EDITORIAL COMMENT

Insulin-like growth factor I treatment for end-stage renal diseaseat the end of the millenniumMarc R. Hammerman

George M. O'Brien Kidney and Urological Disease Center, Renal Division,Departments of Medicine, and Cell Biology and Physiology, Washington UniversitySchool of Medicine, St. Louis Missouri, USA

Correspondence to Marc R. Hammerman, MD, Renal Division, Box 8126,Department of Medicine, Washington University School of Medicine, 660 S. EuclidAve., St. Louis, MO 63110, USA Tel: +1 314 362 8233; fax: +1 314 362 8237;e-mail: mhammerm@imgate.wustl.edu

Current Opinion in Nephrology and Hypertension 2000, 9:000±000

# 2000 Lippincott Williams & Wilkins1062-4821

In 1921, Evans and Long [1] demonstrated that thebovine anterior pituitary gland contains a substance thatpromotes the growth of rats. In 1945, Li et al. [2] ®rstisolated the growth hormone from ox pituitaries.

Within 4 years of its isolation, White et al. [3] reportedthat the administration of growth hormone to hypophy-sectomized dogs increased depressed p-aminohippurate(PAH) and inulin clearances to normal levels or above,and that its administration to normal dogs raised normalclearances twofold. The potential for the use of growthhormone as a pharmacologic agent for the kidney wasnot lost on these investigators. They concluded that`The enhancing effect of growth hormone on renalfunction may ®nd some therapeutic application'.

The observations of White et al. [3] were made at atime when it was thought that all growth hormoneeffects were mediated via a direct action on targettissues. It was discovered almost a decade later [4] thatmost of its growth-promoting actions are mediatedindirectly, via growth hormone stimulating the synthesisof insulin-like growth factor (IGF)-I [5] in the liver andelsewhere [6].

Forty years after the initial observations of White et al., itwas shown [7] that the actions of human growthhormone to enhance rates of glomerular ®ltration inindividuals with normal renal function (inulin clearance120 ml/min per 1.73 m2) could not be recapitulated inpatients with reduced renal function (inulin clearance21 ml/min per 1.73 m2). The effects of growth hormoneon PAH and inulin clearances in rats with normal renalfunction, however, could be reproduced by substitutingIGF-I [8]. Furthermore, normal rates of glomerular

®ltration in humans could be rendered supernormal byadministration of IGF-I [9].

The mechanisms by which IGF-I rapidly enhancesglomerular ®ltration were elucidated in rats [10 ± 12].IGF I decreases the renal glomerular afferent andefferent arteriolar resistances and increases the glomer-ular ultra®ltration coef®cient without changing theglomerular capillary pressure. Therefore IGF-I increasesrates of glomerular ®ltration without inducing hyper®l-tration [13]. In addition, although IGF I dilatespreglomerular vessels, renal autoregulatory capacity isnot reduced by the growth factor [12]. The preservedrenal autoregulatory capacity and absence of hyper®ltra-tion are important considerations regarding the safety oflong-term IGF-I administration in humans.

We ®rst reported in 1993 [14] that, unlike the case forgrowth hormone [7], humans with moderately reducedrenal function (inulin clearances between 22 and 55 ml/min per 1.73 m2) are not resistant to the action of IGF-Ito enhance rates of glomerular ®ltration. A year later, wedemonstrated [15] that IGF-I (100 mg/kg twice per day)increases both inulin and PAH clearances when admi-nistered for 4 days by subcutaneous injection inindividuals whose inulin clearances are at levels suchthat dialysis is contemplated (10.6+2.5 ml/min per1.73 m2). At this dose level, however, patients becomerefractory to its action within 1 ± 2 weeks of initiatingtherapy, and the incidence of serious side effects isunacceptably high.

As reviewed by Vijayan et al. in this issue (pp. 000 ± 000),we subsequently assessed the use of a lower IGF-I dose(50 mg/kg once per day) to reduce side effects, andintermittent administration (4 days per week) toeliminate refractoriness [16]. When administered in thismanner to individuals with end-stage renal disease(ESRD) for whom the initiation of dialysis wascontemplated, IGF-I effected a progressive improve-ment of renal function over a period of 1 month. Patientsreported an amelioration of symptoms associated withuremia, such as nausea and weakness, after beginningIGF-I therapy, and the growth factor was well tolerated.Inulin clearances in patients receiving IGF-I for 1 monthwere increased to about 150% of baseline, and werecomparable to those generally achieved by dialysis [16].

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Recently, Vijayan et al. [17] reported on the use of IGF-Iin lieu of hemodialysis in order to enhance inulinclearances in a patient with ESRD for whom peritonealdialysis had to be temporarily interrupted. The patientremained on IGF-I therapy and off all dialysis for 19weeks. Her baseline inulin clearance was 5.7 ml/min per1.73 m2. It reached levels as high as 10 ml/min per1.73 m2 while she was receiving IGF-I.

Although renal function was not restored to normal byIGF-I, the increases in inulin clearance in IGF-I-treatedpatients occurred over an important range [16]. Theclearances before beginning IGF-I therapy in individualswith ESRD participating in our study were very low(5.0 ± 15.4 ml/min per 1.73 m2). By the time IGF-Itherapy was stopped, approximately 1 month later,clearances had increased such that they were comparableor higher than those generally achieved by any means ofstandard chronic dialytic therapy. An additional theoreticbene®t of IGF-I therapy over dialysis in the setting ofESRD is the more effective removal of `middlemolecules' that would be expected to result fromclearance via the patients' native kidneys comparedwith hemodialysis membranes [16].

White et al. [3] could not have known that the actions ofgrowth hormone to enhance rates of glomerular ®ltrationwere mediated by IGF-I. Fifty years after its ®rstdescription [3], however, the enhancing effect of growthhormone on renal function may indeed `®nd sometherapeutic application' in the administration of IGF-I[16,17].

As pointed out by Vijayan et al. (pp. 000 ± 000), the use ofIGF-I in humans is not without risk, including that ofmalignancy [18,19]. Although any risk of cancer is ofconcern, such a risk in patients with ESRD must beweighed against the fact that the mortality during the®rst year of dialytic treatment for ESRD is approximately25% and the expected remaining lifetimes for patientswho develop ESRD are much shorter that those ofindividuals with normal renal function. For example, thelife expectancies for patients who develop ESRDbetween ages 45 and 54 years and 55 and 64 years are6.9 and 5.3 years, respectively [20].

No ®rm conclusions can be made on the basis of thesmall number of patients to whom we have administeredIGF-I. Given a choice between hemodialysis, peritonealdialysis, or four injections per week of IGF-I, however,our experience is that most patients would choose thelatter. Our anecdotal experience includes not only thepatient described above, who was maintained on IGF-Ialone for 19 weeks while peritoneal dialysis wasinterrupted [17], but also two individuals with ESRD(baseline inulin clearances 58 ml/min per 1.73 m2)

who were maintained on IGF-I for 18 and 32 weeks untilthey received kidney transplants, and another (baselineinulin clearance 57 ml/min per 1.73 m2) whose inulinclearance doubled on IGF-I therapy. She was main-tained on IGF-I for 20 months before her symptoms ofuremia returned and hemodialysis was initiated [16].

As concluded by Vijayan et al. (pp. 000 ± 000), a double-blinded, placebo-controlled, randomized trial will berequired to determine whether IGF-I administration canenhance rates of glomerular ®ltration, and delay the needfor dialysis in patients who develop ESRD during thenext millennium.

AcknowledgementsM.R.H. was supported by grants DK45181 and DK53487 from theNational Institutes of Health and by Genentech Inc., S. San Francisco,CA, USA.

References and recommended readingReferences and recommended readingPapers of particular interest, published within the annual period of review, havebeen highlighted as:. of special interest. . of outstanding interest

1 Evans HM, Long JA. The effect of the anterior lobe administeredintraperitoneally upon growth, maturity and oestrus cycles of the rat. AnatRec 1921; 21:62±63.

2 Li CH, Evans HM, Simpson ME. Isolation and properties of the anteriorhypophyseal growth hormone. J Biol Chem 1945; 159:353±366.

3 White HL, Heinbecker P, Rolf D. Enhancing effects of growth hormone onrenal function. Am J Physiol 1949; 157:47±51.

4 Salmon WD, Daughaday WH. A hormonally controlled serum factor whichstimulates sulfate incorporation by cartilage in vitro. J Lab Clin Med 1957;49:825±836.

5 Daughaday WH. On the nomenclature of the somatomedins and insulin-likegrowth factors. Endocrinology 1987; 121:1911±1912.

6 D'Ercole AJ, Stiles AD, Underwood LE. Tissue concentrations of somato-medin C; further evidence for multiple sites of synthesis and paracrine orautocrine mechanisms of action. Proc Natl Acad Sci U S A 1984; 81:935±939.

7 Haffner D, Zacharewicz S, Mehls O, Heinrich U, Ritz E. The acute effect ofgrowth hormone on GFR is obliterated in chronic renal failure. Clin Nephrol1989; 32:266±269.

8 Miller SB, Hansen VA, Hammerman MR. Effects of growth hormone and IGFI on renal function in rats with normal and reduced renal mass. Am J Physiol1990; 259:F747±F751.

9 Guler H-P, Schmid C, Zapf J, Froesch ER. Effects of recombinant insulin-likegrowth factor I on insulin secretion and renal function in normal humansubjects. Proc Natl Acad Sci U S A 1989; 86:2868±2872.

10 Hirschberg R, Kopple J, Blantz R, Tucker B. Effects of recombinant humaninsulin-like growth factor I on glomerular dynamics in the rat. J Clin Invest1991; 83:1200±1206.

11 Hirschberg R, Adler S. Insulin-like growth factor system and the kidney:physiology, pathophysiology and therapeutic implications Am J Kidney Dis1998; 31:901±919.

12 Tonshoff B, Kaskel FJ, Moore LC. Effects of insulin-like growth factor I on therenal juxtamedullary vasculature Am J Physiol 1998; 274:F120±F128.

13 Brenner BM. Hemodynamically mediated glomerular injury and the progres-sive nature of kidney disease. Kidney Int 1983; 23:647±655.

14 O'Shea MH, Miller SB, Hammerman MR. Effects of IGF-I on renal function inpatients with chronic renal failure. Am J Physiol 1993; 264:F917±F922.

15 Miller SB, Moulton M, O'Shea M, Hammerman MR. Effects of IGF-I on renalfunction in end-stage chronic renal failure. Kidney Int 1994; 46:201±207.

Hormones, autacoids, neurotransmitters and growth factors2

16 Vijayan A, Franklin SC, Behrend T, Hammerman MR, Miller SB. Insulin-likegrowth factor I improves renal function in patients with end-stage chronicrenal failure. Am J Physiol 1999; 276:R929±R934.

17 Vijayan A, Franklin SC, Delmez JA, Miller SB. Medical therapy for end-stagerenal disease? Insulin-like growth factor I enhances renal function in a patientwith chronic renal failure on peritoneal dialysis. Am J Kidney Dis (in press).

18 Chan JM, Stampfer MJ, Giovannucci E, Gann PH, Ma J, Wilkinson P, et al.Plasma insulin-like growth factor-I and prostate cancer risk: a prospectivestudy. Science 1998; 279:563±566.

19 Hankinson SE, Willett WC, Colditz GA, Hunter DJ, Michaud DS, Deroo B, etal. Circulating concentrations of insulin-like growth factor I and the risk ofbreast cancer. Lancet 1998; 351:1393±1396.

20 Agodoa LYC, Held PJ, Port FK. U.S Renal Data System, USRDS AnnualData Report, N.I.H., N.I.D.D.K. Bethesda MD. Am J Kidney Dis 1995; 26(Suppl. 2):S95±S111.

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