Steven B. Miller

Whole body leptin kinetics and renal metabolism in vivo

Leptin metabolism was investigated in male Sprague-Dawley rats by use of125I-labeled leptin plasma kinetic and arteriovenous balance studies. When conscious rats received bolus venous injections of 125I-leptin, intact (precipitable) leptin quickly disappeared from circulation in a biexponential manner during the 2-h experimental period. After substantial delay, most of the injected radioactivity appeared in the urine. The data were described by a two-compartment model, which postulated that plasma leptin exchanged with a nonplasma pool and that all of the tracer cleared from plasma appeared in urine or in a degraded form in plasma. The half-life of leptin was 9.4 ± 3.0 min, and the leptin production rate was 3.6 ± 1.2 ng ⋅ 100 g fat-1 ⋅ min-1. The left kidney extracted 21 ± 1.5% of intact arterial125I-leptin 5 min after femoral venous injection. Endogenous arterial leptin was reduced 21 ± 8 and 18 ± 12%, respectively, in simultaneously sampled left and right renal veins. Renal elimination appears to be the major elimination mechanism for leptin in normal rats, and the kinetic studies suggest that uptake of leptin by renal tissue rather than glomerular filtration is the predominant elimination mechanism.

Living-unrelated renal transplantation provides comparable results to living-related renal transplantation: A 12-year single-center experience

BACKGROUND The increasing success of renal transplantation is paralleled by the increased size of the waiting list. Efforts to increase the donor pool have included the use of living-unrelated kidney donors (LURDs). METHODS During a 12-year period our center performed 309 transplantation from living donors; 279 patients received living-related donor (LRD) transplants, and 30 patients received LURD transplants. During the same period 543 patients received cadaveric renal donor transplants. A total of 86.7% of LURD transplants were spousal transplants. A total of 29% of the patients who received LRDs were human leukocyte antigen-identical with their donors and 53% were haploidentical, versus 0 human leukocyte antigen-identical or haploidentical in the LURD group. RESULTS Twenty-seven (90%) Of 30 LURD recipients are alive, as are 240 (86%) of 279 LRD recipients. Mean current creatinine is 1.6 mg/dl for the LURD group and 1.7 mg/dl for the LRD group Kaplan-Meier 1- and 5-year graft survival was 94.9% and 82.9% for the LRD group, 93.1% and 85.9% for the LURD group (p = not significant), and 84.6% and 70.7% for the cadaveric renal donor group (p < 0.05). CONCLUSIONS LURD patient and graft survival is comparable to LRD transplants despite inferior human leukocyte antigen matching. LURD transplant survival is superior to that of cadaveric renal donor transplants. LURDs are an excellent but underused source of organs for renal transplant recipients.

Insulin-like growth factor I improves renal function in patients with end-stage chronic renal failure.

There is no pharmacological treatment to increase the glomerular filtration rate in end-stage renal disease (ESRD). The administration of 100 μg/kg of insulin-like growth factor (IGF) I twice a day to patients with ESRD increases inulin clearance. However, its effect is short-lived and IGF-I has major side effects when given this way. To assess whether the use of a lower intermittent dose of IGF-I would effect sustained improved function with tolerable side effects we performed 1) a prospective open-labeled 24-day trial in which we enrolled five patients and 2) a 31-day randomized, double-blinded, placebo-controlled trial in which we enrolled 10 patients. Patients with ESRD [creatinine clearance of <15 ml ⋅ min-1 ⋅ (1.73 m2)-1] and scheduled to initiate renal replacement therapy received subcutaneous IGF-I, 50 μg ⋅ kg-1 ⋅ day-1, or vehicle. Treatment with IGF I resulted in significantly increased glomerular filtration rates (inulin clearances) during the 3rd and 4th wk of therapy in both prospective and double-blinded studies. Vehicle had no effect. No patient required discontinuation of drug secondary to side effects. We conclude that IGF-I effects sustained improvement of renal function (clearances comparable to those generally achieved by dialysis) in patients with ESRD and is well tolerated.There is no pharmacological treatment to increase the glomerular filtration rate in end-stage renal disease (ESRD). The administration of 100 microgram/kg of insulin-like growth factor (IGF) I twice a day to patients with ESRD increases inulin clearance. However, its effect is short-lived and IGF-I has major side effects when given this way. To assess whether the use of a lower intermittent dose of IGF-I would effect sustained improved function with tolerable side effects we performed 1) a prospective open-labeled 24-day trial in which we enrolled five patients and 2) a 31-day randomized, double-blinded, placebo-controlled trial in which we enrolled 10 patients. Patients with ESRD [creatinine clearance of <15 ml. min-1. (1.73 m2)-1] and scheduled to initiate renal replacement therapy received subcutaneous IGF-I, 50 microgram. kg-1. day-1, or vehicle. Treatment with IGF I resulted in significantly increased glomerular filtration rates (inulin clearances) during the 3rd and 4th wk of therapy in both prospective and double-blinded studies. Vehicle had no effect. No patient required discontinuation of drug secondary to side effects. We conclude that IGF-I effects sustained improvement of renal function (clearances comparable to those generally achieved by dialysis) in patients with ESRD and is well tolerated.

Effects of growth hormone and insulin-like growth factor I on renal growth and function

Polypeptide growth factors regulate kidney development, growth, and function and participate in the repair processes after renal injury. The use of one or more growth factors as therapeutic agents in the settings of acute and chronic renal failure has been proposed. Insulin-like growth factor I (IGF-I) accelerates the restoration of kidney function and the normalization of structure and reduces mortality rates in animal models of acute renal injury. The mechanisms by which IGF-I acts in acute renal failure include stimulation of anabolism, maintenance of glomerular filtration, acceleration of tubular regeneration, and increased expression of ischemia-induced renal genes. It has been safely used in persons at risk of having acute renal failure and in patients with end-stage chronic renal failure, in whom it increases the glomerular filtration rate. Further studies to determine the role of IGF-I as a therapeutic agent for acute renal failure and its utility as a medical therapy for chronic renal insufficiency are required.

Insulin-like growth factor-I attenuates delayed graft function in a canine renal autotransplantation model

BACKGROUND Insulin-like growth factor-I (IGF-I) has been shown to accelerate recovery in animal models of ischemic or toxic acute renal injury. Ischemic renal injury is frequently encountered after cadaveric transplantation manifested as delayed graft function. This study was performed to determine whether perfusion of kidneys with preservation solution supplemented with IGF-I would improve the course of renal injury in a canine autotransplantation model of delayed graft function. METHODS Dogs underwent unilateral nephrectomy with kidneys perfused and stored in Euro-Collins solution supplemented with vehicle (n = 11) or IGF-I (n = 8). After 24 hours of kidney preservation, a contralateral nephrectomy was performed and the stored kidney was autotransplanted. Renal function was examined for 5 days after the transplantation, and an inulin clearance was obtained at the time of death. RESULTS Compared with dogs that received kidneys preserved in the vehicle, dogs receiving the IGF-I preserved kidneys had significantly lower daily serum creatinine and blood urea nitrogen levels during the course of 5 days after transplantation. Inulin clearance at death was nearly double in the IGF-I treated animals compared with the vehicle-treated controls (1.37 +/- 0.16 ml/min/kg versus 0.77 +/- 0.13 ml/min/kg; p < 0.05). CONCLUSIONS Perfusion and storage of kidneys with preservation solution supplemented with IGF-I can attenuate the course of delayed graft function in a canine renal autotransplantation model. IGF-I may have potential for use in cadaveric human renal transplantation.

Roles of growth hormone and growth factors in the pathogenesis and treatment of kidney disease.

Growth hormone and a number of polypeptide growth factors exert actions on renal development, growth, and metabolism and on repair processes following renal injury. There is increasing evidence that under selected circumstances, these agents play roles in the pathogenesis of kidney disease and that under others, they may be useful in its treatment. Growth hormone, platelet-derived growth factor, or transforming growth factor-beta may be causative of glomerulosclerosis. The reduction in epidermal growth factor expression within the kidney in the setting of acute ischemic injury could delay regeneration, and replacement may be therapeutic. Insulin-like growth factor I may play a role in the regenerative response to acute renal injury. Pharmacologic properties of growth hormone or insulin-like growth factor I to enhance glomerular filtration rate and renal plasma flow and to increase skeletal growth may be harnessable for treating chronic renal failure and its complications. It is likely that strategies designed to employ growth hormone or growth factors as pharmacologic agents or to block their activities will assume increasingly important roles in therapy for renal disease.

Renal cellular biology of growth hormone and insulin-like growth factor I

Growth hormone (GH) and insulin-like growth factor I (IGF I) exert a variety of actions in renal tissue. To shed light upon the renal GH-IGF I axis we have characterized the cell biology of GH and IGF in two parts of the nephron that are targets for these peptides, proximal tubule and collecting duct. Receptors for both GH and IGF I are present in the basolateral membrane of the renal proximal tubular cell. GH activates phospholipase C and IGF I stimulates phosphorylation of its receptor at this site. Both peptides directly enhance gluconeogenesis in proximal tubule. GH stimulates IGF I gene expression in collecting duct. IGFI of collecting duct origin could act as a paracrine growth factor in other portions of the nephron. IGF I may be causative of renal hypertrophy that occurs in the settings of hypersomatotropism, unilateral nephrectomy (compensatory hypertrophy) and diabetes mellitus.

Plasma leptin concentrations are only transiently increased in nephrectomized rats

Leptin is an adipocyte-secreted hormone that has effects on appetite and energy expenditure. Several studies have shown that end-stage renal disease results in elevated plasma leptin concentrations and that the kidney is responsible for most of leptin elimination in rodents. Leptin metabolism was investigated in rats that underwent unilateral nephrectomy to experimentally limit renal elimination function. Within 4 h of nephrectomy, plasma leptin concentrations increased from 2.9 +/- 0.8 to 5.8 +/- 1.0 & microg/l but thereafter rapidly (<24 h) decreased to prenephrectomy concentrations, despite continued elevated plasma creatinine levels. Sham-operated rats maintained presurgical concentrations of leptin and creatinine throughout the experiment. Kinetic studies of 125I-labeled leptin elimination showed that fractional catabolic rates and half-lives of leptin in circulation were similar at 48 h in nephrectomized and sham-operated rats, suggesting that production of leptin was unchanged after nephrectomy. Excretion of 125I derived from leptin in urine of nephrectomized rats was similar to that of sham-operated rats, and residual radioactivity was increased in the remaining kidneys excised from nephrectomized rats. These results demonstrate that 1) leptin concentrations are quickly restored to presurgical levels in nephrectomized rats, and 2) it is leptin elimination, not leptin production, that compensates to maintain leptin concentrations. Rapid metabolic adaptation of remaining renal tissue may explain the restoration of normal leptin elimination in nephrectomized rats.Leptin is an adipocyte-secreted hormone that has effects on appetite and energy expenditure. Several studies have shown that end-stage renal disease results in elevated plasma leptin concentrations and that the kidney is responsible for most of leptin elimination in rodents. Leptin metabolism was investigated in rats that underwent unilateral nephrectomy to experimentally limit renal elimination function. Within 4 h of nephrectomy, plasma leptin concentrations increased from 2.9 ± 0.8 to 5.8 ± 1.0 μg/l but thereafter rapidly (<24 h) decreased to prenephrectomy concentrations, despite continued elevated plasma creatinine levels. Sham-operated rats maintained presurgical concentrations of leptin and creatinine throughout the experiment. Kinetic studies of125I-labeled leptin elimination showed that fractional catabolic rates and half-lives of leptin in circulation were similar at 48 h in nephrectomized and sham-operated rats, suggesting that production of leptin was unchanged after nephrectomy. Excretion of 125I derived from leptin in urine of nephrectomized rats was similar to that of sham-operated rats, and residual radioactivity was increased in the remaining kidneys excised from nephrectomized rats. These results demonstrate that 1) leptin concentrations are quickly restored to presurgical levels in nephrectomized rats, and 2) it is leptin elimination, not leptin production, that compensates to maintain leptin concentrations. Rapid metabolic adaptation of remaining renal tissue may explain the restoration of normal leptin elimination in nephrectomized rats.

Growth factor gene expression in tubular epithelial injury.

In animal models of acute renal injury, administration of epidermal, insulin-like or hepatocyte growth factor accelerates restoration of kidney function and normalization of histology, and reduces mortality. Mechanisms for such action include stimulation of anabolism, maintenance of glomerular filtration, and enhancement of tubular regeneration. Further studies are needed to establish the utility of growth factors as therapeutic agents for acute renal failure in humans.

Clinical use of growth factors in chronic renal failure.

Erythropoietin has been demonstrated to improve the quality of life in patients with chronic renal failure, and growth hormone has been approved for use in children with chronic renal failure and short stature as a growth promoting agent. Growth factors also have great therapeutic potential to improve glomerular function in the setting of chronic renal failure. Further studies are required to delineate the role of insulin-like growth factor I in the setting of end-stage chronic renal failure.