Evidence of a parathyroid hormone-independent chronic effect of estrogen on renal phosphate handling and sodium-dependent phosphate cotransporter type IIa expression.

The effects of estrogen on phosphate metabolism are not well understood. To better define the chronic effects of estrogen on phosphate balance and on renal phosphate handling, the following groups were examined: A. young male and female rats, age- and weight-matched (age 8-10 weeks, 1 (st) study), and B. ovariectomized female rats (OVX), 22 weeks old, ovariectomized aged-matched rats receiving estrogen replacement (15 micromol x 3/week) for 14 weeks (OVX+E), control female rats (intact ovaries), and male rats, both age matched to OVX and OVX+E (2 (nd) Study). In younger females (1 (st) study), plasma phosphate was lower, whereas the urinary excretion of phosphate was higher than in males. In adult intact females and in OVX+E urinary excretion of phosphate was higher than in males and OVX (2 (nd) Study). In these rats, a significant correlation between plasma phosphate and estrogen level was found. Sodium-dependent phosphate cotransporter (NaPiIIa) mRNA expression and protein abundance were higher in the renal cortex of younger male rats than in age- and weight-matched females. In adult rats, NaPiIIa mRNA and protein abundance were higher in OVX than in OVX+E, and in mature males as compared with age-matched females. These differences were not related to the parathyroid hormone (PTH) levels. Chronic estrogen administration was also associated with increased plasma calcium level and urinary calcium excretion. These results suggest that chronic estrogen treatment is associated with an inhibitory, PTH-independent effect on the expression of NaPiIIa in the kidney, leading to sex-related differences in phosphate balance.

Shortening and migration of Wallstents after stenting of central venous stenoses in hemodialysis patients.

PURPOSE: To report our results for the placement of central venous stents in patients undergoing hemodialysis. METHODS: Ten Wallstents (Schneider, Bülach, Switzerland) were placed in 10 patients with shunt thrombosis, shunt dysfunction or arm swelling associated with central vein stenosis or occlusion. Technical success, patency and complications were evaluated. RESULTS: Stent deployment was successful in all cases. In seven cases (70%) there was significant delayed stent shortening. In two of these cases there was also stent migration. All these cases required additional stents. Primary patency rates at 6, 12 and 24 months were 66%, 25% and 0. Twenty-three additional procedures (percutaneous transluminal angioplasty or stenting) were required to achieve secondary patency rates at 6, 12 and 24 months of 100%, 75% and 57%. CONCLUSION: Stent placement in the central veins of dialysis patients has a high technical success rate resulting in symptomatic relief and preservation of access. Repeat interventions are required to maintain patency. Significant delayed shortening of the Wallstent occurred in 70% of patients which may have affected the patency rates. Strategies are suggested to avoid this problem.

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.

Detection of human herpesvirus-8 DNA in kidney allografts prior to the development of Kaposi's sarcoma.

Human herpesvirus-8 (HHV-8) DNA was identified in kidney allografts in 2 of 3 transplant recipients prior to the development of Kaposi's sarcoma, and increase in viral antibody titer was found in the third. Combined genotypic and serologic analyses could be used to identify patients at risk and suggest that the kidney may be a site of HHV-8 latency.

Regulation of ROMK and channel-inducing factor (CHIF) in acute renal failure due to ischemic reperfusion injury.

BACKGROUND: Acute renal failure caused by ischemia followed by reperfusion is often associated with severe hyperkalemia. The present study was undertaken to characterize the effects of renal ischemia and reperfusion on plasma potassium (K) and on the gene expression of channel-inducing factor (CHIF), a putative K channel regulator, and of ROMK, the distal nephron secretory K channel. METHODS: The following groups of rats were studied: (1) sham operated (sham); (2) after one hour of ischemia by bilateral renal artery clamping (I), and after one hour of ischemia; (3) one hour of reperfusion (I-R 1 h); (4) 24 hours of reperfusion (I-R 24 h); (5) 48 hours of reperfusion (I-R 48 h); and (6) 72 hours reperfusion (I-R 72 h). The expression of CHIF and ROMK was examined by Northern blot hybridization in renal cortex, medulla, and papilla and in the colon. The abundance of ROMK protein was determined in the renal cortex and medulla by immunoblotting. RESULTS: Maximal plasma creatinine and potassium levels after ischemia and reperfusion were 470 +/- 16 micromol/L, P < 0.0001 versus sham, and 9.65 +/- 0.33 mmol/L, P < 0.0001 versus sham, respectively. The expression of CHIF was significantly down-regulated in the medulla and papilla, with a maximal decrease of 80% at 48 to 72 hours. In contrast, a most significant increase in CHIF mRNA expression (250% of baseline) was noted in the colon after 24 to 48 hours of reperfusion. ROMK expression was reduced in the cortex and was completely abolished in the medulla at 48 to 72 hours of reperfusion. Ischemia and reperfusion injury significantly decreased ROMK protein abundance to 10% of control in the medullary fractions. CONCLUSIONS: These results suggest that down-regulation of renal CHIF and ROMK may contribute at least partly to the hyperkalemia of acute renal failure after ischemia and reperfusion, while CHIF up-regulation in the colon may act as a compensatory mechanism of maintaining K balance via increased K secretion.

24,25-dihydroxyvitamin D3 in combination with 1,25-dihydroxyvitamin D3 ameliorates renal osteodystrophy in rats with chronic renal failure.

AIMS: This study compares the effects of 1,25(OH)2D3 and 24,25(OH)2D3 alone or in combination on renal osteodystrophy in rats with chronic renal failure (CRF). MATERIAL AND METHOD: One month subsequent to 5/6 nephrectomy animals were divided into four groups and treated for one or four weeks with either vehicle, 1,25(OH)2D3, 24,25(OH)2D3 or 1,25(OH)2D3 + 24,25(OH)2D3. A sham-operated group with normal renal function matched for age and weight was used as control. At the termination of the study blood chemistry, parathyroid hormone (PTH) level and bone histomorphometry were analyzed. RESULTS: The main findings were: amelioration of 1,25(OH)2D3-induced hypercalcemia by 24,25(OH)2D3, and similar suppression of PTH by the two metabolites of vitamin D when administered alone or in combination. Bone histomorphometry showed that 1,25(OH)2D3 alone exerts a potent proliferative effect on the osteoblasts but severely depresses their mineralizing capacity in a dose- and time-dependent manner. By contrast, 24,25(OH)2D3 improved the mineralizing activity with only a limited effect on osteoblast proliferation. Addition of 24,25(OH)2D3 potentiated the beneficial effect of 1,25(OH)2D3 on bone-resorbing parameters and corrected the mineralization failure. CONCLUSIONS: Based on the above observations we suggest that the combined treatment with 1,25(OH)2D3 and 24,25(OH)2D3 markedly improves the morphologic and metabolic abnormalities of renal osteodystrophy.

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.

Heart rate variability during chronic hemodialysis and after renal transplantation: studies in patients without and with systemic amyloidosis.

The present study was undertaken to compare heart rate variability (HRV) values in patients on maintenance hemodialysis with no evidence of ischemic or hypertensive heart diseases to those of age- and gender-matched healthy individuals and those of patients after renal transplantation. To assess the effects of a common confounding factor, HRV values were also determined in patients with systemic amyloidosis, in chronic hemodialysis, and after successful renal transplantation. Spectral analyses of RR intervals from continuous electrocardiogram recordings were performed to quantify ultra low frequency, very low frequency, low frequency, and high frequency powers. HRV determinations were all significantly reduced in uremic patients undergoing hemodialysis compared with the healthy control subjects, especially in those with systemic amyloidosis. Renal transplantation normalized HRV in most patients; HRV, however, remained reduced in isolated amyloidosis patients with cardiac or adrenal involvement. HRV circadian day/night differences were preserved in hemodialysis patients and after renal transplantation in those without amyloidosis but not in those with amyloidosis. These data suggest that reduced HRV in chronic hemodialysis patients may precede other manifestations of cardiovascular disease. In uremic patients with amyloidosis, a more severe form of autonomic failure may occur. Successful transplantation corrects HRV abnormalities in most patients, suggesting that the autonomic dysfunction of uremia is caused by humoral factors reversed by the normalization of the renal function.

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.

Pseudo-normal osmolal and anion gaps following simultaneous ethanol and methanol ingestion.

Methanol, ethylene glycol, and isopropyl alcohol are associated with acute intoxication. The diagnosis is dependent upon high anion-gap metabolic acidosis, and an osmolal gap between the calculated and the measured osmolality. Normal anion gap has been reported in some cases of concomitant methanol and ethanol ingestion, where the high serum levels of ethanol inhibited the metabolism of methanol by alcohol dehydrogenase. The osmolal gap in these cases was higher than expected for methanol, and served as a constant marker for a metabolic derangement. Herewith, we present a patient who presented with normal osmolal and anion gaps 36 h after ethanol and methanol ingestion, yet progressively developing ocular toxicity. Normal anion and osmolal gaps should not rule out earlier methanol poisoning.

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.

Renal failure, paraproteinemia, and lung squamous cell carcinoma.

A 66-year-old man presented with gastrointestinal symptoms and acute renal failure. He had paraproteinemia and tested positive for antinuclear antibodies. There was no evidence for autoimmune disorder or amyloidosis, and bone marrow biopsy was not consistent with multiple myeloma. Three months later he presented with diffuse lymphadenopathy and right lung mass, and lymph node histology revealed metastatic squamous cell carcinoma. This association of paraproteinemia and nonlymphatic neoplasia is unusual and still very rare. A review of the literature is presented.

Clustering of Pneumocystis carinii pneumonia in patients undergoing renal transplantation from living unrelated donors in Iraq and India.

Over the past few years, we have observed a substantial increase in the number of patients followed at our hospital who have undergone renal transplantation from living unrelated donors (LURD). These transplants were all performed in one of two centers: Bagdad, Iraq or Bombay, India. We have observed a parallel increase in the number of cases of Pneumocystis carinii pneumonia (PCP) post-renal transplant. We conducted a ten-year retrospective analysis (1986-1995) of patients who developed PCP post-renal transplant to determine the risk factors associated with the development of this infection, with particular reference to the type of transplant and the center in which the transplant was performed. Over this period, 270 renal transplant patients were followed at this hospital and 10 episodes of PCP were documented (3.7%). Six of these cases occurred within the last 2 years, as compared to only 4 cases in the preceding 8 years. All of the cases observed in the last 2 years occurred in patients who had undergone renal transplantation from LURD in Iraq or in India. During the same period, we observed no cases of PCP in patients who had undergone transplantation in Israel (cadaver or related living donor transplants). We could find no difference between patients undergoing transplant from LURD and those undergoing other transplants in terms of immuno-suppressive therapy, frequency of organ rejection episodes or coexistent CMV infection. All patients were of Arab descent and live in the West Bank. Although we cannot identify any obvious explanation for this association, we believe that these cases represent a true cluster phenomenon. We therefore feel it is warranted for all recipients of renal transplants from living unrelated donors seen in our hospital to receive prophylactic therapy for Pneumocystis carinii pneumonia.

Effect of human recombinant erythropoietin therapy on panel reactive antibodies in chronic dialysis patients.

To examine whether recombinant human erythropoietin (rhEPO) therapy results in decreased presensitization to foreign HLA antigens, we retrospectively analyzed data from 64 of 200 patients treated in a university hospital dialysis center between 1985 and 1995 who had undergone routine panel reactive antibody (PRA%) screening. Though a significant decrease in the annual frequency of highly sensitized patients over the years was noted, 16 patients followed for 27.1 +/- 3.7 months after initiation of rhEPO therapy until transplantation or blood transfusion showed no significant overall decrease in PRA%. Six highly presensitized patients had moderate but significant overall decrease in PRA%. However, in three of these patients the PRA% was unchanged and in the other three patients the PRA% remained over 50%. Thus rhEPO therapy reduced the incidence of highly presensitized patients, but previously presensitized patients remained presensitized. We conclude that removal of transfusional stimulation of lymphocytotoxic antibody production does not appear to benefit previously presensitized patients, possibly due to the maintenance of B-lymphocyte clonal expansion by unknown factors, or even by rhEPO itself.

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.

Renal osteodystrophy in rats with reduced renal mass.

The rat remnant kidney, a popular model of experimental renal failure, has also been used to assess the histological bone changes associated with reduction in renal mass. The suitability of this model has been challenged, especially with regard to the standardization of animals from different age groups and various degrees of renal failure. The present study was undertaken: (1) to better evaluate the histomorphometric changes associated with reduction in renal mass; (2) to assess these changes over a longer follow-up period as compared to those of matched intact animals; (3) to define the response to pharmacological doses of calcitriol. Male rats were evaluated 4 and 8 weeks after induction of renal failure (5/6 nephrectomy) and compared with age-matched control rats with intact kidneys. Plasma biochemistry, creatinine clearance and parathyroid hormone (PTH) were obtained from normal rats and from the rats with chronic renal insufficiency. Histomorphometric studies were performed in all animals on the right tibial bone. Induction of renal failure of 4 weeks' duration (short-term study, age 16 weeks) was associated with increased PTH and bone resorption, but suppressed bone formation. At long-term follow-up (rats aged 20 weeks), the suppression in bone formation was even more prominent. These changes were assessed considering normal bone histomorphometry during the process of growing. Calcitriol administration was associated with a significant suppression of bone resorption and a spectacular increase in all osteoid parameters. The bone formation rate, however, remained in the same low range as that in untreated animals. This model of renal osteodystrophy is similar to human secondary hyperparathyroidism with regard to the enhanced bone resorption, but differs by the marked decrease in bone formation. There was a remarkable similarity between the response of rats with renal failure and that of patients with severe secondary hyperparathyroidism to large doses of calcitriol, leading in both to adynamic bone disease. Keeping in mind the species differences, the bone changes developing in the uraemic rats may be useful in understanding certain aspects of human renal osteodystrophy.