Biomedical subjects
E Ritz
Publications and source records attributed to E Ritz.
Concentration of dimethyl-L-arginine in the plasma of patients with end-stage renal failure.
Abstract. NGNG dimethyl-L-arginine (asymmetric dimethyl-L-arginine; ADMA) and NGNG dimethyl-L-arginine (symmetric dimethyl-L-arginine; SDMA) are naturally occurring analogues of L-arginine, the substrate for nitric oxide (NO) synthesis. ADMA is a potent inhibitor of NO synthesis, and accumulates in the plasma of patients with renal failure. However the precise concentration of ADMA and SDMA in renal patients is still controversial. This study was performed to measure plasma ADMA and SDMA concentrations by two different HPLC techniques in nine healthy controls and 10 uraemic subjects, and to investigate the effects of haemodialysis. In controls, the mean (+/-SEM) plasma concentrations of ADMA and SDMA were 0.36 +/- 0.09 and 0.39 +/- 0.05 mumol/l respectively, yielding an ADMA/SDMA ratio of 1.2 +/- 0.17. In uraemic patients, the plasma concentrations of ADMA and SDMA were 0.9 +/- 0.08 mumol/l (P < 0.001 compared to controls) and 3.4 +/- 0.3 mumol/l (P < 0.001 compared to controls) with an ADMA/SDMA ratio of 0.27 +/- 0.015 (P < 0.001). In the course of one 4 h haemodialysis session, ADMA concentrations decreased from 0.99 +/- 0.13 to 0.77 +/- 0.3 mumol/l and SDMA concentrations from 3.38 +/- 0.44 to 2.27 +/- 0.21 mumol/l. The plasma ADMA/creatinine ratio tended to increase from 1.26 +/- 0.20 x 10(-3) to 2.01 +/- 0.41 x 10(-3). It is concluded that there is a modest (3-fold) but definite increase in plasma ADMA concentration in uraemic patients compared to controls. SDMA accumulates to a greater degree (8-fold increase) and more closely parallels creatinine concentration than ADMA. The change in the ADMA/SDMA ratio is not accounted for by greater renal or dialysis clearance of ADMA, and, even though alternative explanations are not excluded, greater metabolism of ADMA than SDMA is the most likely explanation. Although small in magnitude, the increase in ADMA concentration might by biologically significant.
Activation of human neutrophils after contact with cellulose-based haemodialysis membranes: intracellular calcium signalling in single cells.
PURPOSE OF STUDY: In vitro contact of human leukocytes with cellulose-based dialysis membranes under complement-independent conditions results in activation of various leukocyte functions. To analyse signals involved in the mechanism of cell activation, we measured changes in cytosolic free calcium ([Ca2+]i) in individual human blood neutrophils (PMN) upon contact with flat sheet haemodialysis membranes. RESULTS: By confocal laser-scanning microscopy (CLSM), changes in [Ca2+]i were monitored in Fluo-3-labelled cells up to 10 min after contact with a regenerated cellulose (RC) membrane. Multiple [Ca2+]i transients were observed for cells in contact with RC; biostochastic analysis showed that up to 67% of the PMN responded with a high increase in [Ca2+]i, the rest were low- or non-responding cells. After contact with the new synthetic polycarbonate-polyether (PC-PE) membrane only non-responding cells were seen, indicating reduced cellular contact activation. The increase in [Ca2+]i of cells on RC could be inhibited by 5mM L-fucose. This monosaccharide was recently found to be present in cellulose-based polymers in picomolar concentrations. CONCLUSIONS: The data supports the hypothesis that dialysis-membrane-associated L-fucose residues participate in complement-independent leukocyte activation during haemodialysis therapy.
Papillary necrosis in a ballet dancer with no history of analgesic abuse.
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Survival on renal replacement therapy in Europe: is there a 'centre effect'?
OBJECTIVE: Survival is the ultimate outcome measure in renal replacement therapy (RRT) and may be used to compare performance among centres. Such comparison, however, is meaningless if the influences of comorbidity, age and early deaths are not considered. We therefore studied survival rates on RRT in seven centres in Europe after taking into account the influence of age, early deaths, primary renal diagnoses, and comorbidity. DESIGN: A retrospective survival analysis was carried out on 1407 patients who commenced RRT in seven centres across five European countries during a 7-year period. Patients were stratified into low-, medium- and high-risk groups based mainly on comorbidity and to a lesser extent on age at commencement of RRT. Kaplan-Meier survival and Cox's proportional hazards model were used to compare survival. RESULTS: Before risk stratification overall 2-year survival across the seven centres ranged from 60.2 to 85.3% (69.3-89.9%) after excluding early deaths) masking a range of survivals of 27.4% for the high-risk group with the worst survival to 100% in the low-risk group with the best survival. After excluding early deaths 2-year survival in the low risk groups (n=622) was greater than 90% in all centres. Multivariate analysis showed that the mortality risk increased four fold from low- to medium- and a further 1.6-fold from medium- to high-risk group. However, despite this adjustment for comorbidity and age there still remained a significant difference in survival among some centres, i.e. a 'centre effect' which ranked the centres. CONCLUSION: Risk stratification diminishes the variance in survival between centres but a centre effect remains despite adjusting for age and comorbidity. Multicentre prospective studies are urgently required to identify the reasons for this apparent centre effect.
Perirenal capsula adiposa--is it a sign indicating diabetes mellitus?
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Oral phosphate binders without aluminium and calcium - a pipe-dream?
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Receptors for advance glycation end-products (AGE) - expression by endothelial cells in non-diabetic uraemic patients.
BACKGROUND: Cellular actions of advanced glycation end-products (AGE) are mediated by a receptor for AGE (RAGE), a novel integral membrane protein. Immunohistochemical studies show only low-level RAGE antigen expression in endothelial cells. Design. It was the purposes of the study to compare expression of RAGE antigen by endothelial cells in non-diabetic uraemic patients (n=8) with non-uraemic controls (n=11). Samples of arterial tissue were obtained at the time of renal transplantation (in uraemic patients) and abdominal surgery (in controls). RAGE antigen was visualized using guinea-pig anti-RAGE IgG and PAP technique. RESULTS: Marked staining for RAGE was noted in endothelial cells, both arterial endothelium and endothelium of vasa vasorum of normoglycaemic uraemic patients, but was not demonstrable in endothelial cells of large arteries and only faintly expressed in vasa vasorum of non-uraemic individuals. CONCLUSION: Normal endothelial cells do not constitually express RAGE antigen; in contrast it is expressed by arterial and capillary endothelial cells of uraemic patients. The observation is of note in view of the putative role of AGE of causing atherosclerotic and non-atherosclerotic vascular lesions.
Graves' disease and sarcoidosis in a patient with minimal-change glomerulonephritis.
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Factitious hypertensive crisis (Munchausen syndrome).
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The history of salt - aspects of interest to the nephrologist.
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The Maillard reaction--from food chemistry to uraemia research.
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Albuminuria in normotensive and hypertensive individuals attending offices of general practitioners.
OBJECTIVE: To investigate the rate of albumin excretion and the prevalence of albuminuria in hypertensive individuals relative to the normotensive population, and to clarify the quantitative importance of confounding variables. DESIGN AND METHODS: We examined the morning urines of all consecutive non-diabetic and diabetic hypertensive patients (n = 631; 371 women, 260 men) attending the offices of five general practitioners in a circumscribed geographical area during a 4-month period. To obtain a normotensive control population, all consecutive visitors (n = 375; 217 women, 158 men) were also examined. Urinary albumin excretion was assessed by kinetic nephrelometry in morning urine samples. RESULTS: The median albumin excretion rate was 4.3 micrograms/ml (range 1.9-112) in normotensive individuals; 3.4 micrograms/ml (1.9-1440) in hypertensive and 3.6 micrograms/ml (1.9-2790) in diabetic patients (n = 189; 115 women, 74 men). The overall prevalence of albuminuria above 20 micrograms/ml was 4% in normotensive individuals, 10% in hypertensive patients and 17% in diabetic patients. The proportion of patients with higher-grade albuminuria (> 50 micrograms/ml) was 1% among the normotensive subjects aged below 60 years and 2% in those aged above 60 years; the respective values in hypertensive patients were 3 and 6% and in diabetic patients 8 and 13%. The multivariate regression analysis showed a significant correlation between albuminuria and smoking (P < 0.0001), the presence of hypertension (P < 0.001), the current level of systolic blood pressure (P < 0.01) and age (0.031), but not sex or body mass index. CONCLUSIONS: The present study confirms a higher prevalence of albuminuria above 20 micrograms/ml in individuals with primary hypertension and diabetes mellitus compared with that in normotensive subjects, despite similar median albumin excretion rates. However, the excess of prevalence is moderate. Smoking, advanced age and current level of systolic blood pressure are the important determinants.
Cardiac structure and function in renal disease.
Cardiac death secondary to ischaemia, but not necessarily associated with coronary lesions, is the leading cause of death in uraemic patients. This article reviews recent findings that demonstrate abnormalities of cardiac structure which have a bearing on ischaemia tolerance. These abnormalities comprise the following: (1) left ventricular hypertrophy not fully explained by increased mean arterial pressure, (2) interstitial fibrosis and (3) abnormalities of myocardial microvasculature, i.e. capillary rarefaction and arteriolar-wall thickening.
The role of angiotensin I-converting enzyme gene polymorphism in renal disease.
Some renal diseases (e.g. diabetic nephropathy and IgA glomerulonephritis) cluster within families, consistent with a strong genetic component for the development or progression of these diseases, or both. In this context it is attractive to examine the insertion/deletion polymorphism of the angiotensin I-converting enzyme. This polymorphism determines the concentration of angiotensin I-converting enzyme not only in serum, but also in tissues and thereby presumably the locally available concentration of angiotensin II. Several studies have examined whether this polymorphism is associated with the development of diabetic nephropathy, but most of these failed to show such an association. Studies in patients suffering from IgA glomerulonephritis or other renal diseases, including diabetic nephropathy, demonstrated that the insertion/ deletion polymorphism plays a role in the progression of renal diseases and in the response to treatment with angiotensin I-converting enzyme inhibitor.
Renal 31-phosphorus-magnetic resonance spectral changes in experimental uremia.
Altered renal cellular phosphate (Pi) homeostasis may be involved in disturbed regulation of 1 alpha, 25-dihydroxyvitamin D3 [1,25(OH)2D3] production in chronic renal failure. To assess cytoplasmic concentrations of P(i) and other phosphate metabolites in uremia, phosphorus-magnetic resonance spectroscopy (31P-MRS) studies were carried out in vivo in rat remnant kidney. Five-sixths-nephrectomized animals (Nx, n = 8, serum creatinine 1.28 +/- 0.18 mg/ dl) and sham-operated control animals (n = 8) were pair-fed a high-phosphate diet (1.6% phosphate, 1.0% calcium) for 19 days. In both remnant and intact kidneys, 31P-magnetic resonance spectra displayed six major peaks: phosphomonoesters (PME), P(i), phosphodiesters, and adenosine triphosphate (ATP)-gamma, -alpha, and -beta. Phosphocreatine was absent. The relative intensity of the renal gamma ATP signal was comparable between the remnant kidney in Nx and the sham-operated kidney in control animals and was, therefore, used as the internal standard to assess the P(i)/gamma ATP ratio. The P(i)/gamma ATP ratio was significantly (p < 0.05) increased in the remnant kidney as compared to the sham-operated control kidney (0.97 +/- 0.24 in Nx vs. 0.75 +/- 0.12 in sham-operated controls; means +/- SE). Similarly, the PME/gamma ATP ratio was significantly increased in Nx (p < 0.01), whereas the relative intensities of other phosphate metabolite signals were not altered in Nx. Mean serum 1,25(OH)2D3 concentrations were 62 pg/ml for Nx and 93 for sham-operated controls (p < 0.05); mean serum phosphate levels were 4.35 mmol/l for Nx and 2.61 for sham-operated controls (p < 0.01). The pH in the remnant kidneys was 7.20 +/- 0.06 (mean +/- SE, n = 8), whereas the pH in intact kidneys was 7.29 +/- 0.05 (n = 8, p < 0.05). To examine the contribution of blood cells to 31P-magnetic resonance spectra, an exchange transfusion with a fluorocarbonated oxygen carrier (to a final hematocrit of 8%) was carried out, while animals (n = 5) were monitored by MRS. This did not significantly change the relative intensities of phosphate metabolite peaks, indicating that blood phosphorus did not measurably contribute to the renal P(i) signal. The data suggest that intrarenal P(i) concentration is elevated in renal failure. This could inhibit 25-hydroxyvitamin D3-1 alpha-hydroxylase activity and thus have some relevance for pathogenesis of renal hyperparathyroidism.
Abnormal expression and regulation of vitamin D receptor in experimental uremia.
The low concentration of the biologically active metabolite of vitamin D, namely 1 alpha,25-dihydroxyvitamin D3 (1,25(OH)2D3), is critical to the pathogenesis of secondary hyperparathyroidism in chronic renal failure. The actions of 1,25(OH)2D3 are mediated through binding to a cellular receptor protein, the vitamin D receptor (VDR). In order to further investigate expression and regulation of VDR in uremia, we measured specific [3H]-1,25(OH)2D3 binding capacity and VDR mRNA concentration in intestinal mucosa and in parathyroid glands of subtotally nephrectomized rats (Nx) and compared Nx to sham-operated rats with normal kidney function (Intact). Intestinal [3H]-1,25(OH)2D3 binding capacity in short-term Nx (6-10 days after nephrectomy) was 663 +/- 114 fmol/mg protein; it was 517 +/- 34 in Intact (p = 0.06, n = 6 experiments). Intestinal VDR mRNA concentration was comparable between Nx and Intact. Specific 1,25(OH)2D3 binding capacity in parathyroid glands was higher in Nx (195 +/- 9 fmol/mg protein) than in Intact (116 +/- 14 fmol/mg protein, n = 5, p < 0.05). The affinity of the VDR for 1,25(OH)2D3 (KD) did not change in Nx. The 1,25(OH)2D3 binding capacity in intestinal mucosa of more long-term uremic animals (14-16 weeks after subtotal Nx) was 519 +/- 32 fmol/mg protein versus 349 +/- 31 in Intact (n = 3, p < 0.01). Parathyroid VDR was 171 +/- 9 fmol/mg protein in long-term Nx and 125 +/- 3 in Intact (p < 0.01). These results were confirmed when 1,25(OH)2D3 binding capacity in uremic rats with hereditary polycystic kidney disease was compared to control rats with normal kidney function (757 +/- 54 fmol/mg protein versus 495 +/- 59 in intestinal mucosa, p < 0.05; 273 +/- 48 versus 104 +/- 27 in parathyroid glands, p < 0.05). In parallel to changes in intestinal 1,25(OH)2D3 binding capacity, 1,25(OH)2D3-mediated stimulation of intestinal 25(OH)D3-24-hydroxylase activity was significantly higher in long-term subtotally Nx (1.43 +/- 0.06 pmol 24,25-dihydroxyvitamin D3/mg protein) than in sham-operated normal rats (1.04 +/- 0.10, p < 0.05). Administration of 1,25(OH)2D3 to sham-operated normal rats resulted in an increase of 1,25(OH)2D3 binding capacity by 20-40% in intestinal mucosa and by 40-50% in parathyroid glands. In contrast, 1,25(OH)2D3 caused down-regulation of mean 1,25(OH)2D3 binding capacity in short-term Nx by 38% in intestinal mucosa (p < 0.01) and by 43% in parathyroid glands (p < 0.01). In long-term Nx, mean 1,25(OH)2D3 binding capacity was reduced by 20% in intestinal mucosa (p < 0.05) and by 22% in parathyroid glands (p < 0.01). After prolonged exposure to 1,25(OH)2D3 for 6 weeks, intestinal 1,25(OH)2D3 binding capacity was markedly down-regulated in uremic rats (43% versus vehicle-treated animals p < 0.05). Taken together, our results provide evidence for abnormal expression and regulation of VDR in experimental uremia. This may be relevant for responsiveness to 1,25(OH)2D3 in renal insufficiency.
Changes in plasma phosphate levels influence insulin sensitivity under euglycemic conditions.
The euglycemic clamp technique is a useful tool to evaluate insulin-mediated glucose uptake. The plasma phosphate concentration decreases during euglycemic clamp studies. Because insulin-dependent glucose uptake is closely related to phosphate uptake, we investigated whether modulation of plasma phosphate levels in the range observed during clamp studies influences insulin sensitivity. We studied 11 healthy (phosphate-replete) male volunteers (mean age, 27.5 +/- 1.8 yr;, mean body mass index, 23.9 +/- 1.6 kg/m2) in a double blind placebo-controlled cross-over study. The volunteers received in random order on two occasions either an infusion of sodium chloride (sham infusion) or an infusion of sodium phosphate. Insulin sensitivity was assessed under euglycemic conditions (clamp technique). The mean plasma phosphate concentration decreased with sham infusion from 1.09 +/- 0.17 to 0.64 +/- 0.13 mmol/L, whereas it increased with phosphate infusion from 1.06 +/- 0.19 to 1.32 +/- 0.13 mmol/L. In all volunteers except one the glucose disposal rate (M-value) was higher after phosphate infusion (mean M-value, 10.4 +/- 1.5 mg/kg.min) than that after sham infusion (mean M-value, 9.4 +/- 1.5 mg/kg.min; P < 0.01, by Wilcoxon's test for paired samples). There were no significant differences in mean plasma glucose, sodium, insulin, or arterialized standard bicarbonate levels with the two infusion protocols. Mean plasma calcium, albumin-corrected calcium, and potassium levels, however, were all significantly (P < 0.05) lower after phosphate infusion than after sham infusion. The mean PTH level decreased with sham infusion from 28 +/- 9 to 20 +/- 6 ng/L, whereas it increased with phosphate infusion from 26 +/- 9 to 36 +/- 8 ng/L, whereas it increased with phosphate infusion from 26 +/- 9 to 36 +/- 8 ng/L. The difference between the two infusion protocols was statistically significant (P < 0.01). The data presented illustrate that plasma phosphate (and calcium) levels may be confounders that should be at least monitored, and possibly controlled for, when performing euglycemic clamp studies.