Monoclonal antibodies against luminal membranes of renal proximal tubules which are kidney-specific.

After immunization with porcine brush-border membrane proteins, 11 monoclonal antibodies were generated which react with proximal tubules. Their antigenic polypeptides were characterized with respect to apparent molecular weight, histochemical localization in porcine and human kidney, and tissue distribution in pig. In porcine kidney, six antibodies bind selectively to the proximal tubule whereas the others also react with other nephron segments. With the exception of one antibody which reacts with the luminal and the basolateral membrane of the porcine proximal tubule, the other antibodies specific for the proximal tubule only stain the brush-border membrane. Four of them react along the entire length of the porcine proximal tubule, whereas one (R1A2) binds to the S3-segment in pig and to the entire length of the proximal tubule in man. This indicates that segment-specific expression may be species-dependent. Testing the antibodies in 21 different extrarenal tissues it was found that three of the antibodies, specific for the brush-border membrane in renal proximal tubules, only react in kidney. Two of these are specific for pig kidney whereas one also reacts with human kidney. This antibody (N4A4) is directed against a polypeptide with an apparent molecular weight of 400,000. Electron microscopic immunohistochemistry showed that N4A4 binds to the intervillus region of the brush-border membrane and to subapical vesicles.

Cardiovascular factors influencing survival in end-stage renal disease treated by continuous ambulatory peritoneal dialysis.

To determine whether hemodynamic advantages of continuous ambulatory peritoneal dialysis (CAPD) over intermittent hemodialysis are associated with improved survival and identify cardiac risk factors for early death, 55 patients on CAPD (age 58 +/- 11 years; CAPD duration: 29 +/- 25 months) were followed in a noninvasive prospective analysis over 35 months. At follow-up, 25 patients had died; 16 deaths were related to cardiovascular causes. Nonsurvivors were older (62 +/- 8 vs 55 +/- 12 years; p less than 0.015) and had more angina pectoris (40 vs 20%; p less than 0.05) than survivors, but had comparable CAPD duration, arterial blood pressure, hemoglobin, serum creatinine, urea and parathyroid hormone concentrations. On echocardiography, nonsurvivors had a lower mean left ventricular (LV) ejection fraction (59 +/- 15 vs 66 +/- 9%; p less than 0.03), higher LV end-systolic volume indexes (49 +/- 31 vs 36 +/- 13 ml/m2; p less than 0.03) and a shorter mean LV ejection time (371 +/- 41 vs 390 +/- 22 ms; p less than 0.03). LV muscle mass, LV diastolic and left atrial dimensions, stroke volume and cardiac index were comparable. On pulsed Doppler analysis of a subgroup of 48 patients in sinus rhythm and without valve disease, nonsurvivors (n = 23) had more severely decreased ratios of peak early/atrial filling velocities (0.66 +/- 0.18 vs 0.81 +/- 0.24; p less than 0.03) and increased atrial filling fractions (52 +/- 11 vs 46 +/- 9%; p less than 0.03) than survivors. Mean isovolumic relaxation periods were increased in both groups (135 +/- 39 vs 129 +/- 33 ms; p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Enzyme induction in the uremic liver.

Forty-five days after subtotal nephrectomy or sham-operation of male rats, microsomal enzymes were investigated in vitro. The activities (per milligram) of microsomal protein of two esterases and of two glucuronyltransferases were normal in the uremic rats. The mixed-function oxidation system had lower activities per milligram of protein than that in sham-operated controls. Due to a decrease of the microsomal protein content of the uremic liver, the activities of these enzymes were decreased when calculated for the whole liver. In contrast, the glucoronidation of phenolphthalein remained normal when related to the whole liver, due to an increased activity per mg of protein. Treatment with the plasticizer di-(2-ethylhexyl)-phthalate caused a significant increase of the liver wet weight, the microsomal protein content, and the activity per mg of protein for the demethylation of aminopyrine in subtotally nephrectomized rats but was without influence on the liver of sham-operated controls. It is concluded that uremia itself does not induce liver microsomal enzymes. The microsomal enzymes, however, remain inducible by foreign compounds even under uremic conditions.

Gastrointestinal blood loss in patients undergoing maintenance dialysis.

Gastrointestinal blood loss was measured for 14 days in 19 patients treated by hemodialysis and in 2 patients treated by chronic ambulatory peritoneal dialysis. 51Cr was used as a marker for erythrocytes. Fecal blood loss was 5.0 +/- 3.3 ml/day in hemodialysis patients who were not taking drugs affecting thrombocyte aggregation and 4.6 +/- 4.3 ml/day in those receiving sulfinpyrazone. There was no relationship between the severity of anemia, duration of dialysis, dose of heparin, grade of uremic intoxication, or dose of aluminum hydroxide and amount of fecal blood loss. It is concluded that gastrointestinal blood loss is not a major determinant of anemia in chronic renal failure. However, sulfinpyrazone is preferable to acetylsalicylic acid for prevention of shunt thrombosis in uremic patients because of their propensity for gastrointestinal bleeding.

Simultaneous hemofiltration/hemodialysis: an effective alternative to hemofiltration and conventional hemodialysis in the treatment of uremic patients.

Hemofiltration and hemodialysis were performed simultaneously with the Polyacrylnitrile membrane in a single pass dialyzate flow system. Due to the combination of convective mass transfer and diffusion, the clearances of both small and large molecules were significantly higher than during hemofiltration or hemodialysis alone. The removal of excess water was better tolerated than during hemodialysis. Six patients have been treated by this technique for 6 months 3 X 3 hr/week without side effects, and the new procedure appears to be the method of choice to shorten dialysis time.

Abnormal diastolic left ventricular filling by pulsed Doppler echocardiography in patients on continuous ambulatory peritoneal dialysis.

To determine characteristics of diastolic left ventricular (LV) function in patients on continuous ambulatory peritoneal dialysis (CAPD), two groups of CAPD patients without (n = 23; group 1) vs with (n = 25; group 2) LV hypertrophy (greater than 13 mm) were compared with a group of untreated non-renal hypertensive patients with LV hypertrophy (n = 11; group 3) using Doppler-echocardiography. Age and body surface area were comparable in all three groups, mean CAPD-duration (32 +/- 28 vs 26 +/- 23 months; p = NS) was comparable in renal patients. LV systolic function in echocardiography (LVEF: 62 vs 64 vs 63%) and systolic time intervals were normal and comparable in all three groups. Atrial maximum filling velocities (96 +/- 25 vs 91 +/- 25 vs 67 +/- 8 cm/s) were comparably increased, the ratio of maximal early/atrial filling velocities was comparably decreased (0.73 +/- 0.25 vs 0.77 +/- 0.21 vs 0.99 +/- 0.05) in both groups of renal patients as compared to group 3 (p less than 0.05-0.01). Atrial filling fractions were increased in all three groups, more pronounced in group 1 than in group 3 (50 +/- 11 vs 40 +/- 7%; p less than 0.05). The normal correlation of Doppler parameters with age and with LV radius/thickness ratio was altered in renal patients such that high patient age tended to have an additional negative influence on LV diastolic function of hypertrophied, but not of normal myocardium. Isovolumic relaxation time was prolonged in all three groups (134 +/- 38 vs 131 +/- 34 vs 116 +/- 17 ms; p = NS). We conclude that in patients on CAPD, diastolic LV filling is impaired both in normal and hypertrophied myocardium. High age is a factor that further attributes to diastolic dysfunction of hypertrophied myocardium in CAPD.

Ultrashort hemodiafiltration: efficiency and hemodynamic tolerance.

During hemodiafiltration, solutes are removed simultaneously by diffusion and convection. Increase of the fraction removed by diffusion, by using large surface area hemodiafilters, allows a further reduction of treatment time by hemodiafiltration. To assess the efficiency and biochemical safety of ultrashort treatment (mean duration 3 X 105 +/- 14 min/week) six patients (age 22-64) have been observed for six months. There were no differences in the clinical state or in the biochemical parameters compared to those found during the preceding hemodialysis period (3 X 240 min/week). In a second study, hemodynamic measurements in six individual patients aged 34-72 have been compared during a 90 min ultrashort hemodiafiltration (90 min) and during a 240 min hemodialysis. Circulatory stability was maintained during hemodiafiltration despite a rate of fluid removal that was 2.5 times that which occurred during hemodialysis. During both techniques there was a reduction of stroke volume and an adequate norepinephrine-induced rise of peripheral resistance. Plasma levels of vasopressin did not change during treatment. There were no differences in the frequency and quality of premature ventricular beats between the two treatments. The data from the two studies suggests that ultrashort hemodiafiltration (3 X 1.5-2 hr/week) provides biochemical safety as well as hemodynamic stability.

Asymmetric septal hypertrophy and left atrial dilatation in patients with end-stage renal disease on long-term hemodialysis.

Some literature reports associate a reduced weekly duration of treatment (3 x 4 h/week) for patients on maintenance hemodialysis with an increased cardiovascular mortality. To determine whether the improved survival of patients on long weekly hemodialysis (LHD: 3 x 8 h/week) can be associated with different cardiac changes, the cardiac characteristics of a group of 50 patients on LHD were analyzed in a non-invasive assessment. The main findings were an increased left ventricular (LV) muscle mass (176 + 54 g/m2), mass/volume ratio (1.69 + 0.37 g/ml) and left atrial diameter (39.7 + 5.7 mm). The increase in LV muscle mass was due mainly to a high prevalence of asymmetric septal thickening. The ratio septum/LV posterior wall was directly correlated with the left atrial diameter (r = 0.52), LV end-diastolic diameters were inversely correlated with hemoglobin concentration (r = 0.62). LV dilatation and/or LV systolic dysfunction were not characteristic findings: Only 6% of patients had a moderately enlarged (less than 65 mm) LV diameter, LV ejection fraction was decreased in 12%. There was no significant correlation between the degree of LV hypertrophy or left atrial dilatation and patient age, total dialysis duration, interdialytic weight gain, hemoglobin concentration, parameters of blood purification, blood pressure before and after dialysis, history of hypertension. We conclude that cardiac characteristics in patients on LHD are comparable to those described for large patient groups on short hemodialysis. Our findings do not explain improved survival on LHD.

Influence of fluid removal rate during hemodialysis on left ventricular performance and exercise tolerance in patients with coronary artery disease.

The effect of hemodialysis (HD) on left ventricular (LV) function and exercise tolerance were measured at rest and during exercise using gated equilibrium radionuclide ventriculography in seven patients with confirmed coronary artery disease (CAD). To separate the effects of fluid removal rate on LV function in CAD, we investigated the same patients with identical overall volume loss of 4 liters during two different treatment times (4 hr and 2 hr). HD significantly increased resting LV ejection fraction (EF) from 55.7 +/- 8% to 64.7 +/- 8% (P less than 0.01) during the 4 hr HD and from 58.1 +/- 9 to 68.1 +/- 10 (P less than 0.05) during the 2 hr HD. Indicating ischemia, EF decreased at pre- and postdialysis peak exercise without differences between both treatments. HD also resulted in an improved segmental wall motion score. Exercise duration as well as S-T segment depression and angina score improved during HD, whereas heart rate, blood pressure and double product remained unchanged. We conclude that HD improves global and regional resting LV function and exercise tolerance in patients with CAD. The degree of interdialytic hydration and not the degree of fluid removal per time affects LV performance in CAD. Since LV function is the major prognostic factor in CAD, those patients require volume restriction and/or shorter interdialytic phases.

Regulation of adrenergic receptors in the rat kidney.

Chronic daily application of (+/-)-isoprenaline induced a selective-down regulation of beta-adrenoceptors in the kidney: the concentration of [3H]dihydroalprenolol binding sites was significantly lowered by isoprenaline treatment while [3H]prazosin and [3H]rauwolscine binding, representing alpha 1- and alpha 2-adrenoceptors, respectively, was not markedly altered. Since the proportion of high- and low-affinity sites for the non-selective alpha- but relatively beta 1-selective agonist (-)-noradrenaline remained constant and since in [3H]dihydroalprenolol competition experiments the high- and low-affinity site ratio fitted well to the beta 1/beta 2 relation, determined independently by employing ICI 118551 as a beta 2-selective ligand, a parallel decrease of both beta 1- and beta 2-adrenoceptor density can be concluded.

[Coronary risk factors in chronic hemodialysis patients]. / Koronare Risikofaktoren bei chronisch hämodialysierten Patienten.

BACKGROUND: In contrast to persons with normal renal function, coronary risk factors or indicators until yet could not clearly be defined in renal insufficiency. PATIENTS AND METHODS: 30 patients under chronic hemodialysis therapy were investigated; 15 patients with severe coronary artery disease and 15 patients with normal coronary angiogram were compared. Numerous factors of the manner of living (diet, smoking behaviour etc.) were registered and glucose and lipid metabolism, hemostatic and fibrinolytic system as well as blood pressure level were investigated. RESULTS: Besides higher HDL-cholesterol and tissue plasminogen activator (TPA) levels in patients without coronary heart disease, no significant difference could be found between both groups. The higher HDL levels were mainly due to the higher percentage of women in the coronary healthy group. There was no evidence of insulin resistance as a major pathogenic factor in the group with coronary heart disease. The blood pressure levels were not significantly different in both groups. CONCLUSION: Our quantitative examination of accepted or suspected coronary risk factors revealed no entity which turned out to be a reliable risk indicator for practical purposes.