Haruo Tomonari

Reversal of anemia by erythropoietin therapy retards the progression of chronic renal failure, especially in nondiabetic patients

Therapy with human recombinant erythropoietin (EPO) has been accepted as effective for renal anemia in dialysis patients. However, studies in rats have shown that correcting anemia with EPO may affect the progression of renal dysfunction. In humans, however, the effect of EPO on residual renal function is a matter of controversy. We, therefore, investigated whether the long-term administration of EPO to predialysis patients influences residual renal function. Anemic patients at the predialysis stage with a serum creatinine (Cr) concentration ranging from 2 to 4 (average 2.9) mg/dl and a hematocrit (Ht) of less than 30% were randomly assigned to two groups which consisted of anemic patients not treated with EPO (group I, untreated anemic controls, n = 31) and anemic patients treated with EPO (group II, treated anemics, n = 42). Patients with nonsevere or moderate anemia (Ht > 30%) with a Cr ranging from 2 to 4 (average 2.6) mg/dl were also recruited as nonanemic controls (group III, untreated nonanemic controls, n = 35). Blood pressure was controlled to the same degree among the three groups by combined treatment with calcium antagonists and angiotensin-converting enzyme inhibitors. All patients were kept strictly on a low-protein (0.6 g/kg/day) and a low-salt (7 g/day) diet. The degree of control of dietary protein and blood pressure and the frequency of angiotensin-converting enzyme inhibitor administration were comparable among the three groups. The primary end point for each patient was a doubling of the baseline Cr which yielded cumulative renal survival rates which were plotted against time. Ht rose significantly from 27.0+/-2.3 to 32.1+/-3.2% in group II (n = 42, p < 0.001) with a rate of increase of 0.4+/-0.06%/week. However, it declined from 27.9+/-1.8 to 25.3+/-1.9% in group I (n = 31, p < 0.001) and from 35.9+/-3.5 to 32.2+/-3.9% in group III (n = 35, p < 0.001). Cr doubled in 26 patients (84%) in group I as compared with 22 (52%) in group II and 21 (60%) in group III. The cumulative renal survival rates in groups II and III were significantly better than that in group I: p = 0.0003 (group I vs. group II) and p = 0.0024 (group I vs. group III). However, there was no difference in the renal survival rate between groups II and III (p = 0.3111). The better survival rate obtained in group II was attributable to the better survival rate for the nondiabetic patients in this group. The present study suggests that anemia, per se, is a factor in the progression of end-stage renal failure and that reversal of anemia by EPO can retard the progression of renal failure, especially in nondiabetic patients, provided that blood pressure control, rate of increase in Ht, and dietary protein restriction are appropriate.

Effect of Cilazapril on Hyperdipsia in Hemodialyzed Patients

To investigate whether angiotensin-converting enzyme inhibitor (ACE-I) potentially alleviates hyperdipsia, the effect of cilazapril on dialysis-associated excessive thirst was studied by evaluating various dipsogenic parameters in patients undergoing chronic hemodialysis (HD) who manifest an excessive interdialysis body weight gain of more than 5%, and show simultaneous severe-to-moderate hyperdipsia. An initial single dose of 1 mg of cilazapril given at the end of the HD session produced a marked improvement in the interdialysis thirst scores and a simultaneous reduction in plasma angiotensin II (AII) concentration due to the inhibition of ACE activity. The interdialysis body weight gain in the cilazapril treatment period was significantly smaller than that in the nontreatment period. None of the other parameters including blood pressure, plasma osmolarity, and serum Na and K concentration were different in the treatment vs. the nontreatment period. The present data help to explain the potential pharmacological action of AII in the physiology of thirst and suggest that cilazapril may effectively alleviate dialysis-associated hyperdipsia at least on some occasions. The mechanism by which ACE-I exerts an antidipsogenic action may, in part, be accounted for by the reduction in plasma concentration of AII, as a result of the ACE inhibition.

Successful Treatment of Tumoral Calcinosis Using CAPD Combined with Hemodialysis with Low-Calcium Dialysate

Successful treatment of tumoral calcinosis using continuous ambulatory peritoneal dialysis (CAPD) combined with hemodialysis is described. A 32-year-old male patient with a 2-year history of CAPD rapidly developed multiple metastatic calcification (tumoral calcinosis) adjacent to his fingers, elbows, and knee joints. Tests showed severe hyperphosphatemia, moderate hypercalcemia, and increased Ca-P product without elevation of intact parathyroid hormone. An enlarged parathyroid gland was not found by echography. In order to rapidly lower the excessive Ca and P levels, a combined therapy with CAPD and vigorous transient hemodialysis using a low-Ca dialysate was performed. In parallel, the patient was given calcitonin, bisphosphonate, and short-term Al to ameliorate the metastatic calcifications more effectively. The result was dramatic with disappearance of the tumoral calcinosis as well as improvement in subjective symptoms within a few months. The present case suggests that combined therapy with hemodialysis and CAPD using a low-Ca dialysate, together with Ca-modulating agents, can be effective in ameliorating tumoral calcinosis in patients on CAPD.

Refined Estimation of Kinetic Parameters of the Na+/H+ Antiport in Human Fibroblasts and Platelets

Abstract A technique is presented to estimate the initial rates of Na+-dependent alkal-inization of acidified human fibroblasts and platelets and assess the kinetics of the Na+/ H+ antiport in these cells. Cytosolic pH (pH i ) exhibits an exponential recovery following cellular acidification. Thus, the length of the time interval selected to monitor changes in pH i (ΔpH i ) is critical to estimating the kinetics of the Na+/H+ antiport. We compared kinetic parameters of the Na+/H+ antiport, using computed and observed changes in ΔpH i , for arbitrarily selected time intervals following Na+-dependent activation. In both cells, significant increases in both the [Na+] for half-maximal activation (K 0.5) and maximal velocities (V max) were observed as ΔpH i was decreased. We conclude that kinetic parameters derived from initial rate determinations enable a more accurate characterization of the Na+/H+ antiport.

Antiplatelet therapy decreases the incidence of erythropoietin-induced hypertension in predialysis patients.

The observation that antiplatelet therapy may decrease the incidence of Epo-induced hypertension in dialysis patients remains a subject of particular interest. The aim of the present study was to test this hypothesis in patients at the predialysis stage. Predialysis patients with renal anemia were treated with EPO (6000 IU/week) for 6-12 months. Patients were divided into two groups, one of which received antiplatelet therapy and the other did not, and a comparison was made between them with respect to the incidence of EPO-induced hypertension. Logistic regression analysis was used to determine the risk factors for developing hypertension during the EPO therapy. Such predictors included age, gender, antecedent of hypertension, antiplatelet drugs and diabetes mellitus. Overall, 66 patients were enrolled in the study and 18 developed hypertension (27%). Out of the 35 patients not receiving antiplatelet therapy, 15 developed hypertension (43%). In contrast, out of the 31 patients receiving antiplatelet therapy, only 3 (10%) developed hypertension (p=0.003 by Chi square test). Multiple regression analysis showed that the best predictive variables for the development of hypertension were antecedent of hypertension (odds ratio: 0.064, p=0.0118), and use of antiplatelet drugs (odds ratio: 5.081, p=0.0295). The present data provide evidence that antiplatelet therapy may prevent EPO-induced hypertension in predialysis patients. However, the mechanism to explain such an effect still remains to be elucidated.

Granulocyte colony-stimulating factor-producing primary pericardial mesothelioma

A 54-year-old male patient presented with a granulocyte colony-stimulating factor (G-CSF)-producing primary pericardial mesothelioma, while showing symptoms of congestive heart failure, a fever of 38 to 39 degrees C, and marked leucocytosis of 52.7 x 10(3) cells/mm3. The histopathologic diagnosis was established after autopsy. G-CSF production was confirmed by the expression of G-CSF mRNA in the tumor extract and the patients high serum G-CSF concentration. The expression of G-CSF by benign and malignant mesothelial cells has already been reported. However, this is the first case report of G-CSF production in a pericardial mesothelioma.

PSEUDOHYPERTENSION IN HEMODIALYZED ARTERIOSCLEROTIC PATIENTS

Satoru Kuriyama, MD, Division of Nephrology, Saiseikai Central Hospital, 1-4-17, Mita, Minato-ku, Tokyo 108 (Japan) Fig. 1. Correlation between cuff and intra-arterial systolic (A, Δ) and diastolic (V, T) blood pressure in Osier-positive (Δ ‚ V) and Osier-negative (A ‚ ▼) patients. Cuff pressures were consistently higher than intra-arterial pressure in Osier-positive patients. Furthermore, the atherogenic index (total cholesterol minus HDL/HDL) was higher in Osier’s maneuver-positive patients (3.9 ± 1.3 in 11 Osier’s maneuver-positive subjects versus 2.4 ± 1.1 in 6 Osier’s maneuver-negative subjects; p < 0.05 by Student’s t test). The large difference between the direct and indirect blood pressure values can be due to the increased rigidity of the arterial wall in HD-associated arteriosclerosis. With indirect blood pressure measurements, hard-walled arteries require greater pressure to collapse Dear Sir, One of our long-term hemodialyzed patients with diabetes mellitus presented on admission with a systolic blood pressure of 280 mm Hg, as determined by cuff sphygmo-manometer (indirect method). Simultaneous direct brachiai artery cannulation blood pressure (direct method) showed a systolic blood pressure of 110 mm Hg. This remarkable discrepancy prompted us to investigate blood pressure in our maintenance hemodial-ysis (HD) hypertensive population. We followed all recent American Heart Association recommendations [1], including using a 47 × 13 cm cuff and 24 × 13 cm bladder to avoid ‘cuff hypertension’; also, we checked before starting our trial that there were no significant differences in each subject between left and right arm systolic blood pressure measurements. The cuff was strictly positioned 2 cm above the antecubital crease to obtain a similarly leveled complete compression of the brachiai artery. All subjects had an upper arm circumference of not more than 27 cm, and all blood pressures were averages of 2 measurements. Simultaneously, we measured each subject’s blood pressure directly through a 17-G needle cannula in the opposite brachiai artery. ‘Procedure of Osier’s maneuver: Osier’s maneuver was performed by inflating the blood pressure cuff above systolic blood pressure and carefully palpating the radial artery or brachiai artery. Whenever either of these arteries remained clearly palpable, the patient was described as being Osier-positive. In contrast, when it collapsed and could not be palpated, the patient was described as being Osier-negative.

Differential regulation of cation transport of vascular smooth muscle cells in a high glucose concentration milieu

To gain new insights into the pathogenesis of diabetic angiopathy, the influence of high glucose concentration on cation transport of vascular smooth muscle cell (VSMC) membrane was investigated by measuring Na, K and Ca transport in serially passaged cultured VSMC. (1) Na-K pump activity, described as ouabain sensitive 86Rb uptake, and Na-K cotransport, described as bumetanide sensitive 86Rb washout of VSMC, grown in high glucose concentration medium (460 mg/dl), was lower than that grown in normal glucose concentration medium (100 mg/dl). A smaller 5-N,N-hexamethylene amiloride (HMA) sensitive 22Na uptake (Na-H antiport) in high glucose concentration medium. accounted for this difference. (2) 45Ca uptake was also smaller in VSMC cultured in high glucose concentration medium. However, the washout rate constant for 45Ca was comparable between high and normal glucose cultured VSMC. (3) Both intracellular concentration of Na and cytosolic free Ca concentration concentration ([Ca]i) of high glucose cultured VSMC were greater than normal glucose cultured VSMC. (4) Intracellular water volume based on the equilibrium distribution of 3-O-methyl-[14C]glucose was not different between normal and high glucose cultured VSMC. It is concluded that VSMC grown in high glucose concentration milieu manifests a decreased Na-K, and Ca transport in conjunction with an increase in intracellular concentration of Na and [Ca]i. These results suggest that high glucose, per se, may alter membrane permeability to cations, possibly leading to changes in VSMC contractility and/or proliferation. This abnormality seen in the diabetic state may closely link to the pathogenesis of diabetic angiopathy, thus as a result risking hypertension and vascular disease.

Increased Na-K Transport in Glomerular Mesangial Cell Membrane from Spontaneously Hypertensive Rats

To investigate the differences in the Na-K transport of the mesangial cell (MC) membrane in hypertension versus normotension, the activity of the Na-K pump and the passive cation permeability were measured in serially passaged cultured MC obtained from both spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats. When Na-K pump was active, Na-K pump activity, described as ouabain-sensitive 86Rb uptake, was significantly greater in the cultured MC from SHR than WKY rats. The outward Na-K cotransport, described as the washout rate constant of bumetanide-sensitive 86Rb washout, was also greater in SHR MC than in WKY rat MC. When Na-K pump was inhibited by 1 mM ouabain, overall intracellular Na uptake was significantly greater in SHR MC. A greater 5-(N,N-hexamethylene)amiloride-sensitive Na uptake in SHR MC accounted for this difference. There was no difference in the intracellular concentration of Na and K in the cultured MC from the 2 strains when Na-K pump was active. It is concluded that there is an increased activity of Na-K pump in the cultured MC from SHR, and that this abnormality may be innate to SHR cells. It is also suggested that an increase in Na-K cotransport and Na-H antiport may explain this difference, and that these abnormalities observed in the SHR kidney may be involved in the pathogenesis of hypertension in this model.

Stimulatory effect of serum on 86Rb washout from vascular smooth muscle cells in culture.

In order to elucidate the effect of serum on passive K permeability of vascular smooth muscle cells (VSMC) membrane, outward passive K permeability yielded as washout rate constant (Kc) of 86Rb washout, was measured in the presence and in the absence of cation transport modulators using VSMC in culture. The overall Kc of 86Rb washout subjected to 1% serum was significantly larger than that in controls. This stimulated Kc was substantially blunted in the presence of 10(-4) M amiloride and was partially inhibited with 5 x 10(-4) M bumetanide. Angiotensin II of 10(-5) M exerted to a lesser extent, a similar significant stimulatory effect on Kc of 86Rb washout, which effect was inhibited with application of amiloride. Additionally, Ca-antagonist, 10(-5) M nifedipine reduced serum-stimulated Kc to the basal level. It is concluded that both serum and angiotensin II increase K permeability in cultured VSMC. A part of this effect of serum may be attributable to angiotensin II in the serum. Furthermore, it is suggested that the stimulatory effect of serum on membrane permeability may be exerted, at least in part, via activation of both Na-H antiport and Na-K co-transport, possibly through mechanisms in conjunction with intracellular Ca.