Showing papers by "Tilman B. Drüeke published in 1994"

Hyperhomocysteinaemia : a significant risk factor for cardiovascular disease in renal transplant recipients

Abstract: Moderate hyperhomocysteinaemia has been shown to constitute an independent risk factor for cardiovascular disease (CVD), a frequent cause of morbidity and mortality in renal transplant recipients (RTR). In these patients few data regarding both total homocysteine levels and their influence on cardiovascular risk have been reported. We therefore studied serum homocysteine levels in deep-frozen sera from 42 kidney transplant recipients with a follow-up of 11 +/- 4.5 years (mean +/- SD) after transplantation. Eighteen patients had one or more ischaemic events (CVD (+)) and 24 patients had none (CVD (-)). Serum samples had been drawn 1-6 months prior to the first vascular event in CVD (+) patients and serum storage time was comparable in both CVD (-) and CVD (+) patients. Serum homocysteine levels were measured using a radioenzymatic method. Mean homocysteine level was significantly higher in 42 RTR males and females (15.5 +/- 6.3, 13.5 +/- 5.5 microM respectively) compared with 35 control subjects matched for age and sex (8.7 +/- 1.9, 7.5 +/- 1.9 microM, P 14 microM (the upper limit in healthy controls) versus 7/24 in the CVD (-) group (P = 0.04). In these patients we simultaneously measured in the same serum samples, serum triglycerides, and total and HDL cholesterol, and calculated LDL cholesterol. By stepwise discriminant analysis and by logistic regression analysis in this relatively small patient population, only serum triglycerides and homocysteine were selected as risk factors associated with CVD. We conclude that significant hyperhomocysteinaemia is present in renal transplant recipients and represents a potential risk factor for cardiovascular disease in these patients.

The dilemma of parathyroidectomy in chronic renal failure.

Abstract: Our understanding of the pathogenesis of the secondary hyperparathyroidism of uremia is steadily evolving. New findings have been made and new interpretations provided as to the interaction between calcium, phosphorus, and calcitriol with the parathyroid gland cell, including the discovery of a calcium-sensing receptor in the parathyroid gland, the description of heterogenous distribution of the vitamin D receptor across the parathyroid gland, and the observation of a high prevalence of monoclonal, tumorlike growth of parathyroid tissue. These findings must be integrated into our current way of thinking with respect to the mechanisms involved in parathyroid hyperplasia, and to the potential practical consequences in terms of treatment and prevention. The development of new nonhypercalcemic vitamin D derivatives and specific calcium receptor agonists may help to elaborate more efficient treatment schedules. On the other hand, the occurrence of monoclonal parathyroid growth probably explains, at least in part, the frequently observed resistance to medical treatment. In such patients with severe secondary hyperparathyroidism, surgical parathyroidectomy often remains the only therapeutic alternative.

Reduced inhibitory activity of uronic-acid-rich protein in urine of stone formers.

Abstract: We recently reported that human urine contains a newly identified urinary glycoprotein acting as a potent inhibitor against calcium oxalate crystallization. This inhibitor is a uronic-acid-rich protein (UAP) with a molecular weight of approximately 35 kDa. In the present study, UAP was isolated from urine of stone formers and of subjects without a stone history, and its inhibitory activity was tested in a calcium oxalate crystallization system in vitro. Our results show a weaker inhibitory activity of UAP extracted from the urine of stone formers than that extracted from the urine of healthy subjects. Preliminary analyses of amino acid and carbohydrate content showed some differences between the two groups. The main difference was the reduction in sialic acid in UAP isolated from the urine of stone formers. We suggest that UAP contributes significantly to total urinary inhibitory activity of calcium oxalate crystallization and that the decrease in this activity in the urine of recurrent stone formers is due, in part, to the weak inhibitory activity of UAP. A structural abnormality of UAP could explain the diminution of its inhibitory activity in the urine of stone formers.

Aluminium-related osteodystrophy and desferrioxamine treatment: role of phosphorus

Abstract: We investigated (1) the prevalence of aluminium overload among 96 patients with symptomatic bone disease haemodialysed from 1987 to 1989 in the Sao Paulo area, Brazil; (2) the effect of 6 months desferrioxamine (DFO) treatment (1-2g/week). All patients underwent a first bone biopsy. Aluminium overload (extent of stainable bone aluminium more than 20% trabecular surface) was observed in 74 of 96 patients. Forty overloaded patients were divided into patients with high bone formation rate (BFR) (group 1; n = 17) and patients with low BFR (group 2; n = 23), and had a second biopsy after DFO therapy. In both groups aluminium surface was reduced after treatment (P < 0.001), osteoblast surface (P < 0.02-P < 0.01) and plasma parathyroid hormone (iPTH) (P < 0.01) increased. In group 1 BFR remained high. In group 2 BFR remained low in 16 patients (2a) and increased in seven (P < 0.02) (2b). In group 2a plasma phosphorus was below that in group 2b patients, before (P < 0.03) and after (P < 0.01) DFO. The histological features of group 2a patients resembled hypophosphataemic osteomalacia, those of group 2b patients aluminium osteodystrophy. These data show a high prevalence of aluminium overload in Brazilian patients. Low-dose DFO therapy was safe, decreased bone pain, prevented fractures, and reduced stainable bone aluminium. Bone lesions only partially improved, suggesting that low phosphorus intake and/or plasma calcitriol concentrations may have prevented improvement of bone formation and mineralization.

Duodenal calcium binding protein and active calcium transport in rats: are they functionally related?

Abstract: The effects of calcitriol and a novel calcitriol analogue, 22-oxacalcitriol (OCT) on duodenal Ca transport, calbindin-D9k mRNA, and calbindin-D9k content were studied in two animal models reflecting common human pathologies, namely arterial hypertension and chronic renal failure, as well as in normal rats. The hormone or its analogue were administered intraperitoneally to vitamin-D-replete rats. Active Ca transport was increased in both spontaneously hypertensive rats (SHR) and in normotensive control WKY rats 5 h after calcitriol dosing of either 60 and 600 ng per rat. In WKY, calbindin-D9k content was slightly increased after the injection of 60 ng calcitriol, but not of 600 ng calcitriol whereas calbindin-D9k mRNA stayed essentially unchanged. In contrast, active Ca transport was significantly stimulated after the higher dose of 600 ng calcitriol. In SHR, while both doses of calcitriol increased active Ca transport, they had no stimulatory effect on calbindin-D9k mRNA or protein. In chronically uraemic rats, active Ca transport, duodenal calbindin-D9k and calbindin-D9k mRNA were stimulated after the injection of two subsequent doses of 300 ng calcitriol per rat. OCT treatment at same dosage led to a similar stimulation of calbindin-D9k and calbindin-D9k mRNA, but failed to induce an increase in active Ca transport. These results show that the stimulation of intestinal active Ca transport and calbindin-D9k can be entirely dissociated at the protein synthesis and the mRNA expression level (1) after calcitriol administration to normal and hypertensive rats, and (2) after OCT administration to uraemic rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of various calcium intakes on calcium-oxalate crystalluria in rats on sodium-oxalate diet.

Abstract: Forty adult male Wistar rats were placed in metabolic cages on a Ca-deficient diet (0.1%) for 7 days and then on a Ca-deficient, Na-oxalate (NaOx) enriched diet (20 mg/100 g) for another 14 days. The animals were subdivided into three groups receiving three different types of mineral water: group I (n = 13), Badoit (Ca 222 mg/l); group II (n = 14), Contrexeville (Ca 467 mg/l); and group III (n = 13), Evian (Ca 78 mg/l). Another series of 25 rats (group I, n = 9; group II, n = 8; group III, n = 8) underwent the same study protocol, except that they received a normal Ca diet (1%). On the low-Ca diet, urinary Ca-Ox monohydrate (COM) crystals were observed only under the Na-Ox diet, with a mean crystal number significantly greater in group III (16.7 +/- 4.5 crystals/mm3) than in group I or II rats (2.5 +/- 1.5 or 4.1 +/- 1.5 crystals/mm3, respectively). Urinary Ca concentrations decreased in all groups (P < 0.001) under the Na-Ox diet, while urinary oxalate concentrations increased in all groups (P < 0.001). On the normal Ca diet, COM crystal excretion was observed only with the Na-Ox-enriched diet, but in this case feeding the Na-Ox diet did not modify urinary oxalate excretion. Ca/Ox ratio was significantly lower under 0.1% Ca diet than under normal Ca diet, related with the type and the number of crystals observed, demonstrating that assessment of crystalluria can provide an index of disease severity. Moreover, the hardness of the drinking water influences urinary COM crystal excretion only under a low-Ca, oxalate-rich diet, suggesting that the total calcium intake rather than the water calcium content is an important factor in the occurrence of Ca-Ox nephrolithiasis.

Down-regulation of the PTH/PTHrP receptor in uremia

Abstract: Resistance to the action of PTH has been well characterized in the setting of chronic renal failure. Most evidence points to post-receptor abnormalities in its pathogenesis. The recent cloning of the PTH/PTHrP receptor (PTH-R) has permitted us to examine whether in a 5/6 nephrectomy rat model (CRF) the expression of the PTH-R gene is modified. First, we have found that the renal PTH-R mRNA expression is markedly decreased in CRF compared to normal rats. Diminished PTH-R transcripts were associated with a lower PTH-induced cAMP production in renal membranes in CRF suggesting a decrease in the PTH-R number or post-receptor modifications. Second, thyroparathyroidectomized (TPTX) rats with normal renal function had no change in the renal PTH-R expression whereas TPTX-CRF rats still showed a decreased renal PTH-R mRNA expression suggesting that high plasma PTH levels were not etiologically important in the observed down-regulation. Despite the renal PTH-R down-regulation, CRF rats had a normal renal handling of calcium. They also had a higher phosphate excretion than control rats. TPTX-CRF rats showed a decrease in renal tubular calcium reabsorption and a phosphate retention when compared with CRF animals with intact parathyroid glands. This suggests that a few available PTH-R in the kidney allow PTH to exert, to a certain extent, its physiological role in this experimental model of uremia. In conclusion, these findings indicate a down-regulation of the renal PTH-R expression in CRF which appears to be independent of parathyroid gland function. The relevance of this phenomenon in the setting of the secondary hyperparathyroidism of uremia remains to be elucidated.

Stimulation of ileal calcium absorption by sorbitol, L-xylose, or creatine via a decrease in luminal sodium concentration: relation with concomitant changes in enterocyte energy metabolism.

Abstract: Ligated ileal loops, 30 cm in length, of 4-month-old male Wistar rats were instilled with 3 ml of a 10 mM CaCl2 solution (added with 0.25 muCi 45Ca) in the absence (control) or presence of 100mM sorbitol, L-xylose, or creatine. Ileal calcium (Ca) transport, measured by plasma 45Ca appearance, was found to be similar 30 minutes after fluid instillation in all four instances. However, thereafter, 45Ca appearance in plasma did not increase further in control animals whereas it increased twice as much during the subsequent 30 minutes in the presence of sorbitol, L-xylose, or creatine. However, when loops of similar length were instilled with only 1.0 ml of such solutions, the sorbitol effect was already observed during the first 30 minutes. The stimulation of ileal Ca absorption induced by the presence of sorbitol appeared to be due to a cellular effect, associated with a decreased flux across the paracellular pathway, as indicated by 3H-mannitol absorption. The presence of sorbitol in instilled ileal solution induced a significant decrease in luminal Na, K, bicarbonate, and Cl concentrations at each time point studied (30, 60, 120, or 240 minutes after instillation). Thirty minutes after instillation, no difference in soluble Ca concentration was observed between control and experimental rats. After 60 minutes, Ca concentration was dramatically decreased in control rats but it remained nearly constant in experimental animals. Thus, the presence of substances enhancing ileal Ca transport favored the maintenance of soluble Ca in ileal solution during longer time periods than their absence. In the ileal enterocyte, these substances induced a twofold increase of ATP content compared with controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Does Intravenous Erythropoietin Lead to an Immediate, Transient Increase in Arterial Blood Pressure in Dialysis Patients?

Abstract: 120 no H o 90 so 6 80 S 70 60 50 12 3 4 5 min PLACEBO Dear Sir, The development of hypertension in 20-30% of hemodialysis patients receiving recombinant human erythropoietin (rHuEPO) remains an important side effect often requiring antihypertensive treatment [1-5]. The factors involved in the occurrence or aggravation of high blood pressure with rHuEPO are still matter of controversy. A first explanation is provided by the constant increase in total peripheral resistance secondary to both the rise in hematocrit (and hence blood viscosity) and to the correction of tissue hypoxia. However, our recent findings in rats show that rHuEPO-generated blood pressure elevation cannot be attributed solely to increases in blood viscosity and hemoglobin concentration [6]. It has also been suggested that the pressor effect of rHuEPO may be explained by action of the hormone on vascular smooth muscle, either directly [7] or via an activation of the tissue renin-angiotensin system [8]. Finally, rHuEPO could also induce hypertension by acting on the vascular endo-thelium [9-12]. Because, in a recent preliminary report, a direct blood pressure-raising effect of rHuEPO has been claimed [11], we decided to reexamine this question in 10 chronic hemodialysis patients in our dialysis facility (4 females, 6 males; mean age 47 years, range 20-81 years). The duration of their intermittent hemodialysis treatment was 28.2 months (range 3-120 months). Patients had the usual distribution of nephropathies, with 1 patient having non-insulin-dependent diabetes. Six of the ten patients received antihypertensive therapy (ACE inhibitors in 3 patients, calcium channel-blocking agents in 4, and ß-