- Email: [email protected]
Effects of growth hormone and insulin-like growth factor I on renal growth and function
i!iii! ~
of growth hormone and insulin-like growth factor I on renal growth and function ~. Hamnwrman, AID,and Steven B. Miller, AID
Polypepdde 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
using growth factors to accelerate regeneration or to increase kidney function, if successful, would directly address the cause of the kidney failure itself.
function and the normalization of structure and reduces mortality rates in animal models of acute renal injury. The mechanisms by which I G F - 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
INSULIN-LIKE GROWTH FACTOR I AND ACUTE RENAL FAILURE
end-stage chronic renal failure, in whom it increases the glomerular filtration rate. Further studies to determine the role of I G F - I as a therapeutic agent for acute renal failure and its utility as a medical therapy for chronic renal insufficiency are required. (3 Pediatr 1997;131:S17-9)
Using growth hormone to stimulate skeletal growth in children with chronic renal insufficiency is a therapeutic use of a growth factor in renal failure, because GH acts through insulin-like growth factor I. 1 Modifications of renal metabolism, transport, and growth underlie the processes that result in the repair of damaged kidney tissue after acute injury and the adaptations in renal function that make it possible for homeostasis to be maintained in the face of reduced functional renal mass. Because the
expression of renal growth factors is also altered with these modifications, it has been suggested that one or more growth factors are key effectors of these processes and adaptations.2 Therefore the pharmacologic use of growth factors in the setting of acute renal injury to accelerate regeneration--or in the setting of chronic renal failure to increase kidney function-is, in theory, a logical extension of the roles that these agents play in physiologic or pathophysiologic states. Unlike using GH to increase growth,
From the Department of internal Medici,w and the Department of Cell Biology and Physiology, Washington Universily Schoolof Medicine, St. Louis, Miaeouri.
Supported by the National Institutesof Health (DK-27600, DK-45181) (Dr. Hammerman), by the Missouri KidneyProgram and a Clinician-ScienfstAwardfrom the AmericanHeart Association(Dr. Miller),and by Genentech, Inc. Presented in part at the National CooperativeGrowth Study Tenth Annual InvestigatorsMeeting,Oct. 1720, 1996, supported by an educationalgrant from Genentech, Inc. The articlepresented herein representsthe work and opinionsof the authors and is not intendedto represent the opinionsof Genentech, Inc., the Editors, or the Publisher. Reprint requests:Marc R. Hammerman, MD, Renal Division,Box 8126, Departmentof InternalMedicine, Washington UniversitySchoolof Medicine,660 South Euclid Ave.,St. Louis, MO 63110. Copyright© 1997by Mosby-YearBook, Inc. 0022-3476/97/$5.00 + 0 9/0/81649
Ischemic renal injury in rats results in damage to the most distal ($3) segment of the proximal tubule. 3 Recove W depends on the ability of the tubular cells to regenerate and reline the damaged areas along the nephron. The rationale for using IGFI as a therapeutic agent in acute renal failure comes from_ observations that (1) I G F - I binds to specific receptors in the proximal tubule and regulates metabolic and transport processes at this site; (2) the expression of I G F - I is increased in kidneys that are undergoing compensato W growth; (3) the expression of I G F - I in the kidneys is increased after acute renal inju W in rats; and (4) I G F - I is essential for the growth and development of the metanephric kidney in vitro, a process that may be recapitulated by tubular regeneration after injury. 2' 4
We have shown that IGF-I given after acute ischemic inju W in rats accelerates the recovery of normal renal function and the regeneration of damaged proximal tubular epithelium and reduces mortality rates. 5 Similar f'mdlngs have been reported by Ding eta]. 6 Several explanations for
SI7
HAMMERMAN AND MILLER
THE .JOURNAL OF PEDIATRICS JULY 1997
the effectiveness of IGF-I after ischemic injury in rats have been proposed. First, the increasing of the glomerular filtration rate by IGF-I could alter the course of acute renal failure, possibly by limiting the extent of injury caused by the obstruction of tubules by cellular debris. Second, IGF-I is a renotropic agent for the proximal tubule. Third, IGF-I reduces protein breakdown and exerts a generalized anabolic action that results in attenuating weight loss in the setting of the catabolism that accompanies acute ischemic injury. Fourth, the combination of IGF-I treatment and the induction of ischemic acute renal fal]ure in rats increases the expression of genes in the kidney that are differentially expressed after acute renal failure alone. The products of such genes could participate in the regenerative response.2, 4, 7 Finally, the increase in proinflarnmatory cytokines and in the expression of major histocompatlbility complex that follows renal ischemia can be interrupted by IGF-I treatment. 8 IGF-I has been safely used in human beings, including those with reduced renal function. Therefore we conducted a double-blind, randomized, placebo-controlled trial of IGF-I in patients at risk of having renal dysfunction and acute renal failure. We chose postoperative renal dysfunction, a clinical setting 9 that was very similar to our experimental model, 5' 10 in which the blood flow to the kidney was interrupted for 60 to 70 minutes. Deterioration of renal function that may lead to postoperative renal insufficiency is a prominent complication of surgery that involves the suprarenal aorta and the renal arteries. It is usually a result of the renal ischemia that occurs as a consequence of suprarenal aortic clamping and interruption of the blood flow to the kidneys, followed by reperfusion. 9 We have shown that IGF-I administered subcutaneously (100 pg/kg twice a day) increases the glomerular filtration rate in patients with end-stage chronic renal failure and is well tolerated for a 4day period. 11 Accordingly, and in view of the effects of IGF-I in ameliorating renal dysfunction in rats after bilateral clamping of the renal arteries, we administered
SI8
n° I
1is1 Creatinine clearance (% of baseline)
,,01 ,o, 1 I00--
90 85
tO
14
0
g,
h
Time after surgery (h)
I;'~ure.
Creatinine clearancerates (mean _+SE) in patients given IGF-I or" placebo postoperatively.*p less than 0,05, Student t test,
IGF-I or placebo to 58 patients after abdominal surgery during which the blood flow to the renal arteries had been interrupted, and then measured their glomerular filtration rates (creatinine clearance) for 5 days after the surgery. 12 The primaW end point of the study was the incidence of postoperative renal dysfunction as indicated by the decrease from baseline in the glomerular filtration rate at 24, d8, and 72 hours after the surgery. Baseline glomerular filtration rates were measured before the surgery. IGF-I, 100 btg/kg given subcutaneously every 12 hours for six doses, or placebo was administered beginning immediately after the surgery, when the patients were transferred to the intensive care unit. 12 Twenty-nine patients were enrolled in each group. Two patients in each group were excluded from the study because of severe complications during the surgical procedure. The groups were well matched for sex, age, and type of surgery. The renal ischemic times during surgery, baseline glomerular filtration rates, and baseline serum creatinine levels were not significantly different between the groups. There were no adverse effects attributable to IGF-I 1I' I2 in either the IGF-I or the placebo group. The agent was associated with a significant reduction (33%) in the incidence of postoperative renal dysfunction. The creatinine clearance rates in the study subjects are shown in the Figure. Our findings suggest that IGF-I
given after surgery can reduce the incidence of renal dysfunction in patients at risk of having acute renal failure. 12
GROWTH HORMONE~ INSULIN-LIKE GROWTH FACTOR |~ AND CHRONIC RENAL FAILURE One reason for using growth t~ctors in end-stage chronic renal failure is to reverse the catabolic state that accompanies this condition. GH has been administered to adults with chronic renal failure who were undergoing hemodialysis and has been shown to reduce the generation of urea and to increase the efficiency of dieta W protein use. The administration of GH resulted in increased levels of circulating IGF-I, and the actions of GH in this setting are thought to be mediated by IGF.I.la, 14 Patients with chronic renal ~tilure are not GH deficient; therefore the anabotic effect of GH and IGF-I in this setting reflects a pharmacologic action. The potential therapeutic use of IGF-I to increase kidney function in the setting of chronic renal failure is suggested by clinical and experimental observations of the actions of GH on the kidney, is In short, GH deficiency in both human beings and animals is associated with a re-
THE jOURNAL OF PEDIATRICS Volume 13 I, Number I, Part 2 duction in kidney size, glomezailar filtration rate, and renal plasma flow, and G H excess is associated with an increase in kidney size, glomerular filtration rate, and renal plasma flow. The actions of G H in increasing kidney size, glomerular filtration rate, and renal plasma flow are mediated not by G H directly but, rather, through I G F - I . One mechanism by which I G F - I exerts these actions is rapid alterations of glomerular hemodynamics. Infusion of I G F - I in rats decreases renal glomerular afferent and efferent arteriolar resistances and increases the glomerular ultrafiltration coefficient. 2 Because of the ability of G H and I G F - I to increase the glomerular filtration rate, the potential therapeutic use of these agents in the setting of chronic renal failure has been suggested. 15 However, the results of early investigations into their utility were disappointing. For example, Haffner et al. 13 found that G H had no effect on the glomerular filtration rates in seven patients with chronic renal insufficiency, even though it was anabolic and the identical dosage increased the glomerular filtration rates in subjects with normal renal function. The administration of G H to children with chronic renal insufficiency and growth failure has been found to have no significant effect on renal function despite its ability to increase somatic growth. 1 It has been suggested, on the basis of the evidence from these studies, that the uremic state is one of relative renal resistance to the actions of G H and IGF_I.2, 15 To address the question of whether human beings with reduced kidney function are responsive to the renal effects of IGF-I, we administered I G F - I to patients whose baseline inulin clearance rates
HAMMERMANAND MILLER
were so low that dialysis was contemplated, and then evaluated its effects on inulin andp-aminohippurate clearance rates. We showed that I G F - I increases the glomerular filtration rate and renal plasma flow in these patients with end-stage renal insufficiency to the extent that the rates achieved are higher than those generally achieved with hemodialysis. 11, 16 In addition, I G F - I reduced the symptoms of uremia when it was administered for a 2q-day period. 16 O u r studies suggest that renal functional reserve remains even with severe loss of renal function and that the potential exists to increase the glomerular filtration rate by medical means. A double-blind, placebo-controlled trial of I G F - I in the setting of end-stage chronic renal failure to determine whether IGF-I can delay the need for dialysis is clearly required.
7.
8.
9.
10.
11.
We ac/cnowledyet/ve adminfJtratfve aas&tance of Lynn Wesselmann.
12.
REFERENCES
13.
1. Fine RN. Stimulating growth in uremic children. Kidney Int 1992;42:188-97. 2. Hammerman MR, Miller SB. Therapeutic use of growth factors in renal failure. O Am Soc Nephrol 1994;5:1-1i. 3. TobackFG. Regeneration after acute tubular necrosis. Kidney Int 1992;41:226-46. 4. Hammerman MR, Miller SB. The grmvth hormone/insulin-like growth factor axis in kidney revisited. Am J Physiol 1993;265: Fl-14. 5. Miller SB, Martin DR, Kissane J, Hammerman MR. Insulin-like growth factor I accelerates recovery from ischemic acute tubular necrosis in the rat. Proc Natl Acad Sci U S A 1992;89:11876-80. 6. Ding H, Kopple JD, Cohen A, Hischberg R. Recombinant human insulin-likegrowth factor-I accelerates recovery and reduces
catabolism in rats with ischemic acute renal failure, d Clin Invest 1995;91:2281-7. Padanilam BJ, Martin DR, Hammerman MR. Insulin-like growth factor I-enhanced renal expression of osteopontin after acute ischemic injury in rats. Endocrinology t996; 137:2133-40. Goes N, Urmson J, Vineet D, Rasassar V, Halloran PF. Effect of recombinant human insulin-like growth factor 1 on the inflammatory response to acute renal injury. J Am Soc Nephrol 1996;7:710-20. Allen BT, Anderson CB, Rubin BG, Flye MW, Baumann DS, Sicard GA. Preservation of renal function in juxtarenal and suprarenal abdominal aortic aneurysm repair. J Vase Surg 1995;17:948-59. Miller SB, Martin DR, tGssane J, Hammerman MR. Rat models for the clinicaluse of insulin-likegrowth factor I in acute renal failure. Am a Physiol: Renal, Fluid and Electrolyte Physiolo~ 1994;266:F949-56. Miller SB, Moulton M, O'Shea M, Hammerman MR. Effects of IGF-I on renal function in end-stage chronic renal failure. Kidney Int 1994;46:201-7. Franklin SC, Moulton M, Sicard G, Hammerman MR, Miller SB. Insulin-like growth factor I preserves renal function postoperatively. Am J Physiol 1997;272: 257-9. Haffner D, Zacharewicz S, Mehls O, Heinrich U, Ritz E. The acute effect of growth hormone on GFR is obliterated in chronic renal failure. Clin Nephrol 1989;
32:266-9. 14. Ziegler TR, Lazarus JM, Young LS, Ha!dn R, Wilmore DW. Effects of recombinant human growth hormone in adults receiving maintenance hemodialysis. J Am Soc Nephrol 1991;2:1130-5. 15. O'Shea MH, bayish DT. Growth ho~xnone and the kidney: a case presentation and review of the literature. J Am Soc Nephrol 1992;5:157-61. 16. Franklin SC, Moulton M, Hammerman MR, Miller SB. Sustained improvement of renal function and amelioration of symptoms in patiems with chronic renal failure (CRF) treated with insulin-likegrowth factor I (IGF-I). J Am Soc Nephrol 1995;6: 387.
SI9
of growth hormone and insulin-like growth factor I on renal growth and function ~. Hamnwrman, AID,and Steven B. Miller, AID
Polypepdde 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
using growth factors to accelerate regeneration or to increase kidney function, if successful, would directly address the cause of the kidney failure itself.
function and the normalization of structure and reduces mortality rates in animal models of acute renal injury. The mechanisms by which I G F - 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
INSULIN-LIKE GROWTH FACTOR I AND ACUTE RENAL FAILURE
end-stage chronic renal failure, in whom it increases the glomerular filtration rate. Further studies to determine the role of I G F - I as a therapeutic agent for acute renal failure and its utility as a medical therapy for chronic renal insufficiency are required. (3 Pediatr 1997;131:S17-9)
Using growth hormone to stimulate skeletal growth in children with chronic renal insufficiency is a therapeutic use of a growth factor in renal failure, because GH acts through insulin-like growth factor I. 1 Modifications of renal metabolism, transport, and growth underlie the processes that result in the repair of damaged kidney tissue after acute injury and the adaptations in renal function that make it possible for homeostasis to be maintained in the face of reduced functional renal mass. Because the
expression of renal growth factors is also altered with these modifications, it has been suggested that one or more growth factors are key effectors of these processes and adaptations.2 Therefore the pharmacologic use of growth factors in the setting of acute renal injury to accelerate regeneration--or in the setting of chronic renal failure to increase kidney function-is, in theory, a logical extension of the roles that these agents play in physiologic or pathophysiologic states. Unlike using GH to increase growth,
From the Department of internal Medici,w and the Department of Cell Biology and Physiology, Washington Universily Schoolof Medicine, St. Louis, Miaeouri.
Supported by the National Institutesof Health (DK-27600, DK-45181) (Dr. Hammerman), by the Missouri KidneyProgram and a Clinician-ScienfstAwardfrom the AmericanHeart Association(Dr. Miller),and by Genentech, Inc. Presented in part at the National CooperativeGrowth Study Tenth Annual InvestigatorsMeeting,Oct. 1720, 1996, supported by an educationalgrant from Genentech, Inc. The articlepresented herein representsthe work and opinionsof the authors and is not intendedto represent the opinionsof Genentech, Inc., the Editors, or the Publisher. Reprint requests:Marc R. Hammerman, MD, Renal Division,Box 8126, Departmentof InternalMedicine, Washington UniversitySchoolof Medicine,660 South Euclid Ave.,St. Louis, MO 63110. Copyright© 1997by Mosby-YearBook, Inc. 0022-3476/97/$5.00 + 0 9/0/81649
Ischemic renal injury in rats results in damage to the most distal ($3) segment of the proximal tubule. 3 Recove W depends on the ability of the tubular cells to regenerate and reline the damaged areas along the nephron. The rationale for using IGFI as a therapeutic agent in acute renal failure comes from_ observations that (1) I G F - I binds to specific receptors in the proximal tubule and regulates metabolic and transport processes at this site; (2) the expression of I G F - I is increased in kidneys that are undergoing compensato W growth; (3) the expression of I G F - I in the kidneys is increased after acute renal inju W in rats; and (4) I G F - I is essential for the growth and development of the metanephric kidney in vitro, a process that may be recapitulated by tubular regeneration after injury. 2' 4
We have shown that IGF-I given after acute ischemic inju W in rats accelerates the recovery of normal renal function and the regeneration of damaged proximal tubular epithelium and reduces mortality rates. 5 Similar f'mdlngs have been reported by Ding eta]. 6 Several explanations for
SI7
HAMMERMAN AND MILLER
THE .JOURNAL OF PEDIATRICS JULY 1997
the effectiveness of IGF-I after ischemic injury in rats have been proposed. First, the increasing of the glomerular filtration rate by IGF-I could alter the course of acute renal failure, possibly by limiting the extent of injury caused by the obstruction of tubules by cellular debris. Second, IGF-I is a renotropic agent for the proximal tubule. Third, IGF-I reduces protein breakdown and exerts a generalized anabolic action that results in attenuating weight loss in the setting of the catabolism that accompanies acute ischemic injury. Fourth, the combination of IGF-I treatment and the induction of ischemic acute renal fal]ure in rats increases the expression of genes in the kidney that are differentially expressed after acute renal failure alone. The products of such genes could participate in the regenerative response.2, 4, 7 Finally, the increase in proinflarnmatory cytokines and in the expression of major histocompatlbility complex that follows renal ischemia can be interrupted by IGF-I treatment. 8 IGF-I has been safely used in human beings, including those with reduced renal function. Therefore we conducted a double-blind, randomized, placebo-controlled trial of IGF-I in patients at risk of having renal dysfunction and acute renal failure. We chose postoperative renal dysfunction, a clinical setting 9 that was very similar to our experimental model, 5' 10 in which the blood flow to the kidney was interrupted for 60 to 70 minutes. Deterioration of renal function that may lead to postoperative renal insufficiency is a prominent complication of surgery that involves the suprarenal aorta and the renal arteries. It is usually a result of the renal ischemia that occurs as a consequence of suprarenal aortic clamping and interruption of the blood flow to the kidneys, followed by reperfusion. 9 We have shown that IGF-I administered subcutaneously (100 pg/kg twice a day) increases the glomerular filtration rate in patients with end-stage chronic renal failure and is well tolerated for a 4day period. 11 Accordingly, and in view of the effects of IGF-I in ameliorating renal dysfunction in rats after bilateral clamping of the renal arteries, we administered
SI8
n° I
1is1 Creatinine clearance (% of baseline)
,,01 ,o, 1 I00--
90 85
tO
14
0
g,
h
Time after surgery (h)
I;'~ure.
Creatinine clearancerates (mean _+SE) in patients given IGF-I or" placebo postoperatively.*p less than 0,05, Student t test,
IGF-I or placebo to 58 patients after abdominal surgery during which the blood flow to the renal arteries had been interrupted, and then measured their glomerular filtration rates (creatinine clearance) for 5 days after the surgery. 12 The primaW end point of the study was the incidence of postoperative renal dysfunction as indicated by the decrease from baseline in the glomerular filtration rate at 24, d8, and 72 hours after the surgery. Baseline glomerular filtration rates were measured before the surgery. IGF-I, 100 btg/kg given subcutaneously every 12 hours for six doses, or placebo was administered beginning immediately after the surgery, when the patients were transferred to the intensive care unit. 12 Twenty-nine patients were enrolled in each group. Two patients in each group were excluded from the study because of severe complications during the surgical procedure. The groups were well matched for sex, age, and type of surgery. The renal ischemic times during surgery, baseline glomerular filtration rates, and baseline serum creatinine levels were not significantly different between the groups. There were no adverse effects attributable to IGF-I 1I' I2 in either the IGF-I or the placebo group. The agent was associated with a significant reduction (33%) in the incidence of postoperative renal dysfunction. The creatinine clearance rates in the study subjects are shown in the Figure. Our findings suggest that IGF-I
given after surgery can reduce the incidence of renal dysfunction in patients at risk of having acute renal failure. 12
GROWTH HORMONE~ INSULIN-LIKE GROWTH FACTOR |~ AND CHRONIC RENAL FAILURE One reason for using growth t~ctors in end-stage chronic renal failure is to reverse the catabolic state that accompanies this condition. GH has been administered to adults with chronic renal failure who were undergoing hemodialysis and has been shown to reduce the generation of urea and to increase the efficiency of dieta W protein use. The administration of GH resulted in increased levels of circulating IGF-I, and the actions of GH in this setting are thought to be mediated by IGF.I.la, 14 Patients with chronic renal ~tilure are not GH deficient; therefore the anabotic effect of GH and IGF-I in this setting reflects a pharmacologic action. The potential therapeutic use of IGF-I to increase kidney function in the setting of chronic renal failure is suggested by clinical and experimental observations of the actions of GH on the kidney, is In short, GH deficiency in both human beings and animals is associated with a re-
THE jOURNAL OF PEDIATRICS Volume 13 I, Number I, Part 2 duction in kidney size, glomezailar filtration rate, and renal plasma flow, and G H excess is associated with an increase in kidney size, glomerular filtration rate, and renal plasma flow. The actions of G H in increasing kidney size, glomerular filtration rate, and renal plasma flow are mediated not by G H directly but, rather, through I G F - I . One mechanism by which I G F - I exerts these actions is rapid alterations of glomerular hemodynamics. Infusion of I G F - I in rats decreases renal glomerular afferent and efferent arteriolar resistances and increases the glomerular ultrafiltration coefficient. 2 Because of the ability of G H and I G F - I to increase the glomerular filtration rate, the potential therapeutic use of these agents in the setting of chronic renal failure has been suggested. 15 However, the results of early investigations into their utility were disappointing. For example, Haffner et al. 13 found that G H had no effect on the glomerular filtration rates in seven patients with chronic renal insufficiency, even though it was anabolic and the identical dosage increased the glomerular filtration rates in subjects with normal renal function. The administration of G H to children with chronic renal insufficiency and growth failure has been found to have no significant effect on renal function despite its ability to increase somatic growth. 1 It has been suggested, on the basis of the evidence from these studies, that the uremic state is one of relative renal resistance to the actions of G H and IGF_I.2, 15 To address the question of whether human beings with reduced kidney function are responsive to the renal effects of IGF-I, we administered I G F - I to patients whose baseline inulin clearance rates
HAMMERMANAND MILLER
were so low that dialysis was contemplated, and then evaluated its effects on inulin andp-aminohippurate clearance rates. We showed that I G F - I increases the glomerular filtration rate and renal plasma flow in these patients with end-stage renal insufficiency to the extent that the rates achieved are higher than those generally achieved with hemodialysis. 11, 16 In addition, I G F - I reduced the symptoms of uremia when it was administered for a 2q-day period. 16 O u r studies suggest that renal functional reserve remains even with severe loss of renal function and that the potential exists to increase the glomerular filtration rate by medical means. A double-blind, placebo-controlled trial of I G F - I in the setting of end-stage chronic renal failure to determine whether IGF-I can delay the need for dialysis is clearly required.
7.
8.
9.
10.
11.
We ac/cnowledyet/ve adminfJtratfve aas&tance of Lynn Wesselmann.
12.
REFERENCES
13.
1. Fine RN. Stimulating growth in uremic children. Kidney Int 1992;42:188-97. 2. Hammerman MR, Miller SB. Therapeutic use of growth factors in renal failure. O Am Soc Nephrol 1994;5:1-1i. 3. TobackFG. Regeneration after acute tubular necrosis. Kidney Int 1992;41:226-46. 4. Hammerman MR, Miller SB. The grmvth hormone/insulin-like growth factor axis in kidney revisited. Am J Physiol 1993;265: Fl-14. 5. Miller SB, Martin DR, Kissane J, Hammerman MR. Insulin-like growth factor I accelerates recovery from ischemic acute tubular necrosis in the rat. Proc Natl Acad Sci U S A 1992;89:11876-80. 6. Ding H, Kopple JD, Cohen A, Hischberg R. Recombinant human insulin-likegrowth factor-I accelerates recovery and reduces
catabolism in rats with ischemic acute renal failure, d Clin Invest 1995;91:2281-7. Padanilam BJ, Martin DR, Hammerman MR. Insulin-like growth factor I-enhanced renal expression of osteopontin after acute ischemic injury in rats. Endocrinology t996; 137:2133-40. Goes N, Urmson J, Vineet D, Rasassar V, Halloran PF. Effect of recombinant human insulin-like growth factor 1 on the inflammatory response to acute renal injury. J Am Soc Nephrol 1996;7:710-20. Allen BT, Anderson CB, Rubin BG, Flye MW, Baumann DS, Sicard GA. Preservation of renal function in juxtarenal and suprarenal abdominal aortic aneurysm repair. J Vase Surg 1995;17:948-59. Miller SB, Martin DR, tGssane J, Hammerman MR. Rat models for the clinicaluse of insulin-likegrowth factor I in acute renal failure. Am a Physiol: Renal, Fluid and Electrolyte Physiolo~ 1994;266:F949-56. Miller SB, Moulton M, O'Shea M, Hammerman MR. Effects of IGF-I on renal function in end-stage chronic renal failure. Kidney Int 1994;46:201-7. Franklin SC, Moulton M, Sicard G, Hammerman MR, Miller SB. Insulin-like growth factor I preserves renal function postoperatively. Am J Physiol 1997;272: 257-9. Haffner D, Zacharewicz S, Mehls O, Heinrich U, Ritz E. The acute effect of growth hormone on GFR is obliterated in chronic renal failure. Clin Nephrol 1989;
32:266-9. 14. Ziegler TR, Lazarus JM, Young LS, Ha!dn R, Wilmore DW. Effects of recombinant human growth hormone in adults receiving maintenance hemodialysis. J Am Soc Nephrol 1991;2:1130-5. 15. O'Shea MH, bayish DT. Growth ho~xnone and the kidney: a case presentation and review of the literature. J Am Soc Nephrol 1992;5:157-61. 16. Franklin SC, Moulton M, Hammerman MR, Miller SB. Sustained improvement of renal function and amelioration of symptoms in patiems with chronic renal failure (CRF) treated with insulin-likegrowth factor I (IGF-I). J Am Soc Nephrol 1995;6: 387.
SI9