Norman G. Levinsky

An extrarenal mechanism of potassium adaptation.

Rats fed a diet high in potassium for several days survive an acute load of potassium that is lethal to animals on a regular diet. Previous data suggested that this survival occurred because of enhanced kaluresis. Although increased urinary excretion may occur, the major mechanism of this potassium adaptation phenomenon has been found to be extrarenal. Despite nephrectomy just before study, rats previously fed a high potassium diet maintained lower plasma potassium concentrations for at least 2 hr after an acute potassium load than did rats fed a regular diet. Prior adrenalectomy abolished adaptation. Furthermore, rats fed a low sodium diet as an alternative stimulus to aldosterone secretion demonstrated adaptation to potassium loading, as did adrenalecomized rats given large doses of deoxycorticosterone for several days. Adrenalectomy just before the test load of potassium did not abolish adaptation nor did a large dose of aldosterone at that time reproduce it. These data indicate that adaptation is dependent on a chronic increase in aldosterone secretion. The extra potassium removed from the extracellular fluid by adapted rats was not lost into the gastrointestinal tract. It is concluded that more rapid lowering of plasma potassium after acute potassium loads by adapted rats is due to enhanced uptake of potassium by one or more tissues stimulated by chronic aldosteronism.

Rat aortic smooth muscle cells in culture express kallikrein, kininogen, and bradykininase activity.

We have studied rat vascular smooth muscle (VSM) cells in culture for the presence of key elements of the glandular kallikrein-kinin system. Direct radioimmunoassay (RIA) using antiserum against rat urinary kallikrein detected a glandular kallikrein-like enzyme (GKLE) in VSM cells and in media. VSM homogenates and culture media had kininogenase activity, generating kinins from dog kininogen. About half of the GKLE was enzymatically inactive which could be activated with trypsin. Kininogenase activity was inhibited completely by aprotinin but only 20% by soybean trypsin inhibitor (SBTI). Trypsin liberated kinins from homogenates and media, demonstrating that VSM cells contain kininogen. Homogenates and media rapidly degrade bradykinin. GKLE, kininogen, and bradykininase activity were all present in VSM cells grown in defined media that contain no serum, thus eliminating any contamination or artefacts from fetal calf serum in standard culture media. Blood vessels of the rat have been reported to contain GKLE. Our observations indicate that GKLE is synthesized by VSM cells, not deposited from plasma. Furthermore, VSM cells synthesize kininogen and bradykininase(s), the other key elements of the glandular kallikrein-kinin system. Thus it is possible that the system functions as an autocoid mechanism that regulates local vascular tone.

Intensive care unit use and mortality in the elderly.

AbstractOBJECTIVE: To examine utilization and outcomes of intensive care unit (ICU) use for the elderly in the United States. DESIGN: We used 1992 data from the Health Care Financing Administration to examine ICU utilization and mortality by age and admission reason for hospitalizations of elderly Medicare beneficiaries. MAIN RESULTS: Use of the ICU was least likely for the oldest elderly overall (85+ years, 21.1% of admissions involved ICU; 75–84 years, 27.9%; 65–74 years, 29.7%), but more likely during surgical admissions. Eighty-three percent of the Medicare patients who received intensive care survived at least 90 days. Of the oldest elderly, 74% survived. Even among the 10% most expensive ICU hospitalizations, 77% of all patients and 62% of those 85 years and older survived at least 90 days. CONCLUSIONS: The likelihood of ICU use among these elderly decreased with age, especially among those 85 years or older. Diagnostic mix importantly influenced ICU use by age. The great majority of the elderly, including those 85 years and older and those receiving the most expensive ICU care, survived at least 90 days.

Predictors of patient treatment preferences and spouse substituted judgments: the case of dialysis continuation.

Objectives. To examine the factors predicting preferences for continued hemodialysis treatment among patients with endstage renal disease (ESRD) and to compare these factors to those predicting their spouses’ predictions of patients’ preferences (substituted judgments). Design. Descriptive, crosssectional. Participants. Total of 291 hemodialysis patients, aged 55 years and older, and their spouses. Measurement. Hypothetical scenarios were designed to elicit preferences for dialysis continuation under various health conditions. Other measures included the Philadelphia Geriatric Center Negative Affect Scale, Kidney Disease Symptoms Scale, Brief Multidimensional Measure of Religiousness, single-item global subjective health and quality-of-life measures, 2-item fear of end-of-life suffering measure, and selected demographics. Results. Patients’ preferences and spouses’ judgments were only moderately correlated (r = 0.33). Multiple regression analyses revealed that patients’ preferences to continue dialysis were positively related to education, subjective quality of life, and religious participation and negatively related to months of ESRD treatment and fear of end-of-life suffering (R2 = 0.15). Spouses ’ substituted judgments regarding patients’ dialysis continuation preferences were positively related to African American race and spouses’ perceptions of patients ’ quality of life and negatively related to months of ESRD treatment, spouses’ perception of patients’ negative affect, and spouses’ own fear of end-of-life suffering. Conclusion. Patients and surrogates used different criteria in formulating judgments about continuation of life-sustaining treatment and had different perceptions about the patients’ condition. Furthermore, the substituted judgments of spouses were influenced by their own characteristics. These processes may explain inaccurate substituted judgments.

Prostaglandins mediate the vasodilatory effect of mannitol in the hypoperfused rat kidney.

We have previously reported that mannitol strikingly increases blood flow to rat kidneys hypoperfused at 35-40mm Hg. This vasodilator effect is not due to volume expansion or alterations in plasma osmolality. We have tested the hypothesis that the vasodilatory effect of mannitol in the ischemic rat kidney is mediated by one of the vasoactive renal hormone systems: renin-angiotension, kallikrein-kinin, or prostaglandins. Rats were infused with 5% mannitol in 0.9% saline to 3-5% of body weight. In agreement with our previous studies, RBF increased 1.3 +/- 0.1 ml/min despite maintenance of perfusion pressure at 35-40 mm Hg. The cyclooxygenase inhibitors, meclofenamate and indomethacin had no effect on renal blood flow (RBF) in hypoperfused kidneys. However, in rats pretreated with these inhibitors, expansion with mannitol increased RBF by only 0.37 +/- 0.02 ml/min, 28% of the response in the untreated group (p less than 0.001). Infusion of prostacyclin (PGI2) into the renal artery during reduced perfusion resulted in an increase in RBF of 1.0 +/- 0.1 ml/min. Subsequent expansion with mannitol increased RBF by only 0.5 +/- 0.1 ml/min more, less than one-half of the effect of mannitol in a concurrent group of rats not treated with PGI2. Unlike PGI2 prostaglandin E2 had only a minimal vasodilator effect during hyperperfusion. Imidazole, an inhibitor of thromboxane synthesis, did not alter RBF or renal vascular resistance during hypoperfusion. Treatment of rats during hypoperfusion. with the angiotensin-converting enzyme (kininase II) inhibitor teprotide increased RBF by 1.1 +/- 0.3 ml/min. However, teprotide did not alter the vascular response to mannitol: RBF increased 1.2 +/- 0.1 ml/min more when mannitol was infused into teprotide-treated rats. The renal vascular response to mannitol was not altered by treatment with aprotinin, an inhibitor of the kallikrein-kinin system. Aprotinin was ineffective whether given before or after the vascular response to mannitol was established. We conclude that the vasodilator response to mannitol in the ischemic rat kidney is mediated in large part by increased prostaglandin (PGI2) activity. The failure of converting enzyme inhibition and aprotinin to block the vasodilator response to mannitol is evidence against a role for the renin-angiotension or kallikreinkinin systems in mediating the vasodilator response.

Specialist evaluation in chronic kidney disease: too little, too late.

Maintenance of patients with end-stage renal disease (ESRD) on long-term dialysis is a triumph of modern medicine. In the United States alone, more than 250 000 persons with ESRD, who otherwise would have died, enjoy lifeusually of good qualitybecause of the availability of hemodialysis and peritoneal dialysis. Yet this triumph has a tragic flaw: The lifespan of dialysis patients remains abnormally short. Only about one third survive 5 years. Even patients who start dialysis in their 40s have no more than a 50% chance to live 5 more years (1). Nephrologists caring for patients receiving long-term dialysis have studied and improved several factors that contribute to this high mortality, including some technical features of dialysis and various clinical aspects of the care of patients with ESRD. Nevertheless, mortality rates have remained disappointingly high. One area that has received increasing attention over the past decade is the timeliness of referral of persons with chronic renal failure to nephrologists (2, 3). A consensus statement from the National Institutes of Health recommends that patients should be referred as soon as plasma creatinine levels increase to 132 to 177 mol/L (1.5 to 2.0 mg/dL) (4). There is some evidence that such early intervention by nephrologists may improve morbidity and even mortality of persons receiving long-term dialysis, but it is by no means conclusive (2, 3). In this issue, Kinchen and colleagues (5) provide important new information about the timing of referral of patients with chronic renal failure to nephrologists and the influence of this factor on survival once patients receive dialysis. The investigators prospectively studied more than 800 patients in 81 dialysis units in the United States. They found that nephrologists saw only about half of the patients at least 1 year before the initiation of dialysis. Thirty percent were seen less than 4 months before dialysis beganan interval that is clearly too short for the specialist to provide optimal intervention. For example, patients referred to nephrologists that late were less likely to have received erythropoietin before the start of dialysis or to have had timely placement of permanent vascular access. Most important, patients with diabetic kidney disease referred to nephrologists a year or more before the start of dialysis lived substantially longer than those referred within 4 months of beginning dialysis. The relatively large number of patients and dialysis units and the prospective nature of the study strengthen the observation that late referral affects mortality. However, the study cannot be considered conclusive because no data were available regarding the time of initiation of dialysis in the course of progressive renal failure. As the authors note, it is possible that patients who received early referral to nephrologists started dialysis earlier in the course of disease than did patients who received late referrals. This would cause lead-time biasthat is, an apparent increase in longevity resulting from starting dialysis when renal failure was less advanced. Moreover, the correlation of survival with early referral to nephrologists does not prove a causal relationship. Timely referral may be only one aspect of superior primary care. To interpret the data of Kinchen and coworkers (5) and others (2, 3), we need information about the overall medical care of patients with chronic renal failure. Did they have primary care physicians? How regularly did they see these doctors? Were the physicians well informed about the management of persons with chronic renal failure? What accounts for the late referral of patients to nephrologists? Kinchen and colleagues (5) identify African-American men, persons without medical insurance, and those with more comorbid conditions as especially likely to be referred belatedly. Older age and lack of higher education also correlate with late referrals. These observations suggest that broader issues about medical care may underlie late referral. The special peril of the African American, the uninsured, and the less well educated suggests that limited access to good primary care may be a critical factor for which delay in referral to specialists is only a marker. Persons with chronic renal failure may not be referred to specialists early enough because their generalist care is belated, erratic, discontinuous, or nonexistent. The erroneous presumption of some primary care physicians that elderly persons or those with comorbid conditions cannot be treated successfully with long-term dialysis may lead to delayed referral or even nonreferral, as may ethically dubious attitudes about the use of expensive technology for the elderly or other groups. As important as the potential benefit of early referral in reducing mortality of patients receiving long-term dialysis is the possibility that good medical care of persons with early chronic renal failure may delay or even eliminate the need for dialysis. Compelling evidence supports the conclusion that in patients with early chronic renal failure, blockade of the reninangiotensin system with angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers slows deterioration of renal function, especially in patients with diabetic kidney disease (6, 7). Strict control of hypertension, management of hyperlipidemia, treatment of anemia with erythropoietin, and meticulous management of diabetes and its complications (8) are also important aspects of the care of persons with progressive renal failure. Most patients receiving dialysis die of cardiovascular disease, which clearly begins long before initiation of dialysis and deserves aggressive prophylactic treatment as soon as chronic renal failure is recognized. All these forms of therapy are well within the skills of primary care physicians. It makes sense for generalists caring for persons with chronic renal failure to obtain early and periodic advice from a nephrologist and, in the care of diabetic patients, a diabetologist. Primary care doctors will benefit from up-to-date advice about the management of early renal failure. Specialists will be able to educate patients about alternative methods of dialysis and to facilitate timely placement of vascular access, an important factor in avoiding morbidity and needless hospitalizations for access problems. Such a coordinated approach not only should reduce the morbidity and mortality of persons who eventually require dialysis but, best of all, may delay or even eliminate the need for it in some fortunate patients.

Proximal tubular function in dogs with thoracic caval constriction

The effect of saline infusion on proximal sodium reabsorption was compared in normal dogs and in dogs with acute or chronic partial thoracic vena cava obstruction. After acute vena cava obstruction, proximal fractional sodium reabsorption rose by 74%. During continued caval obstruction, saline loading strikingly reduced proximal reabsorption but sodium excretion remained minimal. In chronic caval dogs, saline loading reduced proximal fractional sodium reabsorption by 31% but sodium excretion in the micropunctured kidney was only 41 muEq/min. After saline infusion in normal dogs, proximal fractional sodium reabsorption fell 39% while unilateral sodium excretion rose to 584 muEq/min. Nephron filtration rate was also measured before and after saline loading in normal and chronic caval dogs in both repunctured and fresh tubules. There was a marked increase in nephron filtration rate in repunctured tubules and no change in freshly punctured tubules in both groups. The effect of saline loading on nephron filtration rate in normal and chronic caval dogs was similar, therefore, whether repunctured or fresh nephrons were considered.We conclude that saline infusion depresses proximal sodium reabsorption in acute and chronic TVC dogs. Since saline loading markedly increases distal delivery without a concomitant natriuresis, enhanced distal reabsorption must play a major role in the sodium retention exhibited by chronic caval dogs. Redistribution of filtrate does not appear to be a factor in this sodium retention.

Hemodynamic effects of different preparations of stroma free hemolysates in the isolated perfused rat kidney.

We have examined the effects of Stroma Free Hemolysate (SFH) solutions in the isolated perfused rat kidney. Three types of SFH, stored for 6 to 8 months at 4 degrees C, were tested: 1) unmodified, 2) glyoxalated and lightly cross linked and 3) pyridoxalated and polymerized. All three SFH solutions, added to the perfusate at a concentration of approximately 420 mg/100ml, increased renal vascular resistance (RVR) and reduced glomerular filtration rate (GFR). Unmodified, glyoxalated and lightly cross linked and pyridoxalated polymerized SFH resulted in a rise in RVR of 55%, 38% and 33% respectively and a fall in GFR of 42%, 57% and 83% respectively. In order to determine whether storage had altered the effect of SFH on renal function, one of the forms of SFH (glyoxalated and lightly cross linked) was studied only 4-6 weeks after preparation. While this preparation caused an increase in RVR of 41% it did not alter GFR; filtration fraction (FF) rose. However, after further storage of this preparation for 6-7 months, the solution resulted in a marked decrease in GFR of 47% as well as a rise in RVR of 23%. We conclude that three different SFH preparations resulted in marked vasoconstriction and reductions in GFR. These deleterious effects on renal hemodynamics were noted at a concentration of hemoglobin well below that necessary to effectively improve oxygen content. Storage of the SFH solutions may cause or contribute to their effects on renal function. SFH solutions intended for use as blood substitutes should be tested for vasoconstrictor activity.

NONALDOSTERONE INFLUENCES ON RENAL SODIUM TRANSPORT

It has been known for many years that the dog responds to saline infusions with a prompt increase both in sodium excretion and in glomerular filtration rate (GFR) . Classically, the natriuresis was attributed to the concurrent increase in filtered sodium, which seemed reasonable, since in most experiments filtered sodium was increased several times as much as sodium excretion. Those occasional experiments in which the increase in sodium excretion apparently exceeded the rise in filtered sodium were usually assumed to demonstrate experimental error. Since small percentual errors in the measurement of GFR can account mathematically for large changes in sodium excretion, this was a reasonable interpretation. The traditional view of saline diuresis in the dog, then, was that the brisk natriuresis could be explained entirely as a response to increased filtered load. Recently, work in a number of laboratoriesl-7 has indicated that this view is, at best, grossly oversimplified. Natriuresis is, at least in large part, due to a prompt decrease in tubular reabsorption during saline loading in the dog. Although this possibility had been suggested now and again by previous workers, it was the papers of DeWardener and associates1,2 which focused recent interest on this concept. In essence, these workers found that sodium excretion increased after saline loading in all of 14 dogs studied, despite spontaneous falls in filtration rate in more than half. Since the dogs had been treated with mineralocorticoid hormones and vasopressin, these observations suggested strongly that saline loading depressed tubular sodium reabsorption by a mechanism independent of changes in endogenous aldosterone and antidiuretic hormone. These results have now been confirmed by various types of experiments in several laboratories. In this paper I shall summarize some of the work from our laboratory which demonstrated that saline loading decreases tubular sodium reabsorption. In addition, data will be presented which bear on the mechanism of this phenomenon and on its quantitative contribution to increased sodium excretion. All dogs used in our studies were treated with large doses of potent mineralocorticoids, including aldosterone in some cases, and with vasopressin. Hence it is assumed that changes in endogenous aldosterone and antidiuretic hormone do not influence the results. Data from a typical experiment are illustrated in FIGURE 1. During the control periods shown at the left of the figure, filtered sodium was approximately 5000 pEq/min; a tiny fraction of this amount, 20 PEqlmin, was excreted in the urine. The scales have been adjusted to bring the control rates of excreted and filtered sodium to the same point on the ordinate. The mean control rates are shown by the solid horizontal line. After control clearance periods had been collected, a rapid infusion of isotonic saline was begun. After 90 minutes, sodium excretion had become stable at 450 PEqlmin. Note, however, that the increase in excretion represented only about two-thirds of the concurrent increase in filtered sodium, so that at this point in the experiment the increase in excretion

Superficial and Juxtamedullary Nephron Function during Saline Loading in the Dog

A modification of the microdissection technique of Hanssen was utilized in dogs to measure superficial (SNGFR) and juxtamedullary nephron filtration rate (JMGFR) in control and saline-expanded dogs. During control studies SNGFR was 60+/-4 and JMGFR was 72+/-5 nl/min. During saline loading SNGFR was 74+/-8 and JMGFR was 65+/-6 nl/min. The ratio SNGFR: JMGFR significantly increased from 0.84+/-0.03 to 1.15+/-0.08. Glomerular perfusion rate (GPR) was measured with the microsphere method during control and saline loading. Superficial GPR did not change significantly but juxtamedullary GPR increased from 225+/-42 to 323+/-39 nl/min. Calculated superficial nephron filtration fraction was unchanged after saline expansion but juxtamedullary filtration fraction decreased from 0.34+/-0.07 to 0.24+/-0.07. The data demonstrate a tendency for filtration to shift toward the superficial part and plasma flow toward the deep part of the kidney cortex. GFR in juxtamedullary nephrons appears to be less plasma flow-dependent than in superficial nephrons. The fall in filtration fraction in the deep cortex may affect sodium excretion by juxtamedullary nephrons.