The acute effect of 25-hydroxycholecalciferol on renal handling of phosphorus. Evidence for a parathyroid hormone-dependent mechanism.

The acute effect of i.v. and direct intrarenal arterial infusion of 25-hydroxycholecalciferol (25HCC) and 1,25-dihydroxycholecalciferol (1,25-DHCC) on renal handling of phosphorus was evaluated in the following groups of rats: (a) intact animals, (b) parathyroidectomized (PTX) hypocalcemic rats, (c) PTX rats in which normocalcemia was maintained with calcium supplements and (d) PTX animals in which urinary phosphorus was augmented by (i) i.v. sodium phosphate, (ii) expansion of the extracellular fluid volume with normal saline, and (iii) i.v. parathyroid hormone (PTH). Clearances of inulin (C(In)), phosphorus (C(P)), and fractional clearances of phosphorus (C(P)/C(In)) of the experimental groups were compared with those of the corresponding control groups, and the clearances of the infused kidneys with those of the contralateral kidneys. In intact animals, i.v. 25HCC decreased C(P)/C(In) from 0.29+/-0.04 (mean +/-SE) to 0.19+/-0.04, and i.v. 1,25-DHCC decreased C(P)/C(In) from 0.25+/-0.04 to 0.15+/-0.02. The intrarenal infusion of both 25HCC and 1,25DHCC into intact animals failed to produce a unilateral change; however, it decreased C(P)/C(In) bilaterally. i.v. and intrarenal infusions of 25HCC or 1,25DHCC in PTX hypocalcemic and normocalcemic rats, and i.v. infusions of 25HCC in PTX rats receiving either sodium phosphate or normal saline, all failed to produce significant changes in C(P)/C(In). In contrast, 24HCC given i.v. to PTX animals receiving exogenous PTH was associated with a significant fall in C(P)/C(In), from 0.34+/-0.08 to 0.13+/-0.02. These results indicate that 25HCC enhances tubular reabsorption of phosphorus in rats, only in the presence of either endogenous or exogenous circulating PTH, but not in its absence and thus imply a PTH-dependent mechanism of 25HCC action on the kidney. This effect does not appear to be related to the conversion of 25HCC into 1,25DHCC, since the latter fails to affect tubular reabsorption of phosphorus in PTX rats.

Regulation by vitamin D metabolites of parathyroid hormone gene transcription in vivo in the rat.

In vitro 1,25-dihydroxycholecalciferol (1,25(OH)2D3) decreased levels of preproparathyroid(preproPTH) hormone mRNA. We have now pursued these studies in vivo in the rat. Rats were administered vitamin D metabolites i.p. and the levels of preproPTH mRNA were determined in excised parathyroid-thyroid glands by blot hybridization. PreproPTH mRNA levels were less than 4% of basal at 48 h after 100 pmol 1,25(OH)2D3, with no increase in serum calcium. Gel blots showed that 1,25(OH)2D3 decreased preproPTH mRNA levels without any change in its size (833 basepair). Microdissected parathyroids after 1,25(OH)2D3 (100 pmol) showed mRNA levels for preproPTH were 40 +/- 8% of controls, but for beta-actin were 100% of controls. The relative potencies of vitamin D metabolites were: 1,25(OH)2D3 greater than 24,25(OH)2D3 greater than 25(OH)D3 greater than vitamin D3. In vitro nuclear transcription showed that 1,25(OH)2D3-treated (100 pmol) rats' PTH transcription was 10% of control, while beta-actin was 100%. These results show that 1,25(OH)2D3 regulates PTH gene transcription. PTH stimulates 1,25(OH)2D3 synthesis, which then inhibits PTH synthesis, thus completing an endocrinological feedback loop.

Renal handling of phosphorus in oliguric and nonoliguric mercury-induced acute renal failure in rats.

The renal handling of phosphorus was evaluated in rats with acute renal failure (ARF) induced by injection of mercuric chloride (HgCl(2)). Clearances of endogenous creatinine (Ccr) and of phosphorus (Cp) were measured in the following groups: 1. Intact animals (control); 2. Parathyroidectomized rats (PTX) with normal kidney function (PTX control); 3. Animals with mercury-induced acute renal failure (Hg-ARF); 4. PTX rats with Hg-ARF; 5. Rats with Hg-ARF maintained normophosphatemic with dietary phosphate restriction; 6. Animals with oliguric ARF following renal artery constriction; 7. Rats with unilateral Hg-ARF. In addition, radioinulin clearances were measured in 6 normal and in 14 azotemic animals and correlated with simultaneously recorded endogenous Ccr. Radioinulin clearance was also used as an estimate of GFR (glomerular filtration rate) in the animals of group 7. The Cp/GFR in the intact animals (group 1) was 0.25 +/-0.06 (mean +/-SD). PTX (group 2) caused a subsequent decrease in Cp/GFR to 0.11 +/-0.04 P < 0.0005. The ARF animals in group 3 were classified either as oliguric (U(vol) [urine volume] <2 ml/24 hr, Ccr 0.008 +/-0.005 ml/min) or nonoliguric (V(vol) >2 ml/24 hr, Ccr 0.136 +/-0.12). The Cp/GFR in the oliguric animals (0.16 +/-0.09) was lower than that in group 1, P < 0.0005, and failed to increase following administration of exogenous parathyroid hormone. The Cp/GFR in the oliguric animals in groups 5 and 7 was also lower than the clearance ratio in group 1, 0.030 +/-0.08 and 0.077 +/-0.006, respectively. In the nonoliguric ARF animals of group 3 the Cp/GFR (0.94 +/-0.29) was higher than that in group 1, P < 0.0005. In the nonoliguric ARF animals of group 4 the Cp/GFR 0.27 +/-0.08 did not differ from the clearance ratio in group 1, however it was higher than that in the PTX animals (group 2) P < 0.0005. Cp/GFR in the nonoliguric animals of group 5 was not different from that in the nonoliguric rats of group 3. In the animals with nonoliguric unilateral Hg-ARF Cp/GFR on the affected side 0.51 +/-0.16 was higher than that on the control (contralateral) side, 0.23 +/-0.07, P < 0.0005. These results indicate that the low Cp/GFR observed in the oliguric ARF animals was not related to the level of circulating parathyroid hormone nor to the presence or absence of azotemia but probably was due to a reduced renal cortical perfusion. The high Cp/GFR in the nonoliguric ARF animals could be explained by secondary hyperparathyroidism and impaired phosphorus reabsorption due to tubular injury.

The acute effect of chlorothiazide on serum-ionized calcium. Evidence for a parathyroid hormone-dependent mechanism.

The acute effects of chlorothiazide (CTZ) on total (TSCA) and ionized (SCA-plus 2) serum calcium concentrations were studied in three groups of people: (a) eight subjects with normal parathyroid function; (b) six patients with hypoparathyroidism; and (c) two patients with hyperparathyroidism. Most subjects were studied on four occasions; at least 3 days intervened between studies on an individual subject. During each experiment the subject received an i.v. influsion of 5% dextrose in water at 1 ml/min from 8 a.m. to 4 p.m. Additions to the infusions were (a) none; (b) CTZ to deliver 3.33 mg/kg/h; (c) parathyroid extract to deliver 1 U/kg/h; or (d) both CTZ and parathyroid extract at the rates previously indicated. CTZ, when used, was added to the infusion at 10 a.m., parathyroid extract at 8 a.m. When CTZ was infused, the diuretic-induced losses of Na and water were replaced by i.v. infusion. In normal subjects 2 h after the start of CTZ infusion, there was a transient increase in SCA-plus 2 which coincided in time of day with a transient decrease in SCA-plus 2 in control experiments. At that time of day SCA-plus 2 was 4.18 plus or minus 0.12 mg/100 ml in control experiments and 4.56 plus or minus 0.08 in experiments with CTZ, P smaller than 0.025. The corresponding values for (TSCA) were 9.32 plus or minus 0.15 and 9.80 plus or minus 0.30, P smaller than 0.01. Such differences were not observed in the group with hypoparathyroidism. In the two patients with hyperparathyroidism, CTZ produced sustained increases in TSCA and SCA-plus 2. In normal subjects and those with hypoparathyroidism, CTZ plus parathyroid extract infusion resulted in sustained increases in both SCA-plus 2 and TSCA throughout the periods of observation when compared to experiments in which only parathyroid extract was infused, P smaller than 0.01 in all instances. The results suggest that the acute hypercalcemic action of CTZ requires the presence of circulating parathyroid hormone.

Octreotide prevents the early increase in renal insulin-like growth factor binding protein 1 in streptozotocin diabetic rats.

The early renal growth in streptozotocin (STZ)-induced diabetic rats is preceded by a transient rise in renal tissue insulin-like growth factor (IGF)-I concentration. Administration of the long-acting somatostatin analog octreotide to STZ diabetic rats inhibits the early increase in kidney IGF-I and the increase in kidney size without affecting metabolic control. We studied the effects of octreotide treatment on the intrarenal IGF axis at 2 and at 7 days after the induction of STZ diabetes. Two days after induction of diabetes, kidney IGF-I was increased from 850 +/- 43 ng/g tissue in controls to 1,648 +/- 165 ng/g tissue (P < 0.001) in diabetic animals. The diabetes-associated increase in renal IGF-I 48 h after STZ injection was totally prevented by octreotide (IGF = 780 +/- 57 ng/g tissue). However, 7 days after the induction of diabetes, kidney IGF-I was similar to that of control and was not affected by octreotide. No difference in serum IGF-I was observed between controls and diabetic rats after 2 days of diabetes; however, octreotide treatment resulted in a significant decrease of serum IGF-I after 2 days when compared with control rats (P < 0.05). Renal IGF-I mRNA was significantly decreased to the same extent in both diabetic groups 2 and 7 days after the induction of diabetes, while renal IGF-I receptor (IGF-IR) mRNA was unchanged in rats from either group. Two days after induction of diabetes, renal insulin-like growth factor binding protein (IGFBP)-1 mRNA and 30-kDa IGFBPs (containing IGFBP-1) increased by 186 and 192%, respectively, in untreated diabetic animals compared with controls. Octreotide treatment prevented the diabetes-associated rise in renal IGFBP-1 mRNA and protein. However, 7 days after the induction of diabetes, renal IGFBP-1 mRNA and protein were similarly increased in both octreotide-treated or untreated diabetic rats. Renal IGFBP-3 gene expression and protein and IGFPB-5 mRNA remained unchanged after 2 and 7 days of diabetes when treated or untreated with octreotide. We conclude that the well-known inhibitory effect of octreotide on the early increase in renal IGF-I concentration and renal size in diabetes may be mediated through a direct effect on renal IGFBP-1 levels.

The renal effect of low-dose dopamine in high-risk patients undergoing coronary angiography.

OBJECTIVES: The purpose of the study was to examine the potential renal protective effect of low-dose dopamine in high-risk patients undergoing coronary angiography. BACKGROUND: Contrast nephropathy is prevalent in patients with chronic renal failure (CRF) and/or diabetes mellitus (DM). Decreased renal blood flow due to vasoconstriction was suggested as a contributory mechanism. Low-dose dopamine has a dilatory effect on the renal vasculature. METHODS: Sixty-six patients with mild or moderate CRF and/or DM undergoing coronary angiography were prospectively double-blindedly randomized, to either 120 ml/day of 0.9% saline plus dopamine 2 microg/kg/min (Dopamine group) or saline alone (Control group) for 48 h. RESULTS: Thirty-three Dopamine-treated (30 diabetics and 6 with CRF) and 33 Control (28 diabetics and 5 with CRF) patients were compared. Plasma creatinine (Cr) level increased in the Control group from 100.6+/-5.2 before to 112.3+/-8.0 micromol/liter within five days after angiography (p = 0.003), and in the Dopamine group from 100.3+/-5.4 before to 117.5+/-8.8 micromol/liter after angiography (p = 0.0001), respectively. There was no significant difference in the change of Cr level (deltaCr) between the two groups. However, in a subgroup of patients with peripheral vascular disease (PVD), deltaCr was -2.4+/-2.3 in the Control group and 30.0+/-12.0 micromol/liter in the Dopamine group (p = 0.01). No significant difference occurred in deltaCr between Control and Dopamine in subgroups of patients with preangiographic CRF or DM. CONCLUSIONS: Contrast material caused a small but significant increase in Cr blood level in high-risk patients. There is no advantage of dopamine over adequate hydration in patients with mild to moderate renal failure or DM undergoing coronary angiography. Dopamine should be avoided in patients with PVD exposed to contrast medium.

New worldwide trends in presentation of renal osteodystrophy and its relationship to parathyroid hormone levels.

AIMS: Abnormal mineral metabolism in chronic renal disease is associated with bone disease and extraskeletal calcifications. High turnover, hyperparathyroid bone disease, the most common form of renal osteodystrophy, has been the target for aggressive therapy. More recently, an increasing occurrence of low turnover bone disease has been reported. The present study was undertaken to evaluate the current prevalence of different forms of bone disease in a large population on chronic hemodialysis and its relationship to parathyroid hormone (PTH) levels. METHODS: Ninety-six chronic hemodialysis patients underwent double tetracycline-labeled bone biopsy. Serum PTH levels were obtained in 52 patients at the time of biopsy. Bone formation rate (BFR/BS) was plotted vs. PTH levels in all patients and in subgroups with PTH ranges between 0-150, 150-500 and 500 - 1,200 pg/ml. RESULTS: The histomorphometric data showed that 40% of all patients were affected by osteitis fibrosa cystica (OFC). In the remaining 60%, various forms of low-turnover bone disease were observed. There was no correlation between PTH and BFR/BS in all patients (r = 0.28) and in subgroups whose PTH levels ranged between 150 - 500 and 500 - 1,200 pg/ml (r = 0.027, r = 0.21), respectively. A close correlation between PTH and BFR/BS (r = 0.84, p < 0.05) was found only in the subgroup with a PTH level ranging low-turnover bone disease. The predictive between 0 - 150 pg/ml. CONCLUSIONS: The histomorphometric findings present a wide spectrum of renal osteodystrophy with a shift towardsvalue of PTH is limited as high-turnover osteodystrophy may present with low PTH levels and that with low turnover may occur with high PTH levels. In the latter parathyroidectomy should be avoided. We share the view that bone biopsy remains the "gold standard" diagnostic tool for renal osteodystrophy.

Angiotensin-converting enzyme inhibitors and glycosuria.

Renal glycosuria associated with the use of angiotensin-converting enzyme inhibitors has been previously reported in two patients. A third patient was studied who developed isolated glycosuria associated with lisinopril therapy. As in the two previously described patients, this patient had a normal serum glucose level, underlying hypertension, and onset of glycosuria between 2 and 16 weeks after initiation of therapy with an angiotensin-converting enzyme inhibitor. The patient had renal artery stenosis with elevated renin levels. Age, time until resolution of glycosuria, and a rise in serum creatinine level did not have a consistent relationship with glycosuria associated with angiotensin-converting enzyme inhibitor therapy. Since glycosuria was the only defect noted, without evidence of any other urinary solutes, angiotensin-converting enzyme inhibitors may exert an effect on the glucose-specific proximal tubule transport system.

Hypercalcemia with elevated dihydroxycholecalciferol levels and hypercalciuria. A parathyroid concentration-independent mechanism.

A 22-year-old man with renal stones had persistent hypercalcemia with massive idiopathic hypercalciuria due to a primary renal tubular phosphorus leak. He did not have hyperparathyroidism or sarcoidosis but did have an elevated dihydroxycholecalciferol level, which contributed to his hypercalcemia.

Hypophosphatemia in a patient with lymphoma in leukemic phase.

A patient with histiocytic lymphoma had abdominal masses, hypophosphatemia, normocalcemia, and a normal serum parathyroid hormone value. After chemotherapy, transient hyperphosphatemia ensued, the abdominal masses resolved, and other manifestations of the disease were suppressed. One week after discontinuation of the chemotherapy, the abdominal masses and other signs indicative of reactivation of the malignant disease reappeared. During the relapse, the serum phosphorus level fell to 0.7 mg/dL, and urinary excretion of phosphorus became negligible. After resumption of chemotherapy, serum concentration and urinary excretion of phosphorus increased. These observation suggest that severe hypophosphatemia may be a complication of hematologic neoplasia. It is proposed that this abnormally may be caused by a shift of excessive amounts of extracellular phosphorus into the rapidly replicating malignant cells.

Dopamine-related polyuria in patients with gram-negative infection.

Two patients developed polyuria with natriuresis while receiving intravenous dopamine hydrochloride for the treatment of hypotension. Both patients had Gram-negative pneumonia and both had evidence of extracellular volume depletion that was considered to be a result of the dopamine-induced polyuria. Following restoration of extracellular volume and withdrawal of dopamine therapy, both patients became normotensive and required no vasopressors. The diuretic action of dopamine, which persisted despite the severe intravascular volume contraction and perpetuated the hypotensive state in these two patients, is not well understood. The Gram-negative infection could play an important role possibly by enhancing the effect of dopamine on the renal vasculature.

1,25-Dihydroxyvitamin D3-induced calcium efflux from calvaria is mediated by protein kinase C.

1,25-dihydroxyvitamin D3 (1,25(OH)2D3) is an important regulator of bone metabolism involved in both formation and resorption. Traditionally it was assumed that vitamin D receptors are intracellular. Recent data indicate that vitamin D may also act through a membrane receptor, specifically raising intracellular calcium and inositol 1,4,5 triphosphate. The present study was undertaken to explore further the mechanism(s) of vitamin D-induced bone resorption in cultured bone. 1,25(OH)2D3 induced a dose-dependent increase of calcium efflux from cultured bone. This increase was completely obliterated by inhibition of protein kinase C (PKC) with either staurosporine or calphostin C. In cultured rat calvariae, 1,25(OH)2D3 also induced a dose-dependent translocation of PKC from cytosol to membrane. The activation of PKC by 1, 25(OH)2D3 occurred following a 30-s incubation, peaked at 1 minute, and disappeared by 5 minutes. 1,25(OH)2D3 did not increase cAMP production in similarly cultured calvaria. These results suggest that the action of 1,25(OH)2D3 on calcium flux from cultured bone is mediated, in part, via activation of PKC.

Quantitative ultrasound of the tibia: a novel approach for assessment of bone status.

An ultrasound instrument has recently been developed for the diagnosis and monitoring of osteoporosis (SoundScan 2000, Myriad Ultrasound Systems Ltd., Israel). The instrument measures the speed of propagation of ultrasound waves (SOS, meters per second) along a fixed longitudinal distance of the cortical layer at the tibial shaft. Its in vivo precision is 0.25%. The performance of the SoundScan 2000 was studied in 307 Caucasian women (age range 24-87 years) who also had their bone mineral density (BMD) measured at the spine, femoral neck, and radial shaft by absorptiometric techniques. The SOS ranged from 3471-4226 m/sec (mean 3867). The standardized coefficient of variation (CV), an expression of the effective clinical precision corrected for the spread of measurements (CV/[range/mean]), was 1.6% for the tibial SOS, compared to 1.5%, 3.8%, and 4.4% for spinal, femoral, and radial BMD, respectively. Tibial SOS significantly correlated with age (r = -0.52), time since menopause (r = -0.43), height (r = 0.29), and weight (r = 0.16), as well as with BMD at the radius (r = 0.63), spine (r = 0.50), and femur (r = 0.47). After classification of bone measurements into tertiles, about 60% of the women with low tertile spinal BMD fell within the low tertile of either tibial SOS, femoral BMD, or radial BMD. The results show that measurement of tibial SOS is a precise method of assessing bone status without exposing the patient to sources of radiation.

22-Oxacalcitriol does not interfere with parathyroid hormone-induced phosphaturia or cyclic-AMP excretion.

The vitamin D analogue, 22-oxacalcitriol [22-oxa-1,25(OH)2 vitamin D3], has pleiotropic effects similar to or greater than calcitriol but has markedly fewer calcemic and phosphatemic effects. To test the hypothesis that the lesser phosphatemic effect of 22-oxacalcitriol is due, at least in part, to a lack of interference with the phosphaturic effect of parathyroid hormone, acute clearance experiments were performed in parathyroidectomized rats receiving continuous 1-34 parathyroid hormone (PTH) infusion together with 22-oxacalcitriol (200 pmol.100 g body weight-1.min-1) or vehicle. In contrast to the previously reported inhibitory effect of calcitriol on PTH-induced phosphaturia, fractional excretion of phosphorus increased similarly in both groups, from 0.05 +/- 0.01 to 0.26 +/- 0.02 (p < 0.01) in the vehicle-infused animals and from 0.04 +/- 0.01 to 0.24 +/- 0.02 (p < 0.01) in the 22-oxacalcitriol-treated rats (p between groups not significant [n.s.]). Urinary cyclic AMP excretion also increased similarly, from 45.5 +/- 5.2 to 101.6 +/- 21.6 (p < 0.01) and from 45.4 +/- 5.6 to 102.6 +/- 16.7 pmol/min (p < 0.01), respectively (p between groups n.s.). In search for a nongenomic mechanism that might account for the disparate effects of 22-oxacalcitriol and calcitriol, OK cells, which are reminiscent of the mammalian proximal tubule cell, were stimulated with calcitriol and 22-oxacalcitriol and free intracellular calcium concentration was determined. At high concentrations, calcitriol caused a dose-dependent increase in [Ca2+]i; 22-oxacalcitriol had no effect on [Ca2+]i at any concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

Stimulation of osteoclastic bone resorption in a model of glycerol-induced acute renal failure: evidence for a parathyroid hormone-independent mechanism.

This study was undertaken to evaluate the bone changes occurring in rats with acute renal failure (ARF). Acute renal failure was induced in rats 24 hours after dehydration by an intramuscular injection of glycerol. After induction of ARF, the rats were divided into two groups, one of which underwent parathyroidectomy (PTX). Rats with normal renal function, matched for age and weight, were used as controls and divided into two groups, one of them for PTX. At termination of the study blood and urine chemistry and bone histomorphometry were analyzed. Rats with glycerol-induced ARF developed bone changes compatible with mild hyperparathyroid bone disease, characterized mainly by increased osteoclastic bone resorption when compared with control rats having normal renal function. Rats with normal renal function following PTX developed bone disease showing complete suppression of forming and resorptive parameters. Rats with glycerol-induced ARF and PTX showed abolishment of all bone forming parameters, but a dramatic increase in osteoclastic resorption was apparent. Based on these observations we suggest that, in this model of glycerol-induced ARF, osteoclastic bone resorption may develop in the absence of parathyroid hormone, probably stimulated by other potent osteoclastogenic factors.

Assessment of combined 24,25(OH)2D3 and 1 alpha (OH)D3 therapy for bone disease in dialysis patients.

An increasing body of experimental data suggests a role for 24,25(OH)2D3 in bone metabolism. The present study was carried out to assess a possible therapeutic role of this vitamin D metabolite in renal osteodystrophy. Twenty-two chronic dialysis patients, most of whom were previously maintained on 1 alpha (OH)D3 therapy, received additional treatment with 10 micrograms/day 24,25(OH)2D3 and were compared to 19 patients receiving 1 alpha (OH)D3 alone. Analysis of transiliac bone biopsies obtained at study entry and following 10-16 months of treatment revealed that the combined therapy produced a decrease in bone turnover. Specifically, the addition of 24,25(OH)2D3 inhibited an increase in trabecular bone volume (BV/TV) and suppressed osteoclastic parameters. Thus BV/TV increased from 26.2 +/- 8.6 to 32.1 +/- 7.5% (p < 0.01) in the 1 alpha (OH)D3 group, but it remained unchanged in the combined therapy group. In contrast, the eroded surface (ES/BS), the osteoclast surface (Oc.S/BS), and the osteoclast numbers were significantly suppressed in patients receiving both 24,25(OH)2D3 and 1 alpha (OH)D3, as compared with those receiving 1 alpha (OH)D3 alone (p < 0.01, p < 0.01, and p < 0.001, respectively). These improvements were independent of changes in 1 alpha (OH)D3 dosage. The extent of bone aluminium deposits was unrelated to the administration of 24,25(OH)2D3 or to its effect. 24,25(OH)2D3 therapy was not associated with any adverse effects.

Effects of alternating phosphorus and calcium infusions on osteoporosis.

The osteoblastic effect of inorganic phosphorus and the inhibitory action of calcium on parathyroid hormone secretion formed the basis for a therapeutic trial in which both elements were given intravenously in an alternating sequence for one year to five patients with severe osteoporosis. During treatment, calcium and phosphorus balances were positive, and serum phosphorus concentrations decreased. Iliac crest bone biopsy specimens obtained one year after beginning treatment demonstrated an increase in the thickness of cortical bone. All patients experienced lasting relief of bone pain, and the rate of spontaneous fractures decreased from at least one fracture per year to none following the beginning of treatment. These findings suggest that long-term treatment with alternating phosphorus and calcium infusions may result in lasting relief of symptomatic osteoporosis. It is proposed that the observed improvement reflects an increase in bone mass resulting from enhanced bone formation.

Erythrocytosis after renal transplantation. The response to theophylline treatment.

Erythrocytosis was found in 20 out of 127 patients who underwent renal transplantation (15.7%). Four were found to have elevated erythropoietin concentrations (139.7 +/- 22.0 microns/ml) and 7 had normal levels (52.3 +/- 84 microns/ml (normal -60). The growth of erythroid CFUs was found to be normal in all patients. Theophylline treatment was given to 11 patients. The patients were divided into 3 groups according to their response: (1) patients with high erythropoietin levels whose hematocrit decreased from 59.6% to 46.3% within 2 weeks of treatment in parallel with a fall in erythropoietin; (2) patients with normal erythropoietin levels in whom theophylline therapy reduced the hematocrit from 58.7% to 47.2%; and (3) patients in whom theophylline had no effect on their erythrocytosis. We conclude that erythrocytosis after renal transplantation is a heterogenous condition and that several mechanisms are involved. In some patients, high erythropoietin levels or high sensitivity to erythropoietin are associated with the erythrocytosis. Theophylline therapy is beneficial in more than 50% of the cases.

Successful renal transplantation from two donors with methanol intoxication.

Two patients with acute methanol intoxication are reported, one with acute renal failure. Both were declared brain-dead and kidneys were harvested at 80 and 130 hr after hospital admission. All four kidneys were transplanted and subsequently functioned well. In both donors who had received ethanol treatment, thrombocytopenia was present. The reluctance to use kidneys from such donors and from donors with acute renal failure before harvesting is discussed. Waiting lists for renal transplantation are growing and there is a world-wide shortage of cadaver organs. We were recently surprised to find reluctance to consider two local patients dying from methanol intoxication as suitable organ donors, and we report the outcome of four kidneys transplanted from these donors. We were unable to find any similar cases reported in the English literature.

The effect of low dose octreotide administration on renal function and on gene expression of IGF-I axis components in experimental diabetes mellitus.

The present study was undertaken to assess the chronic effects of low dose octreotide (Oc) administration in rats with experimental diabetes mellitus (DM). Metabolic and clearance studies were performed in control normal rats, in rats with streptozotocin-induced DM of 1 week duration and in similar DM rats treated with Oc, 10-20 microg/day. Gene expression of IGF-I, IGF-I receptor (IGF-I R) and IGF-binding protein-1 (IGFBP-1) was examined in renal tissue from normal DM animals and DM animals treated with Oc 10, 20 and 100 microg/day. Seven days of Oc administration, 10 microg/day, in rats with experimental DM, was associated with enhanced hyperglycemia, increased glomerular filtration rate and urinary sodium excretion as compared with untreated DM animals. After a higher Oc dose, 20 microg/day, however, there were no significant changes in renal function and in glycemic control. Significant increases in kidney weight and kidney weight/body weight ratio were seen in DM rats as compared with control intact animals. These changes were not affected by Oc therapy in various doses. Induction of DM was associated with a marked increase in renal IGFBP-1 mRNA expression. There were no significant changes in the expression of IGF-I or IGF-I R mRNA. Oc therapy in a low or high dose did not affect gene expression of IGF-I, IGF-I R or IGFBP-1. Thus, the response to chronic low dose Oc administration of DM rats may vary from enhanced hyperglycemia and hyperfiltration to a lack of change in renal function or in glycemic control. Low dose Oc therapy was not associated with significant variations in renal mass or in the gene expression of IGF-I axis components. These findings are at variance with previously published studies which show a suppressive effect of Oc on renal function and growth in experimental diabetes. This apparent discrepancy may be related to the duration of treatment or to a biphasic physiological effect of Oc when used in different doses.