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Biomedical subjects

R Rabkin

Publications and source records attributed to R Rabkin.

At least 37 records · Page 2Linked to original sources
PubMed1997

Insulin-like growth factor-I ameliorates delayed kidney graft function and the acute nephrotoxic effects of cyclosporine.

BACKGROUND: Delayed graft function (DGF) is a relatively common complication after cadaveric renal transplantation. The adverse effect of DGF on long-term graft survival has lead to intensive efforts to reduce ischemic graft injury. In this study we examined the effects of a new protective treatment based on insulin growth factor (IGF)-I. We evaluated the impact of the treatment on renal recovery and on the nephrotoxicity that is a common side effect of mainstream immunosuppressants. Because therapy with IGF-I or the analog des(1-3)IGF-I is effective in treating experimental ischemic renal failure, these peptides may be useful as perspective clinical treatments. METHODS: We have addressed three areas relating to the potential use of IGF-I and its analog des(1-3)IGF-I. First, because of the immunogenic properties of IGF-I, we assessed the effect of des(1-3)IGF-I on the rejection of skin allografts in Lewis rats. Next we determined whether treatment with des(1-3)IGF-I influences the early function of transplanted kidneys in a model of DGF induced by a combination of warm and cold ischemia. Finally we tested whether IGF-I protects against acute cyclosporine nephrotoxicity. RESULTS: Des(1-3)IGF-I did not accelerate the rejection of the skin grafts (P=0.57). The administration of this peptide in a model of syngenic renal transplant improved the early function of the graft. Postoperative values of creatinine and blood urea nitrogen were significantly better (P<0.05) in treated animals. IGF-I also ameliorated the nephrotoxicity of cyclosporine, with better values of creatinine and blood urea nitrogen (P<0.05). CONCLUSIONS: In evaluating this study it should be recognized that the animal models studied, although widely used, differ from the human condition. However, IGF-I and des(1-3)IGF-I exhibit properties that strongly suggest their value in preventing clinical DGF, and they deserve further studies.

Animals↗
PubMed1997

Dextroamphetamine as a treatment for depression and low energy in AIDS patients: a pilot study.

This report documents findings from an open trial of dextroamphetamine in the treatment of depression and low energy in AIDS patients. Dextroamphetamine offers the potential for rapid onset of effect and activation properties, both of which are important to persons with late stage HIV illness. Primary inclusion criteria included having a DSM-III-R depressive disorder, debilitating low energy, CD4 cell count below 200 cells/mm3, and no history of drug dependence. The trial consisted of open treatment in a 6-week protocol, with indefinite follow-up. Twenty-four men entered the study, 18 of 19 (95%) patients who completed at least 6 weeks of treatment reported substantial improvement with regard to both mood and energy at a median dosage of 10 mg/day. These results suggest that dextroamphetamine is a potentially effective, fast acting antidepressant treatment for this population and call for a larger, controlled trial.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Regional changes in the intrarenal insulin-like growth factor-I axis in diabetes.

Since insulin-like growth factor-I (IGF-I) has been shown to promote renal growth and as kidney IGF-I content increases during the early days after the onset of diabetes, it is likely that this growth factor contributes to initial diabetic renal hypertrophy. However, it is unclear whether IGF-I contributes to the continued renal growth that occurs in diabetes. Since IGF-I action is mediated through its receptor and as its bioavailability is regulated by IGF binding proteins (IGFBP), we postulated that changes in IGF-I receptor binding or IGFBP production may favor a role for IGF-I in diabetic renal growth when kidney IGF-I levels have returned to normal. To test this thesis, we studied kidneys of rats after seven days of streptozotocin diabetes. In diabetic cortex and medulla, growth hormone receptor mRNA levels and IGF-I and IGF-I receptor mRNA and protein product levels were unchanged. In cortex IGFBP-1 mRNA levels were increased while IGFBP-2 and -4 mRNA levels decreased. In medulla the only change was a fall in IGFBP-1 mRNA levels. Using Western ligand blot we observed an increase in a 32 kDa plasma membrane-associated IGFBP. Insulin therapy reversed all changes except the elevated cortical IGFBP-1 mRNA levels, indicating the presence of regional heterogeneity in the IGFBP response to diabetes in the kidney. However, the lack of change in IGF-I, IGF-I receptor and growth hormone receptor gene expression and protein products after one week of diabetes argues against a role for IGF-I in sustaining diabetic renal growth beyond the initial growth phase.

Animals↗
PubMed1997

Early experience with extended use of insulin-like growth factor-1 in advanced chronic renal failure.

Short-term high-dose insulin-like growth factor-1 (IGF-1) therapy has been shown to enhance glomerular filtration rate (GFR) in end-stage chronic renal failure (CRF), but the efficacy and safety of prolonged therapy is unproven. To determine if prolonged therapy with IGF-1 can enhance renal function in advanced CRF, eight patients were entered into a study to receive one month of IGF-1 treatment, 60 micrograms/kg subcutaneously b.i.d. Six patients completed the study and two dropped out for reasons considered to be unrelated to the IGF-I treatment. Baseline inulin and PAH clearances averaged 17 +/- 3 and 66 +/- 14 ml/min/1.73 m2, respectively, in the subjects who completed the study. With treatment there was a modest 14% increase in the average GFR which approached statistical significance (P = 0.051). After stopping treatment the clearance values returned to basal values. The PAH clearance showed a similar trend. There were no significant changes in BUN, serum creatinine or electrolyte levels. On the other hand there were marked changes in the serum IGF binding protein (IGFBP) profile. Serum IGFBP-3 levels fell while IGFBP-1 and -2 levels rose during treatment, changes that likely affect the bioavailability of IGF-I. Thus, in this small series of patients IGF-1 treatment produced significant changes in the serum IGFBP profile and a modest upward trend in the GFR.

Adult↗
PubMed1997

The IGF-I axis in kidney and skeletal muscle of potassium deficient rats.

Potassium deficiency in the rat results in growth retardation, muscle wasting and renal hypertrophy. This study tests the thesis that K deficiency leads to tissue distinct changes in the local IGF-I system and cell sensitivity to IGF-I that favors renal enlargement on the one hand and impaired muscle growth on the other. In rats after eight days of K deficiency, compared to pair-fed control rats, food utilization and muscle and body wt gain were attenuated while the kidneys enlarged. In muscle GH receptor and IGF-I gene expression, IGF-I peptide and IGF binding protein-5 (IGFBP) levels were decreased. Together with reduced food utilization, these changes may contribute to the attenuated muscle growth. In the enlarged kidneys despite a fall in IGF-I mRNA level, IGF-I peptide concentration was increased more than twofold. This increase in IGF-I could be caused by the increase in kidney IGFBP-1 gene and protein expression and the decrease in kidney IGF-I degrading activity noted in K deficiency. Treatment with IGF-I failed to induce body or muscle growth, but induced a further increase in kidney size and enlargement of the spleen. Thus, in K deficiency the spontaneous increase in IGF-I levels in the kidney that is IGF-I sensitive may well be a cause of the renal hypertrophy.

Animals↗
PubMed1997

Effect of insulin-like growth factor binding proteins on the response of proximal tubular cells to insulin-like growth factor-I.

The insulin-like growth factor binding proteins (IGFBP) are major modulators of insulin-like growth factor-I (IGF-I) action, but relatively little is known about their production by kidney tubular cells or about their modulating effects on the action of IGF-I on these cells. In this study we demonstrated that rabbit proximal tubular cells express the genes for IGFBP-2, -4 and -5 and secrete 24 and 32 kDa size binding proteins. The rate of IGFBP production by these cells was regulated by several growth factors including hydrocortisone, which was potently stimulatory, and EGF, which was inhibitory. The overall effect of these kidney cell-secreted IGFBPs was to inhibit the mitogenic activity of IGF-I. Similarly, recombinant IGFBP-3, the major circulating IGFBP that in kidney is produced close to the proximal tubules, also inhibited IGF-I stimulated DNA synthesis in cultured rabbit proximal tubular cells and in cultured opossum kidney (OK) cells. IGFBP-3 also inhibited basal DNA synthesis in OK cells in the absence of added IGF-I, suggesting that this IGFBP may have an IGF-I independent action. These findings highlight the important effect that IGFBPs have on the action of IGF-I on kidney cells and support the notion that the changes in IGFBPs observed in various renal diseases may contribute to the pathophysiology of these diseases.

Animals↗
PubMed1997

The use of growth factors to increase glomerular filtration rate in chronic renal failure patients.

Insulin-like growth factor-1 has been safely administered to humans with chronic renal failure in an attempt to increase glomerular filtration rate. The results of short-term studies have been encouraging. Further studies will be required to better define the role of this or other growth factors in increasing glomerular filtration rate in patients with chronic renal failure.

Glomerular Filtration Rate↗
PubMed1997

IGF-I receptor binding, autophosphorylation, and kinase activity in kidney and muscle of acutely uremic rats.

Following acute tubular necrosis (ATN), kidney plasma membrane insulin-like growth factor-I (IGF-I) receptor number increases markedly, although IGF-I receptor mRNA levels do not change. To determine whether this increase could represent a redistribution of intracellular receptors and whether receptor function is intact in acute uremia, rats with ATN of 2 days duration and pair-fed controls were studied. Skeletal muscle receptor binding was unchanged. In contrast, binding to receptors in solubilized cortex and isolated cortical plasma membranes increased significantly due to an increase in receptor number. However, the increase in membrane binding was threefold greater than the increase in solubilized cortex binding. This indicates that the increase in total cellular IGF-I receptors can only account for a minor portion of the increase in abundance of plasma membrane receptors number and is consistent with a redistribution of receptors from an intracellular to a membrane location as the major mechanism. Autophosphorylation and receptor kinase activity were unaffected by the uremia (blood urea nitrogen of approximately 198 mg/dl). Since these early steps of IGF-I receptor signaling are intact early in acute uremia, it is likely that at this time in the course of the disease the increase in receptor number will heighten the sensitivity to IGF-I and may thus favor its participation in renal repair.

Acute Kidney Injury↗
PubMed1997

Nuclear transport of insulin-like growth factor-I and insulin-like growth factor binding protein-3 in opossum kidney cells.

When added to cultured opossum kidney cells, IGF-I is internalized and transported to distinct intracellular compartments that depend on the cell location within the monolayer. In resting cells away from the periphery of the monolayer, IGF-I is internalized by a clathrin coated pit pathway and delivered to the endosomal compartment. In contrast, cells growing at the edges of a monolayer or an experimental wound internalize IGF-I by an alternative route which rapidly delivers IGF-I to the nucleus. Similarly to IGF-I, IGFBP-3 is also internalized and accumulates in the endosomal compartment in resting cells whereas it is targeted to the nucleus in proliferating cells. IGFBP-3, which contains a putative nuclear targeting signal, may act as a carrier for IGF-I nuclear transport. The transport of IGF-I and IGFBP-3 to two different compartments may influence their biological activity.

Animals↗
PubMed1997

Testosterone treatment of clinical hypogonadism in patients with HIV/AIDS.

The use of testosterone to treat clinical symptoms of hypogonadism and wasting among patients with HIV/AIDS is a relatively new area of inquiry and clinical application. Outcome measures have included changes in mood, libido, energy, weight and muscle mass. The purpose of this review is to identify the questions most commonly raised about risks of testosterone therapy, to review available data which address these questions, and to discuss issues of clinical management. These include treatment indications, measurement issues, and side effects and their management.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Nutrient regulation of insulin-like growth factor-I.

Insulin-like growth factor-I (IGF-I) is a nutrient-regulated growth factor. In malnutrition, serum IGF-I levels fall despite normal or elevated growth hormone (GH) levels and this is caused by resistance to GH, defects in IGF-I gene transcription and translation and mRNA instability. Because IGF-I production is sensitive to protein and energy deficiencies serum IGF-I levels may be valuable in the assessment of the nutritional status of patients with wasting diseases, including advanced renal failure. It should be recognized, however, that serum or tissue IGF-I peptide levels do not always reflect IGF-I gene expression. For example, in the K-deficient rat, kidney IGF-I levels are increased even though IGF-I mRNA levels are low. This appears to be due in part to increased sequestration by IGF-binding proteins and by decreased kidney IGF-I degradation. The increase in kidney IGF-I may contribute to the exaggerated renal growth that occurs in hypokalemia.

Animal Nutritional Physiological Phenomena↗
PubMed1996

Processing of 125I-insulin by polarized cultured kidney cells.

Renal clearance of insulin is achieved by glomerular filtration and by passage from the postglomerular peritubular circulation into the renal interstitium. In the proximal tubule, filtered insulin binds to the apical membrane and is internalized and degraded while insulin in the interstitium is taken up by receptor-mediated endocytosis and degraded. To study these processes we have utilized cultured opossum kidney cells. These cells have proximal-like features and process insulin in a manner consistent with that described in vivo. To study apical and basolateral uptake and metabolism of insulin independently, cells were grown on filters suspended in culture wells. insulin was degraded to large insulin-size intermediates and low-molecular-weight products. This occurred whether the protein was internalized from the apical or basolateral pole of the cells. Analysis of the intermediate products by reverse-phase high-performance liquid chromatography revealed that products formed after apical or basolateral internalization were similar. Since products were preferentially released from the side of uptake, it is likely that apically and basolaterally internalized insulin is degraded in comparable organelles located in different regions of the cell. Most of the internalized insulin traversed the degradative pathway but some insulin followed a retroendocytic or minor transcytotic pathway. Degradation was inhibited by chloroquine, which also selectively increased the release of internalized insulin from the apical pole irrespective of the side of uptake. Thus while the polar degradative processes appear to be similar in nature, the polar exocytotic processes appear to be different.

Animals↗
PubMed1996

Pharmacokinetics of insulin-like growth factor-1 in advanced chronic renal failure.

Information regarding the impact of chronic renal failure (CRF) on IGF-1 serum clearance is limited. Thus we evaluated the pharmacokinetics of insulin-like growth factor-1 (IGF-1) in six normal adults and six adults with advanced CRF (serum creatinine 7 +/- 0.8 mg/dl). All subjects were given 80 micrograms/kg recombinant human IGF-1 s.c. and blood was sampled over 48 hours. Baseline total serum IGF-1 levels were similar in both groups, but peak levels were elevated significantly in CRF; this was apparently related to the reduced distribution volume in CRF subjects. CRF did not affect the metabolic clearance rate (MCR) of total serum IGF-1. Immunoreactive IGF binding protein-3 (IGFBP-3) levels were greater in CRF. Western immunoblots revealed that the apparent increase in IGFBP-3 was largely due to an increase in immunoreactive fragments. IGFBP-3 protease activity was not increased. Thus IGFBP fragment accumulation likely reflects reduced fragment clearance. Western ligand blots revealed elevated 30 and 34 kDa IGFBP levels and IGFBP products in CRF serum. Serum acid labile subunit levels were unchanged in CRF. Peak free IGF-1 levels and the MCR of free IGF-1 did not differ between groups. In both groups the MCR of free IGF-1 exceeded the MCR of total IGF-1 by approximately 30-fold. These data suggest that in CRF patients receiving s.c. IGF-1: (a) total serum IGF-1 levels are increased as a result of elevated circulating IGFBPs that may restrict the distribution of IGF-1 beyond plasma; (b) serum free IGF-1 levels are not altered; and (c) the IGF-1 MCR is unchanged in CRF. Thus, in advanced CRF, apart from a reduction in the total IGF-1 volume of distribution the pharmacokinetics of IGF-1 are largely unaltered.

Adult↗
PubMed1996

Response of the intrarenal insulin-like growth factor-I axis to acute ischemic injury and treatment with growth hormone and epidermal growth factor.

We previously reported that following bilateral acute tubular necrosis (ATN) profound changes in the intrarenal insulin-like growth factor-I axis occurs which are unrelated to altered nutritional intake. In this current report we studied rats with unilateral ATN to assess whether these changes reflect a response to acute injury or the accompanying uremia. Compared to the contralateral kidney, the injured kidney showed an increase in IGF-I receptor number without a change in IGF-I receptor mRNA levels, a decrease in IGF-I mRNA and IGF-I protein levels, a decrease in growth hormone (GH) receptor mRNA abundance and receptor binding. There was also a decrease in IGF binding protein-2, -3 and -5 mRNA levels together with a fall in protein products. Since this unilateral ATN model excludes the influence of uremia and reduced nutritional intake, we surmised that these changes reflect a direct response to injury. Next, because of the reduced GH receptor binding noted above and the reported decrease in epidermal growth factor (EGF) expression in ATN, we tested the thesis that the low kidney IGF-I mRNA levels in ATN are partly due to a relative or absolute deficiency of these hormones. Administration of EGF or GH promptly increased ATN kidney IGF-I mRNA levels to control kidney values, lending support to the thesis. The response to EGF also suggests that the salutary effect of EGF treatment in ATN may partly be mediated by stimulating IGF-I production.

Animals↗
PubMed1996

Protein turnover in the hypertrophying kidney.

To establish whether altered proteolysis contributes to the increase in protein content in hypertrophying kidneys, we studied protein turnover in proximal renal tubules isolated from rats with three forms of renal hypertrophy, diabetes mellitus (DM), ammonium chloride-induced acidosis and compensatory renal growth (CRG). We found that in DM and in chronic acidosis the normal balance in protein turnover is altered due to attenuated proteolysis and accelerated protein synthesis. Together this favors an increase in kidney protein content. In contrast, in CRG, the increase in protein content is entirely due to increased protein synthesis. Thus, the changes in protein turnover leading to the net gain in kidney protein content in renal hypertrophy depends on the cause of hypertrophy.

Acidosis↗