Bone loss after renal transplantation: role of hyperparathyroidism, acidosis, cyclosporine and systemic disease.

UNLABELLED: In order to determine risk factors for bone loss after renal transplantation, dual energy X-ray absorptiometry was performed in 125 renal transplant patients. The bone mineral density (BMD) was expressed as a percentage of the normal population (BMD%) and Z-score (SD from normal). The whole body, lumbar spine and femoral neck BMD% (Z-score) values were 93.9 +/- 8.9 (-0.90 SD), 91.6 +/- 14.9 (-0.98 SD) and 87 +/- 15.3 (-1.0 SD)%, respectively. Low BMD% was associated with low creatinine clearance ( < 40 mL/min: 91.6 +/- 7.9, > 40 mL/min: 95.6 +/- 8.0, p < 0.01), repeated graft loss (0: 94.4 +/- 9.1, > 1: 87.4 +/- 9.3, p < 0.05), long dialysis duration ( < 1 yr: 95.2 +/- 7.9, > 5: 90.1 +/- 10.6, p < 0.05), acidosis (bicarbonate < 21 mmol/L: 89.6 +/- 8.0, > 27: 96.7 +/- 7.2, p < 0.01), secondary and tertiary hyperparathyroidism ( < 50 ng/L: 95.9 +/- 7.1, > 200: 87.7 +/- 5.0, p < 0.01), raised alkaline phosphatase ( < 200 units/L: 95.7 +/- 7.2, > 300: 85.6 +/- 13.2, p < 0.001), osteocalcin ( < 50 microg/L: 95.2 +/- 6.7, > 100: 89.3 +/- 7.6, p < 0.01) and urinary deoxypyridinoline (< 5 nM/mM creatinine: femoral neck 89.6 +/- 10.7, > 10: 82.1 +/- 20.1, p < 0.05), low 25-OH-vitamin D ( < 10 microg/L: 91.3 +/- 9.8, > 20: 96.9 +/- 7.4, p < 0.001) and high cyclosporine concentration (0 ng/L: 98.3 +/- 7.0, > 150: 92.1 +/- 9.3, p < 0.05). Patients with clinical atherosclerosis (91.7 +/- 8.6 vs. 95.4 +/- 8.8, p < 0.01), hypoalbuminemia ( < 550 micromol/L: 87.6 +/- 13.2, > 550: 94.2 +/- 7.8, p < 0.01), renovascular disease (89.7 +/- 5.7 vs. 95.0 +/- 5.7, p < 0.05) and diabetic nephropathy (femoral neck 76.6 +/- 8.8 vs. 89.3 +/- 15.1, p < 0.01) had lower bone masses. High bone mass was associated with previous dialysis alphacalcidol therapy (0: 92.2 +/- 7.5, > 3 microg/wk: 97.3 +/- 6.9, p < 0.05). No relationships with transplantation duration, 1,25-OH-vitamin D, aluminium, calcium or steroid dose were found. No involutional changes in tertiary hyperparathyroidism could be discerned. CONCLUSION: The major threats to bone mass after renal transplantation appear to be ongoing hyperparathyroid bone disease, low renal function, acidosis, systemic disease and hypo-vitaminosis D.

Behçet's syndrome presenting with peripheral arterial aneurysms.

A case of Behçet's syndrome is described presenting with several peripheral arterial aneurysms. The diagnostic criteria are discussed and the need for increased vigilance of this disease is stressed due to an increasing number of immigrants.

Efficacy of recombinant human erythropoietin administered subcutaneously to CAPD patients once weekly.

OBJECTIVE: The purpose of the present study was to compare the dosage requirements of recombinant human erythropoletin (rHuEPO) administered subcutaneously (SC) either one or three times weekly. DESIGN: A randomized, prospective study. SETTING: The patients were recruited from two university hospitals and five county hospitals. PATIENTS: Thirty-three anemic patients on continuous ambulatory peritoneal dialysis (CAPD) treatment for end-stage renal failure completed the study. INTERVENTIONS: Initially, all were treated with rHuEPO SC three times a week until hemoglobin blood levels (Hb) remained constant between 105 and 121 g/L for three months. Following randomization, 17 patients continued the same treatment schedule (group A), while 16 patients received the same dose, but administered only once weekly for three months (group B). MAIN OUTCOME MEASURES: The Hb levels and rHuEPO doses at the start and at the end of the three-month study period. RESULTS: In group A the median Hb at randomization was 118 g/L (109-119) (25-75 percentiles) and, after three months, was 113 g/L (106-119) (p = 0.13), while in group B the median Hb was 114 g/L (108-119) and 114 g/L (106-120), respectively (p = 0.50). In group A the weekly dose of rHuEPO remained virtually unchanged during the study period, 65 (55-86) and 66.3 (55-95) U/kg/week, respectively, while in group B it was increased from 60.2 (46-88) to 77 (60-90) U/kg/week. The 22% increase (p = 0.03) took place during the last two weeks. CONCLUSIONS: Our findings indicate that a once-weekly SC dosing regimen of rHuEPO in anemic CAPD patients was equally effective in maintaining a stable hemoglobin level as a thrice-weekly dosing regimen.

Intermittent intravenous followed by intermittent oral 1 alpha(OH)D3 treatment of secondary hyperparathyroidism in uraemia.

OBJECTIVES: To examine whether intermittent oral 1 alpha(OH)D3 treatment of patients on haemodialysis with secondary hyperparathyroidism (HPT) was able to maintain the marked suppression of PTH, which previously had been induced by an intermittent intravenous administration of 1 alpha(OH)D3. Simultaneously, the effect of the different routes of administration of 1 alpha(OH)D3 on the circulating levels of N- and C-terminal PTH fragments was measured. DESIGN: An open study of patients on chronic haemodialysis. SETTING: Renal division, Rigshospitalet, Copenhagen, Denmark. SUBJECTS: A total of 26 patients started and five patients completed the total protocol. INTERVENTIONS: The treatment protocol was divided into three parts: (i) 1 alpha(OH)D3 administered intravenously for > 300 days; then (ii) 1 alpha(OH)D3 administered orally for 100 days, followed by (iii) 1 alpha(OH)D3 administered intravenously again for another 100 days. 1 alpha(OH)D3 was given three times a week at the end of each dialysis. MAIN OUTCOME MEASURES: Intact PTH, N- and C-terminal PTH. RESULTS: Intact PTH levels were significantly (P < 0.0001) suppressed by 90.4 +/- 3.3% after 56 days of intermittent intravenous 1 alpha(OH)D3 treatment. This degree of suppression remained stable during the following period of oral treatment and did not change further when intravenous treatment was reinstituted. The circulating levels of intact PTH and N- and C-terminal iPTH were not influenced by the administered route of 1 alpha(OH)D3. CONCLUSIONS: Intravenous 1 alpha(OH)D3 treatment of the secondary HPT in dialysis patients can safely be changed to oral treatment at the time when optimal suppression of PTH has been achieved.

Serum ionized calcium, parathyroid hormone and phosphate in uremic patients during and between hemodialysis.

The serum concentrations of actual ionized calcium (at actual pH), adjusted ionized calcium (at pH 7.4), pH, intact parathyroid hormone (PTH) and phosphate were studied in ten patients during and between two hemodialysis sessions using a dialysate containing 1.66 mmol/l of calcium. Actual ionized calcium and adjusted ionized calcium increased during hemodialysis from 1.19 to 1.38 and 1.43 mmol/l, respectively (mean values) and returned to predialysis values within five and nine hours postdialysis. Serum PTH decreased from 165 ng/l to 55 ng/l (median values) during hemodialysis but two-hour postdialysis the level did not differ significantly from the predialysis level. Serum phosphate decreased from 2.05 mmol/l to 1.11 mmol/l during hemodialysis, and increased slowly towards the predialysis level. The level of pH increased from 7.40 to 7.47 during hemodialysis and reached predialysis level after nine hours. In a multivariate analysis including actual and adjusted ionized calcium, pH, phosphate and PTH, only actual or adjusted ionized calcium was associated with the level of PTH. We conclude that the effect of dialysate calcium on the levels of ionized calcium and PTH is of very short duration postdialysis.

Long-term suppression of secondary hyperparathyroidism by intravenous 1 alpha-hydroxyvitamin D3 in patients on chronic hemodialysis.

The effect of intravenous 1 alpha-hydroxyvitamin D3 [1 alpha(OH)D3] on circulating levels of intact parathyroid hormone (PTH 1-84) and COOH-terminal immunoreactive PTH(PTH 53-84) was examined in 13 patients on chronic hemodialysis. Thirteen patients were treated for 300 days (10 months), 9 patients for 520 days (14 months) and 6 patients for 720 days (2 years) with increasing doses of 1 alpha(OH)D3 intravenously under careful control of plasma Ca2+. Blood samples were obtained 1 week before start of treatment and then at every 2nd week. None of the patients had previously been treated with oral vitamin D metabolites. Intact PTH levels were maximally suppressed after 27-33 weeks of treatment by approximately 73%. At the end of the study periods, PTH 1-84 was still suppressed by 78 +/- 4.3% after 300 days, 78 +/- 8.8% after 520 days and 85 +/- 6.5% after 720 days. Plasma Ca2+ was kept within normal levels, but showed an initial increase from 1.14 +/- 0.03 to 1.27 +/- 0.15 mmol/l, and an adjustment of the doses of 1 alpha(OH)D3 was necessary. The present investigation demonstrated (1) that intravenous administration of the 1-hydroxylated vitamin D metabolite 1 alpha(OH)D3 induced a significant decrease in circulating levels of biologically active intact PTH, and (2) that it was possible to maintain the marked suppression of PTH secretion by intravenous treatment of 1 alpha (OH)D3 for up to 2 years. Hypercalcemia could be avoided by careful monitoring of plasma Ca2+ and adjustment of the doses of 1 alpha(OH)D3.

Effect of intravenous 1-alpha-hydroxyvitamin D3 on secondary hyperparathyroidism in chronic uremic patients on maintenance hemodialysis.

The effect of intravenous 1 alpha(OH)D3 on circulating intact parathyroid hormone (PTH) and COOH-terminal immunoreactive PTH was examined in 21 patients on chronic hemodialysis. The patients were treated for 3 months with increasing doses of 1 alpha(OH)D3 under careful control of serum Ca2+. 1 alpha(OH)D3 was given intravenously at doses of up to 4 micrograms three times a week, and blood samples were obtained every week, including 1 week before treatment (basal control). No patients were treated with oral vitamin D metabolites. At the end of the study intact PTH levels were reduced by an average of 67 +/- 6%, and COOH-terminal immunoreactive PTH levels were reduced by 35 +/- 6%. Serum Ca2+ was kept within normal levels, but showed a slight increase from 1.17 to 1.30 mmol/l. An effect of calcium on PTH secretion could not be excluded, but an effect of 1 alpha(OH)D3, independent of serum Ca2+ was also found. This effect may be mediated by 1,25(OH)2D3, assuming a large capacity of the 25-hydroxylase in the liver to convert 1 alpha(OH)D3 to 1,25(OH)2D3. Also, the parathyroid glands may possess receptors for 1 alpha(OH)D3 with an effect similar to that established for the 1,25(OH)2D3 receptors. Thus, although the exact mechanisms of the action of 1 alpha(OH)D3 have not yet been completely clarified, it is concluded that intravenous administration of 1 alpha(OH)D3 may be of benefit in the treatment of secondary hyperparathyroidism of uremia.

Alphacalcidol and renal function in normal subjects.

Sixteen young healthy adults were treated for 3 weeks with alphacalcidol (1 alpha OHD3), 1 microgram orally per day, and renal function tests were performed before, at the end and 3 weeks after termination of the drug. No significant changes occurred in the serum concentrations of calcium or phosphate, whereas the serum calcium-phosphorus product and the urinary excretion of calcium increased significantly. Serum creatinine and the urinary excretion of creatinine showed no significant changes. Inulin clearance decreased by 4% (p = 0.11). The total plasma clearance rate of 51Cr-EDTA and the 24-hour endogenous creatinine clearance both decreased by 4% during the treatment (p less than 0.05). It is concluded that treatment of normal subjects with 1 alpha OHD3, in a modest dose causing no significant change in serum calcium, is associated with a small but reversible decrease in renal function.

Arterial disease in chronic renal failure--an experimental study in the rabbit.

Epidemiological studies have indicated an increased incidence of cardiovascular events among patients with chronic renal failure. An acceleration of the atherosclerotic disease process in uremia has been proposed and a few studies have even suggested the existence of a specific pathological entity, uremic arterial disease, characterized by medial degeneration and calcification rather than by accumulation of cholesterol. As an experimental model of arterial disease in uremia, rabbits with chronic renal failure (CRF rabbits) induced by renal cauterization and contralateral nephrectomy were studied. Serum levels of creatinine were increased 2-3 times and the glomerular filtration rate reduced to 1/3-1/4 of the normal value. The CRF rabbits had lower body weights, hematocrit values and serum albumin concentrations than corresponding control animals. The arterial blood pressure was normal in all rabbits studied. The serum calcium concentration was significantly increased as was the serum phosphate. The gastrointestinal absorption of calcium of the CRF rabbits was decreased in contrast to an increased absorption of phosphate. The possible regulatory mechanisms responsible for the peculiar aspects of the mineral metabolism in normal and CRF rabbits are discussed but have not been clarified in detail. As regards the serum lipids, increased triglyceride levels were the most constant finding whereas serum cholesterol was only increased in rabbits with rather severe renal insufficiency. The earliest morphological changes were observed in the media of the aorta following seven weeks of CRF. Increased amounts of alcianophilic intercellular substance and a wavy pattern of the elastic membranes were seen. After three months of CRF, medial focal proliferations of smooth muscle cells accompanied by degenerative changes and calcifications were seen, frequently associated with increased thickness of the overlying intima due to accumulation of smooth muscle cells. After eight months of CRF the aorta was often transformed into a stiff, calcified tube and similar changes were observed in all major systemic arteries, including the coronary arteries. No evidence of lipid accumulation was found. Chemical analysis confirmed that accumulation of calcium, phosphate and magnesium was a prominent feature of the arterial changes, whereas the aortic content of cholesterol was not increased. Restriction of dietary calcium and phosphate decreased the mineral accumulation as well as the severity of the morphological changes. Increased amounts of calcium and phosphate in the diet increased the mineral accumulation of the aorta.(ABSTRACT TRUNCATED AT 400 WORDS)

An abnormal response of the adrenal cortex to insulin: glucose in essential hypertension.

This investigation demonstrates an abnormal response to the adrenal cortex to modulation of the potassium metabolism by an intravenous infusion of insulin-glucose in patients with essential hypertension. In response to insulin-glucose there was a transient decline of plasma aldosterone and plasma cortisol concentrations in control subjects with normal blood pressure, whereas a temporary increase of both hormones was found in patients with essential hypertension. Treatment with thiazide diuretics further magnified the different aldosterone response between the two groups. It is suggested that the abnormal response of patients with essential hypertension may be of significance to the understanding of the pathogenesis of this important disease.

Functional status of the liver during chronic renal failure: an experimental study in the rabbit.

Quantitative and qualitative measures of liver function were investigated in rabbits with chronic renal failure (CRF) induced 3 months earlier by surgical reduction of renal mass, and compared with a sham-operated control group. In the CRF group the galactose elimination capacity (GEC) was significantly decreased by 25%, but when related to liver weight the difference was not statistically significant. The clearance of antipyrine was unaffected. The serum activities of alanine aminotransferase, lactate dehydrogenase and alkaline phosphatase were similar in the two groups. The prothrombin index was increased by 20%, and the serum albumin concentration decreased by 9%. By light microscopy no significant morphological changes were found in the livers of the CRF rabbits. The results do not indicate significant changes of the hepatic functional status during moderate chronic renal insufficiency.

Uremic arterial disease in rabbits with special reference to the coronary arteries.

In rabbits with chronic renal failure of 9 months' duration, the distribution and morphological characteristics of uremic arterial disease were investigated, with special reference to the coronary arteries. All major systemic arteries were affected, large vessels more severely than smaller ones, and within each artery the changes were most pronounced in the proximal part of the vessel. The intimal lesions consisted primarily of smooth muscle cells without calcification or lipid accumulation. A reduction of the lumen exceeding 50% of the normal cross sectional area was not seen and mural thrombosis was not encountered. In the media, degenerative changes with increased amounts of proteoglycans and calcifications were prominent, but foci of increased cellularity were also seen. There was no evidence of lipid accumulation in the media either. Similar changes were found in the coronary arteries, but coronary angiography revealed no irregularities or stenosis. The calcified medial degenerative changes and intimal cellular lesions without lipid accumulation in non-cholesterol-fed rabbits distinguish uremic arterial disease from atherosclerosis.

Aldosterone response to modulation of potassium in patients on dialysis or with essential hypertension.

This investigation demonstrates in patients with essential hypertension an abnormal response of the adrenal glands to modulation of potassium metabolism by infusion of insulin-glucose. Similar results have been reported in anephric patients, while the inverse response of non-nephrectomised patients on dialysis corresponded to that of normal subjects. It is suggested that the abnormal response of patients with essential hypertension may be of importance to the understanding of the pathogenesis of this important disease.

Liver function during chronic renal failure in rabbits.

In rabbits with chronic renal insufficiency the prothrombin index was increased by 25% and the alanine aminotransferase activity decreased by 20%; the results of other routine tests of hepatic function were not affected. The galactose elimination capacity was decreased by 12%, whereas the body clearance of antipyrine was unchanged. No change in hepatocytic structure was found.

Inhibition by methylprednisolone treatment of the aortic mineral accumulation in rabbits with chronic renal failure.

The effect of methylprednisolone treatment on the mineral accumulation in the rabbit aorta during chronic renal failure (CRF) was investigated. Groups of rabbits with surgically induced CRF and sham operated controls were treated for 14 weeks with 0.40 mg of methylprednisolone per day and compared to corresponding groups receiving placebo. After sacrifice the thoracic aorta was excised and divided into an inner intima-media and an outer media layer before determination of the content of cholesterol and minerals. The surface area and wet weight of both layers were significantly increased in the CRF groups but methylprednisolone treatment had no effect on these parameters. Neither CRF nor methylprednisolone caused significant changes of the cholesterol content of the intima-media. Methylprednisolone treated CRF rabbits had a significantly decreased mineral content of the intima-media layer compared to CRF rabbits receiving placebo although the treatment caused no significant changes in the serum concentrations of calcium and phosphate. In rabbits with normal renal function a similar effect could not be demonstrated.

Effect of chronic renal failure and methylprednisolone treatment on the uptake of labelled plasma cholesterol into the aorta of normocholesterolemic rabbits.

The effects of chronic renal failure (CRF) and corticosteroid treatment on the aortic uptake of labelled free and esterified cholesterol (FC and EC) were investigated in normocholesterolemic rabbits. Methylprednisolone, 0.4 mg/day, or placebo was administered for 14 weeks to rabbits with normal renal function and with CRF. Then [3H]- and [14C]cholesterol were administered intravenously and orally, respectively. The radioactivity levels of FC and EC in plasma were measured at regular intervals. After 48 h the accumulation of 3H and 14C radioactivity of FC and EC in the intima-media of the thoracic aorta was determined. An aortic uptake coefficient was calculated by dividing the tissue radioactivity (dpm/cm2/h) by the mean plasma radioactivity (dpm/ml). The mean uptake coefficient of EC in normal rabbits was 6 nl/cm2/h, the value for FC being 180 nl/cm2/h. In normal rabbits treated with methylprednisolone the uptake coefficients of both FC and EC were significantly decreased to about 50% of the values in normal rabbits receiving placebo. A similar significant decrease in the uptake coefficients was found in the CRF rabbits receiving placebo. No further decrease was observed in the CRF rabbits treated with methylprednisolone. The cholesterol content of the aortic intima-media was significantly decreased only in CRF rabbits on methylprednisolone treatment. The results do not indicate an acceleration of uremic arterial disease by steroid treatment in the rabbit.