associated with isolated elevations in systolic blood pressure as well as the safety and efficacy of interventions to reduce blood pressure. These trials have shown that systolic blood pressure can be reduced by interventions such as weight loss, restriction of dietary sodium intake, and drugs. In several new trials, the long-acting dihydropyridine calcium channel blockers have been found to be safe and effective in these patients but not superior to other drugs. As in younger individuals with hypertension, drug therapy should be targeted to address comorbidity. Education of primary care physicians concerning these new findings is the next step in reducing the morbidity and mortality of this common problem in the elderly.

Acid-base balance in dialysis patients.

Acid-base balance in dialysis patients is achieved by a unique interaction between the patient and the particular mode of renal replacement therapy. The prevailing serum HCO3- in these patients is determined not only by endogenous acid production but also by the nature of the dialysis prescription and, in particular, by the bicarbonate (or lactate) concentration of the bath solution. Despite the technical advances in dialysis therapy, pre-dialysis serum HCO3- remains lower than normal in most patients receiving hemodialysis and in many patients receiving peritoneal dialysis. A central question is whether even a mild degree of acidosis increases morbidity and mortality in patients with end-stage renal disease. This article reviews the nature of the acid-base equilibrium achieved in patients receiving hemodialysis or peritoneal dialysis, addresses the question of whether correction of acidosis is beneficial, and reviews the techniques for increasing serum HCO3- in these patients. Based on the information available, it is clear that the patient with a serum HCO3- less than 19 mEq/L should be assessed to determine the cause of the low value and steps undertaken to correct the acidosis. Whether patients with steady-state values between 19 and 24 mEq/L require specific attention remains an issue for further investigation.

Effect of acute increases in filtered HCO3- on renal hydrogen transporters: II. H(+)-ATPase.

Adaptive increases in renal bicarbonate reabsorption occur in response to acute increases in filtered bicarbonate (FLHCO3). In a previous study, we showed that an increase in FLHCO3 induced by plasma volume expansion increased the Vmax for Na+/H+ exchange activity in renal cortical brush border membrane vesicles (BBMV), providing a potential mechanism for the adaptive increase in HCO3- reabsorption. The present studies were undertaken to determine whether the increase in FLHCO3 induced by plasma expansion also stimulates the other major H+ transporter in cortical BBMV, the H(+)-ATPase. H(+)-ATPase activity was assessed in BBMV obtained from hydropenic and plasma expanded Munich-Wistar rats, using a NADH-linked ATPase assay. H(+)-ATPase activity was measured as the ouabain and oligomycin-insensitive, bafilomycin A1-sensitive component of total ATPase activity. Acute plasma expansion doubled single nephron FLHCO3, and this change was associated with a 64% increase in the Vmax for H(+)-ATPase activity, with no change in apparent Km. The Vmax for H(+)-ATPase activity correlated directly with whole kidney GFR and FLHCO3 (r = 0.68 and 0.72, respectively), and with single nephron GFR and FLHCO3 (r = 0.76 and 0.80, respectively). Thus, the mechanism for the adaptive increase in proximal tubular HCO3- reabsorption that occurs in response to acute increases in FLHCO3 appears to be related to increased activity of both H(+)-ATPase and Na+/H+ exchange in the apical membrane of the proximal tubule epithelium.

End-stage renal disease. Measures to prevent it or slow its progression.

Studies conducted over the past 10 years have indicated that end-stage renal disease can be prevented or its progression slowed in many cases. Although prevention involves lifestyle changes, which many patients find difficult to make, strategies must be developed to help patients achieve the changes. Tight glycemic control in diabetic patients, control of blood pressure, and use of angiotensin-converting enzyme inhibitors are the essential features of the care needed to prevent renal failure.

Atherosclerotic renovascular disease and progressive renal failure.

PURPOSE: To evaluate information on the prevalence and rate of progression of atherosclerotic renovascular disease and the effect of angiotensin-converting enzyme inhibition on this process, with the goal of developing a rational approach to the diagnosis and management of this disorder. DATA SOURCES: Relevant articles were identified from the authors' files and from MEDLINE searches. Additional references were obtained from the bibliographies of identified articles. STUDY SELECTION: Virtually no controlled prospective studies have been reported. The articles presented are primarily retrospective analyses and include those that provide sufficient information about the incidence or progression of renovascular disease and about the outcome and mortality rate associated with various treatments, to allow evaluation. DATA EXTRACTION: For the outcomes of interest, data from individual reports are presented in tabular form, the results summed, and averages obtained. RESULTS: Atherosclerotic renovascular disease, in many cases involving both renal arteries, is a common finding in patients older than 50 years, particularly those with diffuse atherosclerotic vascular disease. Hypertension is not a particularly sensitive indicator of this disease (almost one half are not hypertensive). The disease progresses and may account for 5% to 15% of all patients developing end-stage renal disease each year. Angiotensin-converting enzyme inhibition may damage ischemic renal tissue, but this is counterbalanced by beneficial effects of this therapy. Once end-stage renal disease is present, mortality rates are high despite dialysis support (> 50% over 3 years). Both surgery and angioplasty can preserve or improve renal function and may delay or prevent the need for dialysis therapy. These invasive procedures may have lower rates of morbidity and mortality than the so-called "conservative" approach of dialysis therapy when renal failure develops. CONCLUSIONS: Given available information, diagnosis and intervention should be considered seriously in patients at high risk for renovascular disease who have clearly progressing renal insufficiency. Prospective trials are needed, however, to determine the costs and benefits of each approach to treatment in all patients with renovascular disease and renal insufficiency.

Effect of acute changes in glomerular filtration rate on Na+/H+ exchange in rat renal cortex.

Studies were undertaken in Munich-Wistar rats to assess the influence of changes in filtered bicarbonate (FLHCO3), induced by changes in GFR, on Na+/H+ exchange activity in renal brush border membrane vesicles (BBMV). Whole-kidney and micropuncture measurements of GFR, FLHCO3, and whole-kidney and proximal tubule HCO3 reabsorption (APRHCO3) were coupled with BBMV measurements of H+ gradient-driven 22Na+ uptake in each animal studied. 22Na+ uptake was measured at three Na+ concentration gradients to allow calculation of Vmax and Km for Na+/H+ exchange. GFR was varied by studying animals under conditions of hydropenia, plasma repletion, and acute plasma expansion. The increase in GFR, FLHCO3, and APRHCO3 induced by plasma administration correlated directly with an increase in the Vmax for Na+/H+ exchange in BBMV. The Km for sodium was unaffected. In the plasma-expanded rats, the Vmax for Na+/H+ exchange was 22% greater than in the hydropenic rats (P less than 0.025) whereas APRHCO3 was 86% greater (P less than 0.001). These results indicate that increases in FLHCO3, induced by acute increases in GFR, stimulate Na+/H+ exchange activity in proximal tubular epithelium. This stimulation is a mechanism which can, in part, account for the delivery dependence of proximal bicarbonate reabsorption.

Influence of extracellular pH and perfusion rate on Na+/H+ exchange in cultured opossum kidney cells.

Studies were undertaken in cultured opossum kidney (OK) cells to determine whether the rate of H+ secretion by apical membrane Na+/H+ exchange is modulated by changes in extracellular pH or perfusion rate. H+ secretion was assessed in single cells by measuring the rate of Na(+)-dependent intracellular pH recovery after NH4Cl loading, using the pH-sensitive fluorescent dye, 2'7'-bis(carboxyethyl)-5,6-carboxyfluorescein, in monolayers mounted to allow independent perfusion of the apical and basolateral surfaces. At constant intracellular pH, Na(+)-dependent H+ secretion was found to be inversely related to extracellular H+ activity, and directly related to the perfusate flow rate. Inhibition of H+ secretion by perfusate acidity occurred immediately and was greater when perfusate Na+ was reduced, consistent with H+ competition with Na+ for binding to the transporter. By contrast, the effect of the perfusion rate was a delayed response, requiring 20 min of exposure, and was independent of perfusate Na+ concentration. The results indicate that both extracellular pH and the perfusion rate modulate H+ secretion by OK cells, and that the two effects are independent.

Delivery dependence of early proximal bicarbonate reabsorption in the rat in respiratory acidosis and alkalosis.

In the intact rat kidney, bicarbonate reabsorption in the early proximal tubule (EP) is strongly dependent on delivery. Independent of delivery, metabolic acidosis stimulates EP bicarbonate reabsorption. In this study, we investigated whether systemic pH changes induced by acute or chronic respiratory acid-base disorders also affect EP HCO3- reabsorption, independent of delivery (FLHCO3, filtered load of bicarbonate). Hypercapnia was induced in rats acutely (1-3 h) and chronically (4-5 d) by increasing inspired PCO2. Hypocapnia was induced acutely (1-3 h) by mechanical hyperventilation, and chronically (4-5 d) using hypoxemia to stimulate ventilation. When compared with normocapneic rats with similar FLHCO3, no stimulation of EP or overall proximal HCO3 reabsorption was found with either acute hypercapnia (PaCO2 = 74 mmHg, pH = 7.23) or chronic hypercapnia (PaCO2 = 84 mmHg, pH = 7.31). Acute hypocapnia (PaCO2 = 29 mmHg, pH = 7.56) did not suppress EP or overall HCO3 reabsorption. Chronic hypocapnia (PaCO2 = 26 mmHg, pH = 7.54) reduced proximal HCO3 reabsorption, but this effect was reversed when FLHCO3 was increased to levels comparable to euvolemic normocapneic rats. Thus, when delivery is accounted for, we could find no additional stimulation of proximal bicarbonate reabsorption in respiratory acidosis and, except at low delivery rates, no reduction in bicarbonate reabsorption in respiratory alkalosis.

Metabolic acidosis stimulates bicarbonate reabsorption in the early proximal tubule.

The early proximal tubule is the major site for renal bicarbonate reabsorption but little is known about the influence of acidosis on transport in this segment. This study examined early proximal bicarbonate reabsorption in rats with chronic metabolic acidosis (MA) (induced by NH4Cl administration). Rats were studied by free-flow micropuncture techniques, after varying degrees of plasma volume expansion to vary the filtered load of bicarbonate (FLHCO3). At FLHCO3 less than 700 pmol/min, both control and acidotic animals reabsorbed greater than 80% of the filtered load by 2 mm from Bowman's space. At higher FLHCO3 (700-1,100 pmol/min), reabsorption in the early proximal tubule was significantly greater in MA rats vs. control (633 +/- 26 vs. 449 +/- 24 pmol/min, between 1 and 2 mm from Bowman's space, P less than 0.001). This MA-induced stimulation of early proximal bicarbonate reabsorption was completely reversed by restoring systemic pH to normal either by acute hypocapnia or alkali infusion. Thus bicarbonate reabsorption in the early proximal tubule correlated closely with changes in systemic pH in rats with MA when bicarbonate delivery was increased by plasma expansion. The mechanism of this effect remains to be determined.

Analysis of PCO2 variations in the renal cortex. I. Single nephron.

A mathematical model was developed to predict differences in CO2 partial pressure between afferent arterioles and peritubular capillaries, based on the flow rate and composition of afferent arteriolar blood. Buffering reactions in blood were described by use of conditions of chemical equilibrium and electroneutrality in separate plasma and red cell compartments, with inclusion of such factors as the effect of hemoglobin oxygenation (alkaline Bohr effect) and formation of carbamino compounds. Steady-state mass balance equations allowed the prediction of peritubular capillary blood composition based on the inputs of blood from the efferent arteriole and the addition of water, CO2, NaHCO3, and NaCl derived from tubule reabsorbate. Models developed previously to describe the rates of glomerular filtration, and of proximal tubule reabsorption of HCO3- and CO2, were combined with the peritubular capillary model to allow realistic simulations for a single superficial nephron. The predicted difference of 5.5 mmHg between the CO2 partial pressures in peritubular capillaries and afferent arterioles (delta PCO2) was in good agreement with values reported for normal Munich-Wistar rats. For a given afferent arteriolar blood composition, the calculated delta PCO2 generally decreased with increasing blood flow rate. At a given blood flow rate and afferent PCO2, delta PCO2 decreased as afferent plasma HCO3- concentration was increased. When afferent PCO2 was varied at constant blood flow rate and HCO3- concentration, delta PCO2 changed in parallel with afferent PCO2.

Analysis of PCO2 variations in the renal cortex. II. Countercurrent exchange.

In an effort to explain the relatively high values of CO2 partial pressure (PCO2) that have been measured in the superficial renal cortex of the rat, we developed a mathematical model based on the concept of countercurrent exchange between blood vessels. The model includes the possibility of exchange of CO2 between interlobular arteries and veins throughout the cortex, and between "terminal" arterioles and venules (those associated with the most superficial nephrons). The effect of countercurrent exchange is to amplify the increases in PCO2 that occur in the microcirculation of individual nephrons, which are due to the addition of metabolic CO2 and reabsorbed HCO3- and CO2 to peritubular capillaries. The model is formulated in terms of correlations that describe blood buffering equilibria in peritubular capillaries and in interlobular arteries and veins, and steady-state mass balances for the interlobular vessels. By use of physically reasonable vascular permeability values, simulations for the normal euvolemic Munich-Wistar rat yielded values of the surface-to-arterial PCO2 difference (delta PCO2) comparable to previously measured values. Predicted variations in delta PCO2 with afferent arteriolar blood flow rate and systemic arterial PCO2 were also in accord with available data. These results suggest that the amplifying effect of countercurrent exchange is in fact adequate to explain the high values of PCO2 measured in surface structures. The solutions to the mass balance equations are in closed analytical form and can be readily adapted to describe countercurrent exchange in the renal cortex of solutes other than CO2.

Hyperkalemia as a complication of drug therapy.

A wide array of drugs in common use can produce hyperkalemia. We reviewed our experience with severe hyperkalemia (potassium levels greater than 5.9 mEq/L [greater than 5.9 mmol/L]) in adult inpatients during a one-year period, to evaluate the extent to which drugs could be implicated in this electrolyte disorder. Excluding hemolyzed samples, single unexplained values, and measurements obtained during cardiopulmonary bypass or resuscitation, drug therapy was a probable contributing factor in more than 60% of the hyperkalemic episodes; in 25%, drugs were temporally linked to the onset of the hyperkalemia. In declining order of frequency, the drugs associated with hyperkalemia were potassium chloride, captopril, nonsteroidal anti-inflammatory agents, and potassium-sparing diuretics. In more than 80% of the drug-related hyperkalemic episodes, potassium regulation was compromised by underlying disease states. The most common was renal insufficiency, followed by diabetes mellitus and metabolic acidosis. This review underscores the dictum that caution should be exercised when drugs with hyperkalemic potential are used in patients with impaired potassium homeostasis.

The early proximal tubule: a high-capacity delivery-responsive reabsorptive site.

The proximal convoluted tubule is responsible for reclaiming almost all of the filtered bicarbonate, glucose, and amino acids, as well as 40% or more of the filtered sodium, fluid, chloride, and phosphate. Walker and co-workers demonstrated the importance of this nephron segment as a high-capacity transport site in the first mammalian micropuncture studies, and they suggested that the first portion of the proximal tubule played a particularly important role in the ability of the nephron to adapt to variations in filtered load. Since then, many studies using micropuncture and in vivo and in vitro microperfusion techniques have confirmed that the early proximal tubule has a higher transport capacity than the late proximal tubule for a number of solutes. Moreover, at least for bicarbonate, fluid, and chloride, the transport capacity is not static, but is in a dynamic state, adapting in response to changes in filtration. In this review we have focused on the high capacity and load dependence of early proximal bicarbonate and fluid reabsorption. In addition, we summarize the evidence for axial heterogeneity along the proximal convoluted tubule for transport of a variety of other solutes.

Load dependence of proximal tubular fluid and bicarbonate reabsorption in the remnant kidney of the Munich-Wistar rat.

Studies were undertaken to characterize the pattern of proximal tubular fluid (APRH2O) and bicarbonate reabsorption (APRHCO3) in the remnant kidney of euvolemic Munich-Wistar rats. The remnant kidney rats were placed on a diet containing either low or normal protein. Collections were obtained in the early, mid-, and late proximal convoluted tubule. Single nephron glomerular filtration rate (SNGFR) increased from 40.2 nl/min in controls to 58.8 nl/min in low protein remnant kidney and 78.1 nl/min in normal protein remnant kidney rats. The filtered load of bicarbonate was 1,272, 1,641, and 2,013 pmol/min, in the three groups, respectively. APRH2O and APRHCO3 increased nearly in parallel. Most of the increase in reabsorption occurred in the early proximal tubule. Tubular hypertrophy could account for at least 20-40% of the increase in reabsorption, but the majority of the increase appeared to be a delivery-dependent response similar to that observed in normal rats after an acute increase in SNGFR.