Parameters for successful monthly extended dosing of darbepoetin-alpha in patients undergoing hemodialysis.

AIM: To document the feasibility and report the results of dosing darbepoetin-alpha at extended intervals up to once monthly (QM) in a large dialysis patient population. MATERIAL: 175 adult patients treated, at 23 Swiss hemodialysis centres, with stable doses of any erythropoiesis-stimulating agent who were switched by their physicians to darbepoetin-alpha treatment at prolonged dosing intervals (every 2 weeks [Q2W] or QM). METHOD: Multicentre, prospective, observational study. Patients' hemoglobin (Hb) levels and other data were recorded 1 month before conversion (baseline) to an extended darbepoetin-alpha dosing interval, at the time of conversion, and once monthly thereafter up to the evaluation point (maximum of 12 months or until loss to follow-up). RESULTS: Data for 161 evaluable patients from 23 sites were included in the final analysis. At 1 month prior to conversion, 73% of these patients were receiving darbepoetin-alpha weekly (QW) and 27% of the patients biweekly (Q2W). After a mean follow-up of 9.5 months, 34% received a monthly (QM) dosing regimen, 52% of the patients were receiving darbepoetin-alpha Q2W, and 14% QW. The mean (SD) Hb concentration at baseline was 12.3 +/- 1.2 g/dl, compared to 11.9 +/- 1.2 g/dl at the evaluation point. The corresponding mean weekly darbepoetin-alpha dose was 44.3 +/- 33.4 microg at baseline and 37.7 +/- 30.8 microg at the evaluation point. CONCLUSIONS: Conversion to extended darbepoetin-alpha dosing intervals of up to QM, with maintenance of initial Hb concentrations, was successful for the majority of stable dialysis patients.

Stabilization of calcium oxalate suspension by urinary macromolecules, probably an efficient protection from stone formation.

INTRODUCTION: Crystal aggregation (AGN) destabilizes crystal suspensions and during crystalluria probably favors crystal apposition to kidney calcifications and preexisting stones. We analyzed inhibition of AGN and stabilization of calcium oxalate suspensions by urinary macromolecules (UM), urine and solutions with urinary citrate concentration. MATERIALS AND METHODS: Solutions of UM (UMS) were obtained by a hemofiltration procedure from urine of 6 healthy men. Calcium oxalate suspensions were prepared in all solutions and urine by adjusting Ca2+ to 1.5 mM and by an oxalate titration to 1.0 mM. Crystallization was monitored measuring optical density (OD). Stability of suspensions (SS) was defined as the time without sedimentation and zeta potential (ZP) of crystals was measured. AGN was visualized by scanning electron microscopy and quantified by maximal OD. RESULTS: UMS inhibited AGN and increased ZP and SS. Most inhibitory activity of urine could be attributed to UM. 3.3-fold dilution of UM reduced SS only by 30%. CONCLUSIONS: During crystalluria, UM of healthy men are supposed to protect from stone formation by inhibiting AGN and stabilizing crystal suspensions. As a probably important aspect, this protection was found to be limited in time and may favorably be influenced by an increase of diuresis.

Cardiovascular and renal profile of acute peripheral dopamine1-receptor agonism with fenoldopam.

Whether the dopaminergic system may be involved in essential hypertension is of pathogenetic as well as therapeutic interest. Therefore, we investigated in eight hypertensive and 12 normal subjects cardiovascular, endocrine, and renal responses to fenoldopam, which has been characterized experimentally as an agonist of peripheral postsynaptic dopamine1 receptors. A single oral dose of fenoldopam, 100 mg, changed blood pressure (BP) in hypertensive subjects (from 163/103 to 147/76 mm Hg; p less than 0.01 for systolic and p less than 0.001 for diastolic BP) and normal subjects (from 121/81 to 123/65 mm Hg; p less than 0.001 for diastolic BP); percentage decreases in diastolic BP averaged -20 +/- 6 and -16 +/- 7%, respectively. Fenoldopam-induced effects on other variables were similar in the two groups. Heart rate rose (p less than 0.001) on average from 69 to 92 beats/min in hypertensive and from 64 to 84 beats/min in normal subjects. Effective renal plasma flow increased (from 552 to 765 and 634 to 937 ml/min/1.73 m2; p less than 0.01), while glomerular filtration rate tended to decrease (from 121 to 99 ml/min/1.73 m2 in the hypertensive and from 119 to 97 ml/min/1.73 m2; p less than 0.001 in the normal group). Fractional sodium clearance was elevated (from 2.8 to 5.2 and 1.7 to 3.8%; p less than 0.01), as was free water clearance (from -1.7 to 0.6 and -1.7 to 0.1 ml/min/1.73 m2; p less than 0.01). Potassium clearance was largely unchanged. Plasma renin activity increased about twofold (p less than 0.01 in normal subjects), and plasma aldosterone by 40% (NS). Plasma norepinephrine levels increased twofold to 2.5-fold (p less than 0.001), and urinary norepinephrine excretion fivefold to 10-fold (p less than 0.01). Fenoldopam-induced changes were not significantly modified by intravenous and/or oral pretreatment with the dopamine-receptor antagonist metoclopramide or the cyclooxygenase inhibitor indomethacin. These findings suggest that in humans, fenoldopam may acutely override the dopaminergic antagonism of metoclopramide given in clinical dosage and that its cardiovascular and renal effects are not prostaglandin-mediated. Although acute sympathetic stimulation may be partially antagonistic, the concomitant BP-lowering, renal vasodilating, and natriuretic actions of fenoldopam represent a desirable profile of a potential antihypertensive agent.

Effects of short-term norepinephrine infusion on plasma catecholamines, renin, and aldosterone in normal and hypertensive man.

The acute responsiveness of plasma catecholamine, renin (PRA), and aldosterone levels to exogenous norepinephrine was studied under placebo conditions and following renin (PRA), and aldosterone levels to exogenous norepinephrine was studied under placebo conditions and following renin-angiotensin activation by diuretic pretreatment in 25 normal subjects and 34 patients with borderline-to-moderate essential hypertension. Norepinephrine infusion caused increases in plasma norepinephrine (PNE) that correlated with the infused norepinephrine dose (p < 0.001); this relationship was similar in normal and hypertensive subjects and unaltered by diuretic therapy. Plasma epinephrine and dopamine levels were unchanged during norepinephrine infusion. Norepinephrine infusion at pressor doses stimulated PRA (p < 0.01). The PRA responses correlated with the dose of infused norepinephrine (p < 0.0025), and norepinephrine-stimulated PRA correlated with basal PRA (p < 0.001). These norepinephrine-PRA relationships were unaltered by diuretic treatment and similar in normal and hypertensive subjects. In both groups, norepinephrine also caused a similar increase in plasma aldosterone (p < 0.05) under placebo conditions, but not following diuretic therapy. These findings demonstrate that an acute increase in the blood levels of the adrenergic neurotransmittor, norepinephrine, causes mild but distinct stimulation of plasma renin and aldosterone levels. Renin release in response to exogenous norepinephrine is not enhanced following renin-angiotensin activation by diuretic pretreatment. The responsiveness of the renin-angiotensin-aldosterone system to an acute norepinephrine input seems to be intact in essential hypertension.

Pressor factors and cardiovascular pressor responsiveness in borderline hypertension.

The role of various pressor factors and cardiovascular responsiveness to norepinephrine or angiotensin II in the pathogenesis of borderline hypertension was evaluated. Exchangeable body sodium, blood volume, plasma renin activity, norepinephrine or dopamine levels, and norepinephrine or epinephrine excretion rates were similar between 24 patients with borderline hypertension (mean age 34 +/- 4 (SEM) years and 22 normal subjects matched for age; the patients had a slight increase in supine plasma epinephrine. Pressor doses of norepinephrine or angiotensin II were significantly lower (p less than 0.01 and 0.001, respectively) in the borderline hypertensive group. These findings suggest that borderline hypertension may be maintained by inappropriately increased cardiovascular response to norepinephrine and angiotensin II in the presence of normal sympathetic and renin activity and a normal body sodium-volume state.

Increased serum low-density lipoprotein cholesterol in men treated short-term with the diuretic chlorthalidone.

The effect of the diuretic chlorthalidone (100 mg/day for 6 weeks) on serum lipoproteins was evaluated in 37 subjects. In 19 men with essential hypertension (aged 41 +/- 3 yr), 8 normal men (26 +/- 3 yr), or all of these men considered together, chlorthalidone significantly increased serum low density lipoprotein--cholesterol (LDL-C) by 20% (p less than 0.05 to less than 0.01). There was also a tendency for increased LDL-C in seven postmenopausal women (+/- 15%) but not in three premenopausal women with essential hypertension. High density lipoprotein--cholesterol was not significantly changed in hypertensive women or normal men and decreased slightly (p less than 0.05) in hypertensive men. Apolipoproteins A-I, A-II, and B were not changed significantly in women or men. Diuretic-induced lipoprotein alterations were not associated with altered plasma volume and unrelated to variations in serum potassium, glucose, insulin levels, blood pressure, and body weight. Short-term diuretic therapy with chlorthalidone may increase serum LDL-C in young or middle-aged men with normal or high blood pressure.

Correction of altered noradrenaline reactivity in essential hypertension by indapamide.

Fourteen patients with untreated mild to moderate essential hypertension had, on average, an abnormally high cardiovascular reactivity to exogenous noradrenaline and angiotensin II, while plasma noradrenaline, renin activity, exchangeable body sodium, and blood volume were normal. Treatment with a low dose of indapamide (2.5 mg/day) for 6 weeks decreased blood pressure by 10% in these hypertensive patients but not in 13 normal control subjects. Plasma or blood volume and exchangeable sodium were not changed significantly; nevertheless, the latter, and body weight, tended to be decreased slightly. Though a mild reduction in extracellular sodium in both normal and hypertensive subjects appears possible, it may not fully explain per se the blood pressure-lowering effect of indapamide in essential hypertension. Indapamide induced a mild decrease in angiotensin II pressor responsiveness in normal or hypertensive subjects, but a possible depressor influence from this change was probably antagonized by a concomitant pronounced increase in plasma renin activity. In hypertensive patients, the abnormally high noradrenaline reactivity was corrected by indapamide without an accompanying increase in endogenous plasma noradrenaline levels. Indapamide-induced changes in blood pressure correlated with those in noradrenaline pressor dose. It was concluded, therefore, that indapamide may decrease blood pressure in essential hypertension at least in part by lowering an abnormally high cardiovascular noradrenaline reactivity without causing an equivalent increase in adrenergic nervous activity.

Acute gout of the right sacroiliac joint.

An eighty-year-old woman suffered from acute idiopathic gout of the right sacroiliac joint and tophaceous deposits in two fingers of her right hand. Hyperuricemia and findings consistent with gout detected by histological examination of a biopsy specimen taken from the digital nodules supported the diagnosis. The radiological workup revealed osteolytic changes at the bases of the phalanges in Roentgenograms of the feet. Various aspects of the very rare incidence of sacroiliac gout are discussed.

Dermatomyositis, carcinoma of colon and meningioma in the same patient.

Dermatomyositis and carcinoma of colon were diagnosed in a 66-year-old woman. Meticulous physical examination excluded further systemic or cutaneous involvement. The musculocutaneous disorders responded well to daily oral corticosteroid, and the malignant tumor was totally removed surgically. After a seven-year follow-up of actual dermatomyositis controlled by maintenance doses of prednisone ranging from 5 to 15 mg daily, the patient developed a meningioma. Current concepts and data regarding various aspects of the combination between dermatomyositis and tumors are discussed. To our knowledge, this is the first reported case of meningioma associated with dermatomyositis.

Sebaceous adenomas, squamous cell carcinoma and skin infections in a patient with carcinoma of the colon, rectum and bladder.

Sebaceous adenomas and squamous cell carcinoma developed in a male patient in addition to viral, mycotic and bacterial infections, several years after the removal of three malignant tumors from his lower gastrointestinal and urinary tract. Skin tests with trichophytin, candidin, and mixed bacteria were negative. Various aspects regarding cutaneous changes associated with colorectal and bladder carcinomas are discussed.

Coincidence of vitiligo and Paget's bone disease in a patient.

Paget's bone disease developed in a patient with vitiligo. Scrupulous physical examination excluded further systemic or cutaneous involvement. The immunological workup revealed a reversed CD4/CD8 ratio due to a very low CD4 cell percentage and almost negligible responses to PHA as well as Con A, T cell mitogens. The pathogenic significance of these results, which point to phenotypic and functional T cell defects, is discussed.

Long-standing dermatological manifestations in a patient with chronic heavy metal intoxication.

A patient with chronic metal intoxication is described, presenting during four years after the cessation of her exposure to industrial substances, maculo-papular eruptions with several ulcerated lesions and excoriations on her abdomen and buttocks. She also had pallor of her face, greyish-dark discoloration of the hair, while the fingernails were brittle and sensitive. Scrupulous physical examination excluded further cutaneous involvement. The immunological workup revealed both phenotypic and functional defects in cellular immunity.

Fulminant dermatomyositis after removal of a cancer.

Dermatomyositis developed suddenly in a diabetic patient with CREST syndrome after the removal of a malignant tumor. Scrupulous physical examination excluded further systemic or cutaneous involvement. We raise certain still unsolved aspects regarding the association between dermatomyositis and neoplastic disorders.

Vitiligo, rheumatoid arthritis and pernicious anemia.

A patient with a 46-year history of vitiligo who also presented rheumatoid arthritis and pernicious anemia is described. Meticulous physical examination excluded further systemic or cutaneous involvement. The immunological workup revealed a low CD4 cell percentage with T cells mostly composed of CD8 cells, a discrepancy between the high percentage of cumulative CD4 + CD8 cells and the measured CD3 proportions, very low NK cytotoxicity toward K562 cells, and almost negligible responses to PHA, Con A and PWM mitogens. The results point to severe T and NK cell functional defects. The pathogenetic significance of these data is discussed.

Gore-tex versus Oreopoulos peritoneal catheters: clinical evaluation and comparison.

Ten Gore-tex and ten Oreopoulos peritoneal catheters were evaluated in a comparative clinical trial with an average follow-up of 13 1/2 months per catheter. Catheter survival was significantly poorer in the Gore-tex group (p = 0.0016) because of catheter-related complications like tunnel infections, fissure, migration and painful catheter which made it necessary to remove seven Gore-tex catheters. Substantial corrections of the Gore-tex catheter design are proposed.

[A rare cause of nephrotic syndrome in a young woman with flank pain, milky urine and leukocyturia]. / Seltene Ursache eines nephrotischen Syndroms mit Flankenschmerzen, milchigem Urin und Leukozyturie bei einer jungen Frau.

A 27 year old patient presented with a sudden acute illness showing right flank pain, milky urine, nephrotic range proteinuria, erythrocyturia and leukocyturia in the urinary sediment with a negative leukocyte test stick. The proof of a pronounced hypertriglyceriduria led to the diagnosis of Chyluria. The lymphangiogram confirmed the presence of a retroperitoneal lymphatic dysplasia with evidence of communication with the right renal pelvis on the CT-lymphogram. Chyluria is generally the result of parasitic infection and is extremely rare in Europe. In the presence of symptoms including milky urine, proteinuria and leukocyturia in the urinary sediment and a negative urine leukocyte stick test and absence of infectious signs, chyluria must be suspected. The diagnosis should be substantiated through proof of hypertriglyceriduria and confirmed by lymphangiography.