Marked hyponatremia with consciousness disturbance probably caused by linezolid in a patient with acute myeloid leukemia

We report the case of a 75-year-old man with acute myeloid leukemia who developed hyponatremia after linezolid administration. Because induction therapy did not achieve complete remission for this man, we initiated re-induction therapy with enocitabin and daunomycin. Seven days after chemotherapy, the patient experienced a catheter-related blood stream infection (CRBSI) due to methicilin resistant staphylococcus aureus (MRSA). When treatment with albekacin and fosfomycin was in effective, linezolid was administrated intravenously and he became afebrile. On day 8 after linezolid administration, however, he reported general fatigue and slight consciousness disturbance. His serum sodium concentration was 119 mEq/L and his urinary sodium excretion rose to 143 mEq/day, although intravenous sodium intake was 98 mEq/day. Because of the sufficiency of urine volume and weight loss, we surmise that inappropriate ADH secretion (SIADH) syndrome was unlikely. We diagnosed renal salt wasting syndrome (RSWS) based on calculation of the amount of sodium intake and the amount of sodium excreted from the kidneys. After linezolid was discontinued and aggressive treatment with sodium supplement begun, his consciousness cleared as his low serum sodium level rose. This is, to the best of our knowledge, the first case reported on the development of RSWS after linezolid treatment. Although the process remains unclear, our case suggests that linezolid may induce RSWS after intensive chemotherapy.     

Myelodysplastic syndromes with nephrotic syndrome

It is sometimes reported that the immunological abnormalities in myelodysplastic syndromes (MDS) induce autoimmune disease (i.e., acute systemic vasculitic syndrome, chronic cutaneous vasculitis, polyneuropathy, relapsing polychondritis, and steroid-responsive pulmonary disorders). We investigated the clinical features of patients with MDS accompanied by nephrotic syndrome. We enrolled 125 patients with MDS who were admitted between January 1979 and May 1996 in this study. The renal function was assessed based on the laboratory data and the findings at the physical examination. The diagnoses of nephrotic syndrome and glomerular disease were established when 24-hr urinary excretion was more than 3.5 g and serum total protein was less than 6.0 g/dl, and when the 24-hr protein excretion was more than 1.5 g. Five patients (4%) had glomerular disease, and three (2.4%) had nephrotic syndrome. Of the five patients with glomerular disease, two had refractory anemia (RA), and three had chronic myelomonocytic leukemia (CMMOL). Three of the total 11 patients with CMMOL were diagnosed as having nephrotic syndrome. Among the CMMOL patients, those with nephrotic syndrome showed higher absolute monocyte numbers than did those without nephrotic syndrome (8830 +/- 4677/microl vs. 3061 +/- 2887/microl, P = 0.03). One CMMOL patient was treated with VP-16 and hydroxyurea. As the white blood cell count in this patient decreased, the 24-hr urine protein excretion and the serum tumor necrosis factor alpha level decreased. The relationship between nephrotic syndrome and CMMOL was not clear. High monocyte count and the serum cytokines in MDS patients may play a partial role in the evolution of glomerulonephritis, and CMMOL may be closely related to nephrotic syndrome.     

Different mechanisms of polyuria and natriuresis associated with paroxysmal supraventricular tachycardia.

The mechanism of polyuria associated with paroxysmal supraventricular tachycardia (SVT) was investigated in 8 patients. SVT was induced artificially and sustained for 60 minutes. Urine and blood samples were collected every 30 minutes. During the latter half of SVT, urine flow increased twofold in the control subjects before SVT. Urinary sodium excretion increased significantly (p less than 0.01) within 30 minutes after SVT. Urinary excretion of antidiuretic hormone (ADH) decreased (p less than 0.01) during the latter half of SVT and increased (p less than 0.01) after SVT, respectively. Plasma level of ADH did not change during SVT but increased (p less than 0.05) after SVT. The concentration of plasma atrial natriuretic polypeptide (ANP) increased significantly (p less than 0.05) before SVT ended. Urinary excretion of prostaglandin E2 increased significantly (p less than 0.05) after termination of SVT. The percent changes in the urinary excretion of prostaglandin E2 were correlated (r = 0.713, p less than 0.001) with those of ADH. There was also a correlation (r = 0.6, p less than 0.001) between the percent changes in the urinary excretion of prostaglandin E2 and those of sodium. Their findings suggest that the polyuria during SVT is attributed mainly to the inhibition of ADH release and that the natriuresis after SVT is due not only to the increased ANP but also to the increased renal prostaglandin E2 probably stimulated by ADH.     

The syndrome of inappropriate antidiuretic hormone secretion (SIADH): pathophysiologic mechanisms in solute and volume regulation.

1. Studies on eight patients were performed to clarify the mechanism(s) of altered sodium metabolism and volume regulation in SIADH. The mechanism controlling water excretion was also studied to determine whether there is evidence that altered osmoregulation may be the basis for inappropriate ADH secretion in some patients. 2. These studies show that cumulative sodium balance and aldosterone secretion rates in patients with SIADH are negatively correlated with water intake. There is also a negative correlation between aldosterone secretion and urinary sodium excretion. In the absence of normal urine diluting ability, this increased excretion of sodium becomes a mechanism that allows an increased quantity of water to be excreted despite the persistence of an ADH effect on the renal tubules. 3. Within the range of hyponatremia observed in our studies, changes in serum sodium concentration were accounted for by changes in solute and water balance. One patient, who was potassium deficient during the studies, retained large quantities of sodium and potassium that could not be accounted for by an increase in either serum osmolality or body weight. These observations suggest that intracellular osmotically active solute is either lost or "inactivated" in some manner as intracellular potassium is replenished. 4. Marked impairment of urine diluting ability was demonstrated in all patients. However, two patients with SIADH associated with pulmonary tuberculosis exhibited graded responses to water loading, which suggests that ADH secretion may have been suppressed as serum osmolality was progressively reduced. Whether this can be attributed to a basic alteration or "re-setting" or osmoreceptor function, or is merely an indication that greater than normal reductions of serum osmolality are required to inhibit potent nonosmotic stimuli, remains to be determined.     

A case of syndrome of inappropriate secretion of antidiuretic hormone (SIADH) with low plasma concentrations of antidiuretic hormone.

A 66-year-old Japanese man presented with persistent hyponatremia without polydipsia and polyuria. Laboratory examination showed serum sodium of 117 mEq/l, plasma osmolality 239 mosm/kg, urine sodium 108 mEq/l, urine osmolality 577 mosm/kg, and normal levels (less than 2.0 pg/ml) of serum antidiuretic hormone (ADH). ADH release was regulated normally with changes in plasma osmolality. No obvious cause for the syndrome of inappropriate secretion of ADH (SIADH) could be detected. However, 20 months later, the patient had bouts of hematuria and was found to have cancer of the urinary bladder. Increased renal sensitivity to ADH was suspected as the underlying mechanism of SIADH.     

Urinary excretion of parathyroid hormone-related protein in patients with adult T-cell leukemia and other hematologic disorders]

Urinary excretion of parathyroid hormone-related protein (PTH-rP) was measured by radioimmunoassay in 25 patients with adult T-cell leukemia (ATL), in 68 patients with other hematologic disorders and in 13 asymptomatic individuals seropositive for human T-cell leukemia virus type I (HTLV-I). The mean levels of urinary PTH-rP in ATL patients with hypercalcemia (11.01 micrograms/g.Cr) were higher than in ATL patients with normocalcemia (5.16 micrograms/g.Cr). The mean levels in patients with acute type (8.84 micrograms/g.Cr), lymphoma type (4.18 micrograms/g.Cr) and crisis ATL (18.20 micrograms/g.Cr) were significantly higher than in urine of healthy controls. However, all asymptomatic carriers of HTLV-I and patients with chronic and smoldering ATL had normal urinary PTH-rP levels. In 7 patients with acute myelogenous leukemia, 1 patient with blastic crisis of chronic myelogenous leukemia and 3 patients with malignant lymphoma, the urinary levels of PTH-rP were above the normal range. Urinary levels of PTH-rP of the ATL patients with hypercalcemia correlated with the serum calcium levels. Urinary levels of PTH-rP of the all ATL correlated with serum lactic dehydrogenase level. These findings suggest that the measurement of urinary levels of PTH-rP is useful for evaluation of ATL and that some tumor cells of other hematologic diseases may produce PTH-rP.     

A patient with meningeal carcinomatosis accompanied by a small pituitary metastatic lesion from gastric cancer who developed cerebral salt wasting syndrome

A 68-year-old man with disturbed consciousness had repeatedly developed light-headedness and dizziness since the summer of 1996 and was admitted to a hospital for detailed examinations on October 8, 1996. On admission, he weighed 49 kg and showed subclinical hypothyroidism with low T3 syndrome. The adrenal function and serum electrolytes were normal. Since the stool samples were positive for occult blood, gastroscopy was performed. Examination of the biopsy specimens demonstrated gastric cancer. On October 21, blood examination showed hyponatremia (127 mEq/l). On October 22, marked disturbance of consciousness developed. On October 24, the serum Na level further decreased to 116 mEq/l. On November 8, he was referred to our hospital. On admission, his skin and tongue showed marked dehydration, and severe disturbance of consciousness and neck stiffness were observed. The central venous pressure was 4 cmH2O. In the cerebrospinal fluid, atypical cells were observed, and a diagnosis of meningeal carcinomatosis was made. Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) was excluded because of marked dehydration, a normal blood ADH level, and because plasma osmotic pressure was greater than urinary osmotic pressure. Considering the possibility of cerebral salt wasting syndrome (CSWS) or hypoadrenocorticism, Na supplementation and drip infusion of prednisolone (20 mg/day) were performed. The serum Na has normalized (140.1 mEq/l), and his consciousness improved. He died of aggravation of the general condition on December 16. Pathological examination demonstrated a small metastatic lesion in the infundibular part of the pituitary gland and a small metastatic lesion in the parenchyma of the bilateral adrenal glands. However, since neither hypotension nor hypoglycemia was observed before treatment, and the blood cortisol level and the serum K level were normal, hypoadrenocorticism was excluded. Hypoaldosteronism was also excluded because of a normal serum K level. CSWS has been reported to be caused by head trauma, subarachnoid hemorrhage, or trans-sphenoidal pituitary operation. This patient is a rare case of CSWS developed in the presence of meningeal carcinomatosis accompanied by a small pituitary metastatic lesion from gastric cancer. The aged with decreased ability to retain water and sodium in the body are more susceptible to CSWS than the young. In the aged with central hyponatremia, the possibility of CSWS should be considered, and early diagnosis and treatment are necessary.     

Atrial natriuretic factor-specific antibody as a tool for physiological studies. Evidence for role of atrial natriuretic factor in aldosterone and renal electrolyte regulation

Numerous studies have shown that administration of atrial natriuretic factor (ANF) increases urinary sodium excretion and urine flow, decreases blood pressure, and inhibits renin and aldosterone release. However, the role of endogenous ANF in the regulation of renal sodium excretion, blood pressure, plasma renin activity, and aldosterone level remains to be elucidated. To examine this issue, endogenous ANF was blocked by administering rat ANF-(99-126) specific antiserum (Ab) to anesthetized rats (n = 7). Control animals received either no injection (time controls, n = 10) or preimmune serum (n = 8). Blockade of endogenous ANF caused a 28 +/- 0.09%, 47 +/- 0.08%, and 51 +/- 0.08% fall in sodium excretion at 15, 30, and 45 minutes after Ab injection (p less than 0.05, p less than 0.01, p less than 0.01, respectively). Urine flow fell 35 +/- 7% at 45 minutes after ANF inhibition (p less than 0.05). Plasma ANF levels were suppressed to undetectable levels. However, there were no changes in blood pressure throughout the experiment nor plasma renin concentration when measured at 45 minutes after Ab injection. Interestingly, plasma aldosterone concentration increased significantly (by approximately 50%, p less than 0.025), in response to Ab. Completeness of blockade was demonstrated by the absence of sodium excretion response to exogenous ANF (500 ng). In either the time control or the preimmune serum group, urinary excretion, blood pressure, plasma ANF, plasma renin concentration, and plasma aldosterone concentration were unchanged throughout the experiment. In contrast to the Ab group, a challenge with exogenous ANF (500 ng) increased sodium excretion by 2.17 mueq/min in the preimmune serum group.(ABSTRACT TRUNCATED AT 250 WORDS)     

Blood pressure response during long-term treatment with magnesium is dependent on magnesium status. A double-blind, placebo-controlled study in essential hypertension and in subjects with high-normal blood pressure

Both experimental and epidemiological studies support the idea of magnesium supplementation in essential hypertension. We added 15 mmol Mg to a free diet in 71 subjects with mild essential hypertension or a high-normal blood pressure in a double-blind, placebo-controlled study over 6 months. The treatment, which raised urinary magnesium excretion 30%, induced no general effects on the blood pressure. However, when the changes in blood pressure in the actively treated group were related to the pretreatment magnesium status, a correlation was found between pretreatment urinary magnesium excretion and the induced change in supine blood pressure (P less than .05) with a blood pressure reduction in subjects with a low pretreatment urinary excretion of magnesium, and a pressor effect in the subjects with the highest pretreatment levels of urinary magnesium. The induced change in blood pressure was furthermore found to be inversely correlated to the changes in serum magnesium and urinary excretion of sodium (P less than .03) induced by treatment indicating that both a direct calcium antagonist action of magnesium at the cellular level as well as a diuretic effect of the increased magnesium load might be involved in the blood pressure effects of magnesium. Pretreatment serum potassium concentration also appeared to be a predictor of the induced change in standing blood pressure (P less than .03). In conclusion, magnesium supplementation does not seem to be effective in unselected mild hypertensive subjects or in subjects with a high-normal blood pressure and can therefore not be generally recommended.(ABSTRACT TRUNCATED AT 250 WORDS)     

Significance of oxytocin to disorders of fluid and electrolyte metabolism in patients with essential hypertension

A possible involvement of oxytocin (OT) has been indicated in regulation of water and electrolyte metabolism, based on findings that the secretion of OT is increased by either water deprivation or sodium loading. However, to date, no informations have yet been obtained about the role of OT in hypertension. The present study was therefore undertaken to elucidate the role of OT for abnormalities of fluid and electrolyte metabolism in essential hypertension (EH) in comparison with normotensive subjects (NT). The major results were as follows. Plasma level of OT was 3.7 +/- 2.1 pg/ml (mean +/- SD) in EH, not significantly higher than that in NT (3.2 +/- 1.7 pg/ml). Plasma OT in low-renin EH (4.8 +/- 2.5 pg/ml) was significantly different from that in high-renin EH (2.9 +/- 1.4 pg/ml, p less than 0.05) and NT (p less than 0.05), but not in normal-renin EH (3.8 +/- 2.0 pg/ml). Plasma OT was inversely correlated with plasma renin activity (PRA) in EH (r = -0.384, p less than 0.01), but not in NT (r = 0.102). No significant correlation was found between plasma OT and plasma aldosterone concentration (PAC), plasma concentration of antidiuretic hormone (ADH), serum sodium and potassium, blood pressure and renal function in either EH or NT. I.m. injection of OT (0.04 IU/kg) increased significantly urinary excretions of sodium and potassium in EH and NT. However, the increment in sodium excretion was greater in low-renin EH than that in normal-renin EH (0.05 less than p less than 0.10), high-renin EH (p less than 0.05) and NT (p less than 0.05). PRA, PAC and ADH were significantly decreased after OT injection, but blood pressure, serum sodium and potassium were not altered in both EH and NT. I.v. administration of OT (0.1 approximately 0.2 IU/min) suppressed angiotensin II-induced increase of PAC and elevation of blood pressure in both EH and NT. The decrease in PAC by the OT administration was the greatest in low-renin EH. The reduction of blood pressure was significantly greater in EH than in NT (p less than 0.05). I.v. administration of hypertonic saline (5%) resulted in a significant increase of plasma OT in EH and NT, and the increment in OT was the greatest in low-renin EH. Serum sodium concentration was increased by the infusion, positively correlated with plasma OT in both EH (r = 0.458, p less than 0.05) and NT (r = 0.830, p less than 0.05).(ABSTRACT TRUNCATED AT 400 WORDS)     

Role of prolactin in disorders of water and salt metabolism in patients with hypertension

The relationship between water-salt balance and blood prolactin (Prl) level was examined in 22 male patients with essential hypertension, stages IB-IIA. Blood Prl and urinary potassium and sodium excretion were measured initially, using the parlodel (2.5 mg) test, and the acute and chronic furosemide test. Water-salt status was found to be different in patients with baseline hyperprolactinemia who made 2/3 of the sample. Following parlodel administration, Prl level declined in all patients, with daily electrolyte excretion also decreasing in originally-hyperprolactinemic patients. The rise in electrolyte excretion following lasix administration was accompanied with a fall in Prl in hyperprolactinemic patients. Following the chronic furosemide test, all patients showed a tendency to Prl rise, while the hyperprolactinemic patients also exhibited sodium retention. Therefore, blood Prl decrease leads to sodium retention in hyperprolactinemic hypertensive patients that may have an adverse pathogenetic significance.     

Severe hyponatremia caused by syndrome of inappropriate secretion of antidiuretic hormone developed as initial manifestation of human herpesvirus‐6–associated acute limbic encephalitis after unrelated bone marrow transplantation

Severe hyponatremia is a critical electrolyte abnormality in allogeneic stem cell transplantation (allo‐SCT) recipients and >50% of cases of severe hyponatremia are caused by the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Here, we present a patient with rapidly progressive severe hyponatremia as an initial sign and symptom of human herpesvirus‐6–associated post‐transplantation acute limbic encephalitis (HHV‐6 PALE) after allo‐SCT. A 45‐year‐old woman with acute lymphoblastic leukemia received unrelated bone marrow transplantation from a one locus‐mismatched donor at the DR locus. On day 21, she developed a generalized seizure and loss of consciousness with severe hyponatremia, elevated serum antidiuretic hormone (ADH), and decreased serum osmolality. A high titer of HHV‐6 DNA was detected in cerebrospinal fluid. Treatment with foscarnet sodium and hypertonic saline was started with improvement of neurological condition within several days. Although an elevated serum ADH, low serum osmolality, and high urinary osmolality persisted for 2 months, she had no other recurrent symptoms of encephalitis. Our experience suggests that hyponatremia accompanied by SIADH should be recognized as a prodromal or concomitant manifestation of HHV‐6 PALE, and close monitoring of serum sodium levels in high‐risk patients for HHV‐6 PALE is necessary for immediate diagnosis and treatment initiation.     

Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and adrenal insufficiency induced by rathke's cleft cyst: a case report

We report a case of a seventy-year-old woman with syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and adrenal insufficiency induced by Rathke's cleft cyst. She experienced nausea, vomiting, diarrhea, and headache and disturbance of consciousness induced by hyponatremia at a serum sodium level of 100 mEq/l. In spite of severe hyponatremia, urinary sodium excretion was not suppressed and serum osmolality (270 mOsm/kg) was lower than urine osmolality (304 mOsm/kg), and arginine vasopressin (AVP) remained within normal range. SIADH was diagnosed because she was free from other diseases known to cause hyponatremia such as dehydration, cardiac dysfunction, liver dysfunction, renal dysfunction, hypothyroidism, and adrenal insufficiency. Cranial computed tomographic (CT) scan and cranial magnetic resonance (MR) imaging showed a cystic lesion of approximately 2 cm in diameter in the pituitary gland. These images suggested that the cystic lesion was a Rathke's cleft cyst, which was the cause of SIADH. Water restriction therapy normalized her serum sodium concentration and improved her symptoms. After one year, she suffered from general fatigue, appetite loss, fever, and body weight loss (5 kg/2 months). She had neither hypotension nor hypoglycemia, but her serum sodium level was low and serum cortisol, ACTH, and urine free cortisol were very low. Therefore, secondary adrenal insufficiency was suspected and diagnosed by stimulation tests. After start of hydrocortisone replacement therapy (10 mg/day), her symptoms disappeared. In conclusion, Rathke's cleft cyst should be kept in mind as a potential cause in a patient with SIADH, hypopituitarism, and/or adrenal insufficiency.     

Methylprednisolone-induced hypertension in the rat: evidence against the role of plasma volume changes, vasopressin and renal prostaglandin E2

The purpose of the study was to clarify the mechanism(s) of glucocorticoid-induced hypertension. Hypertension was induced in rats by single i.m. injection of methylprednisolone (MP) 20 mg/kg. In normal Wistar rats, systolic blood pressure (SBP) increased by 30 mmHg from days 2 to 10 after MP. Urinary sodium excretion increased transiently and sodium balance was negative. Plasma volume (PV; ml/100 g body weight) increased on day 5, but was unchanged on day 2 after MP, at a time when SBP had already increased. In rats with chronic renal failure (CRF) and low sodium intake, SBP increased more than in control rats (48 versus 22 mmHg on day 10). Hypertension was not accompanied by a significant drop in urinary excretion of prostaglandin E2 (PGE2; measured by radio-immunoassay). In normal MP-injected rats, PGE2 excretion decreased slightly and then increased; in CRF rats, basal PGE2 excretion was too low to evaluate the effect of MP. In homozygous Brattleboro rats lacking antidiuretic hormone (ADH), MP increased SBP by 28 mmHg (day 10). Similar changes were obtained in heterozygous Brattleboro rats. The changes in PV were identical to those found in Wistar rats. We conclude that increase in PV, change in PGE2 and vasopressin do not play a key role in MP hypertension. Direct effect of glucocorticoid on vascular receptors is likely to be involved in this model.     

Common variants of the UMOD promoter associated with blood pressure in a community-based Chinese cohort

Hypertension is an important risk factor for chronic kidney disease. The kidney, in turn, has an important role in the regulation of blood pressure (BP). On the basis of a genome-wide association study, single-nucleotide polymorphisms in the uromodulin (UMOD) promoter region had been considered to influence both renal sodium reabsorption and BP. In this study, we asked whether common variants across the UMOD gene influence BP in a community-based Chinese cohort. We screened seven common variants across the UMOD locus in a community-based population from Beijing, including 1000 individuals with 48% males and an average age of 63.7±9.0 years. The urinary UMOD concentration was measured by enzyme-linked immunosorbent assay. We then analyzed the association of common variants of UMOD with BP. The UMOD promoter common variant rs13333226 G/A is associated with diastolic BP (DBP), and G allele carriers have higher DBP compared with A/A homozygotes (P=0.035). The variant rs6497476 C/T predicted the DBP level, with C homozygotes having a higher DBP compared with CT heterozygotes and T homozygotes (P=0.025). Urinary UMOD excretion was correlated with urinary sodium excretion (R=0.239, P=0.656*10(-13)). We determined that common variants of UMOD are associated with DBP level in a community-based Chinese cohort.     

Common variants of the UMOD promoter associated with blood pressure in a community-based Chinese cohort

Hypertension is an important risk factor for chronic kidney disease. The kidney, in turn, has an important role in the regulation of blood pressure (BP). On the basis of a genome-wide association study, single-nucleotide polymorphisms in the uromodulin (UMOD) promoter region had been considered to influence both renal sodium reabsorption and BP. In this study, we asked whether common variants across the UMOD gene influence BP in a community-based Chinese cohort. We screened seven common variants across the UMOD locus in a community- based population from Beijing, including 1000 individuals with 48% males and an average age of 63.7 ±9.0 years. The urinary UMOD concentration was measured by enzyme-linked immunosorbent assay. We then analyzed the association of common variants of UMOD with BP. The UMOD promoter common variant rs13333226 G / A is associated with diastolic BP (DBP), and G allele carriers have higher DBP compared with A / A homozygotes (P = 0.035). The variant rs6497476 C / T predicted the DBP level, with C homozygotes having a higher DBP compared with CT heterozygotes and T homozygotes (P = 0.025). Urinary UMOD excretion was correlated with urinary sodium excretion (R = 0.239, P = 0.656×10 -13 ). We determined that common variants of UMOD are associated with DBP level in a community-based Chinese cohort.     

The effects of aprotinin, a kallikrein inhibitor, on renin release and urinary sodium excretion in mild essential hypertensives

The effects of aprotinin on renin release and renal function were evaluated in 24 male essential hypertensive patients, on unrestricted (n = 17) and on chronic low as well as on high sodium intake. Aprotinin (1 X 10(6) kallikrein inhibitor units) or saline (200 ml) were infused in all patients for 6 h. Blood samples were taken for plasma renin activity (PRA) and 6-h urine collections were obtained for active and inactive kallikrein, sodium and potassium excretion measurement. In patients on unrestricted sodium diet, aprotinin had no effect on blood pressure (BP), glomerular filtration rate, renal plasma flow, urinary sodium and potassium excretion. However, an inverse relationship was found between pretreatment urinary sodium excretion and the per cent reduction of the latter after aprotinin. A significant reduction in urinary sodium excretion was induced by aprotinin in patients on high sodium intake, whereas no change was observed in the same patients when on a low sodium diet. Aprotinin reduced the urinary excretion of active kallikrein by 81% and the active to total kallikrein ratio from 24 to 6%. Infusion of aprotinin induced a significant decline in active renin but did not modify inactive renin levels in patients on unrestricted sodium diet as well as in patients on low or high sodium intake. Our data suggest that the inhibition of kallikrein and/or other serine proteases by aprotinin can interfere with renal release of active renin and also support the hypothesis that the renal kallikrein system exerts a regulatory control on sodium excretion in salt replete hypertensives.     

Clinical and hormonal conditions associated with sodium retention in cirrhotic patients with ascites

Using multiple regression analysis, we have evaluated the clinical and hormonal conditions associated with impaired urinary sodium excretion in normoazotemic patients with cirrhosis and ascites. We retrospectively identified 13 patients with a urinary sodium excretion lower than 15 mmol/day and 13 patients with a sodium excretion higher than 15 mmol/day. Using univariate analysis, all the patients with poor sodium excretion had abnormally high levels of plasma renin activity, plasma aldosterone, and arginine vasopressin. In addition, they had a diastolic blood pressure lower than patients with high urinary sodium excretion, although otherwise were comparable as regards clinical and biochemical data. The consistency of the above associations was then tested by multiple-regression analysis in an attempt to control for potentially confounding factors and to identify only true, independent associations. After a discriminant stepwise procedure, we found that low diastolic blood pressure (P<0.01) and high plasma aldosterone levels (P<0.05) were the only two conditions independently associated with abnormally low urinary sodium excretion. These findings are consistent with the view that sodium retention in decompensated cirrhosis results from a concomitant severe contraction in the effective blood volume and an increased production and/or retention of aldosterone. The concordance between our results and several pathophysiological findings supports the validity of this statistical approach to confirm physiological and/or clinical predictions.Portions of this work were presented at the Annual Meeting of the Italian Association for the Study of the Liver, Rome, June 1984.     

Renal prostaglandin E in the hypotensive mechanism of MK-421 in conscious rats

To assess the role of renal prostaglandin E in the hypotensive mechanism of MK-421, we evaluated the effects of chronic infusion of MK-421 (6 mg/kg/day i.p.) on systolic blood pressure and urinary prostaglandin E excretion in conscious rats in states of sodium repletion or depletion and also during chronic infusion of norepinephrine (1.8 mg/kg/day i.p.) or vasopressin (7.2 U/kg/day i.p.). The hypotensive effect of MK-421 was greater in sodium depleted than in sodium repleted rats. The hypertensive effect of norepinephrine or vasopressin was inhibited by the simultaneous administration of MK-421. MK-421 induced an increase in the excretion of urinary prostaglandin E, in both sodium repleted and depleted rats. However, simultaneous administration of MK-421 had no influence on the increase in urinary prostaglandin E excretion induced by norepinephrine or vasopressin. In addition, the combined administration of MK-421 with indomethacin (10 mg/kg/day s.c.) still abolished the hypertensive effect of norepinephrine or vasopressin. The disparate effect of MK-421 on urinary prostaglandin E excretion suggests that the renal prostaglandin system is not essential for the mechanism of the hypotensive effect of MK-421.     

Angiotensin II type 1 receptor blocker, olmesartan, restores nocturnal blood pressure decline by enhancing daytime natriuresis

OBJECTIVE: We have shown that as renal function deteriorated, night-time fall in both blood pressure and urinary sodium excretion were diminished. We have also reported that sodium intake restriction and diuretics both normalized circadian blood pressure rhythm from nondipper to dipper patterns. In this study, we investigated whether an angiotensin II receptor blocker, olmesartan, could restore night-time blood pressure fall. METHODS: Twenty patients with chronic kidney disease (13 men, seven women; mean age 44.8 +/- 18.1 years; BMI 22.9 +/- 3.5 kg/m2) were studied. At baseline and 8 weeks after the treatment with olmesartan medoxomil (10-40 mg/day), 24-h blood pressure monitoring and urinary sampling for both daytime (0600-2100 h) and night-time (2100-0600 h) were repeated to compare the circadian rhythms of blood pressure and urinary sodium excretion. RESULTS: The 24-h mean arterial pressure was lowered by olmesartan, while urinary sodium excretion remained unchanged. On the other hand, daytime urinary sodium excretion was increased from 4.8 +/- 2.2 to 5.7 +/- 2.1 mmol/h, while night-time urinary sodium excretion tended to be reduced from 3.9 +/- 1.7 to 3.4 +/- 1.6 mmol/h. Night/day ratios of mean arterial pressure (0.98 +/- 0.1 to 0.91 +/- 0.08; P = 0.01) and urinary sodium excretion (0.93 +/- 0.5 to 0.68 +/- 0.4; P = 0.0006) were both decreased. Olmesartan enhanced night-time falls more in mean arterial pressure (r = 0.77; r2 = 0.59; P < 0.0001) and urinary sodium excretion (r = 0.59; r2 = 0.34; P = 0.007), especially in patients whose baseline night-time falls were more diminished. CONCLUSIONS: These findings demonstrated that olmesartan could restore night-time blood pressure fall, as seen with diuretics and sodium restriction, possibly by enhancing daytime sodium excretion. Since nocturnal blood pressure is a strong predictor of cardiovascular events, olmesartan could relieve cardiorenal load through normalization of circadian blood pressure rhythm besides having powerful ability to block the renin-angiotensin system.