`The growth hormone–insulin-like growth factor axis in kidney re-revisited

Marc R. Hammerman

George M. O'Brien Kidney and Urological Diseases Center, Renal Division, Department of Internal Medicine and Cell Biology and Physiology, Washington University School of Medicine, St Louis, MO, USA

Correspondence and offprint requests to: Marc R. Hammerman, MD, Renal Division Box 8126, Department of Internal Medicine, Washington University School of Medicine, 660 South Euclid Ave, St Louis, MO 63110, USA.

Keywords: acute renal failure; chronic renal failure; growth hormone; insulin-like growth factor I; metanephros; transplantation

Introduction

We published comprehensive reviews on the renal growth hormone (GH)–insulin-like growth factor (IGF) axis in 1989 [1] and 1993 [2]. These reviews summarized what was known concerning the synthesis of IGF I, and IGF-binding proteins in kidney, and the roles of GH and IGF I as regulators of renal development, growth and function. During the years since 1993, a good deal of additional information about the GH–IGF I axis in kidney has been provided by a number of laboratories. Much of this work has been catalogued and discussed elsewhere [36].

New insights have been gained into the role that IGF I plays in renal organogenesis [7,8], and relating to novel uses for IGF I to promote kidney development. Several clinical studies have tested the efficacy of IGF I in humans as a therapy to prevent the development of acute renal failure (ARF) in susceptible individuals [9], to accelerate recovery from established ARF [10] and to enhance kidney function in the setting of end-stage renal disease (ESRD) [1115]. The purpose of this review is to summarize these findings of potential clinical relevance, and to speculate regarding their significance in terms of the therapeutic potential for IGF I in kidney disease.

IGF I and kidney development

Metanephric organ culture
The identities of agents that control and regulate the post-inductive growth and differentiation of the metanephros and that determine nephron number are incompletely delineated [16,17]. However, studies from many laboratories provide strong evidence for the participation of a number of growth factors of renal origin in the process of metanephric growth [18]. Most of this evidence originates from studies of metanephroi grown in organ culture. The process of nephron segment growth and differentiation that occurs in metanephric organ culture recapitulates closely that which occurs in vivo. One exception is that vascularization of the nephron does not take place in the organ culture system because the origin of much of the renal vasculature is extra-metanephric [16,18].

Sufficient quantities of growth factors are produced within the growing metanephros in vitro such that it develops in serum-free chemically defined medium [7]. We have shown that IGFs I and II are produced by cultured metanephroi and released into the medium used to support them [7].

IGF I of metanephric origin enhances kidney development in vitro because blocking its expression with specific antibodies prevents growth and development in vitro [7]. Blocking the action of IGF I by incubating metanephroi with antisense oligonucleotides that block expression of the IGF I receptor also inhibits kidney development in vitro [8].

IGF I-/- transgenic mice

In view of the requirements of IGF I for growth of metanephroi in vitro, it is somewhat surprising that no abnormalities in kidney development are reported in transgenic mice that do not express IGF I [19] or other growth factors shown to be important in vitro [20]. Several possible explanations exist for the discrepancies between the studies that utilize metanephric organ culture and those that utilize transgenic mice. One explanation is that redundancies among growth factors may exist in terms of the role they play in kidney development. The absence of one growth factor might be compensated for by another growth factor present in the renal vasculature or peripheral circulation in vivo, but not in vitro, where this is no renal vasculature or peripheral circulation [20]. A second explanation is that abnormalities in kidney development are present in growth factor-deficient mice, but of a nature sufficiently subtle such that they do not result in overt renal disease. We have generated data to suggest that the latter may be the case in mice lacking IGF I.

Mice with an inactive IGF I gene were generated by homologous recombination in embryonic stem cells by Powell-Braxton et al. (Genentech Inc., South San Francisco, CA). Heterozygous mice are healthy and fertile, but are 10–20% smaller than wild-type littermates. At birth, homozygous mutant mice (IGF I-/-) are <60% of the body weight of IGF I+/+ littermates. Approximately 95% of IGF I-/- pups die perinatally. However, 5% of IGF I-/- mice survive beyond birth for up to 4 months [21]. These animals are ~28% of the weight of their wild-type siblings at 10–11 weeks of age. Kidney weights are also proportionately smaller in IGF I-/- mice such that the ratios of kidney weight to body weight at birth are similar [21,22].

Figure 1Go shows representative sections stained with haematoxylin and eosin of kidneys originating from IGF I-/- and IGF I+/+ mice that survived past birth (age 10–11 weeks). It illustrates that both glomeruli and proximal tubules have normal morphologies in kidneys from IGF I-/- mice although glomeruli appear to be smaller than in IGF I+/+ littermates. In fact, they are smaller [22]. In addition, the mean number of glomeruli per section of kidney originating from IGF I-/- mice is ~20% less than the mean number per section of kidney originating from IGF I+/+ mice. This is consistent with a subtle abnormality of nephrogenesis in the absence of IGF I, perhaps in that component that occurs following birth in rodents [22].



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Fig. 1. A representative section of renal cortices stained with haematoxylin and eosin obtained from IGF I+/+ wild-type (WT) or IGF I-/- `knockout' (KO) mice 10–11 weeks following birth. Reproduced with permission [22] Wiley-Liss InCo.

 
IGF I and metanephric transplantation

Recently, we have shown that is possible to transplant metanephroi from an embryonic rat into the omentum of an outbred adult rat host without using immunosuppression. Under similar conditions, developed kidneys transplanted from rat to rat are rejected [23]. At 4–10 weeks post-implantation, metanephroi are enlarged, have become vascularized from arteries originating from the host's omentum, and have formed mature tubules and glomeruli. Ureters of metanephroi transplanted into the omentum can be anastomosed to hosts' ureters (Figure 2Go). Four weeks following ureteroureterostomy, and immediately after removal of all host native renal mass, inulin clearances can be demonstrated in transplanted developed metanephroi [23].



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Fig. 2. Photographs of rat ureters (A) or a metanephros implanted in a unilaterally nephrectomized rat (B and C), 6 weeks (A) or 10 weeks (B and C) post-transplantation into the omentum of host rats and photomicrographs of haematoxylin and eosin-stained sections of a metanephros 10 weeks post-transplantation (D and E). Anastomosis is shown (arrow, A and C) between the host ureter and the ureter from implanted metanephros (m). An artery originating from the omentum (a) is shown (C). Glomerulus (g), proximal tubule (p), brush border (arrowhead), distal tubule (d) and collecting duct (cd) are shown (D and E). Magnifications are shown for (A), (B) and (C) and for (D) and (E). Reproduced with permission [23].

 
To provide insight into the potential utility of IGF I as a growth/function-promoting agent for transplanted metanephroi, we administered IGF I to rat hosts in which metanephroi had been transplanted. The administration of IGF I in this manner significantly increased inulin clearances in transplanted metanephroi [22].

IGF I and acute renal failure

The kidney is one of the best oxygenated organs in the human body. However, the bulk of this blood supply is delivered to the cortex. The poorly oxygenated medulla, a property of all mammalian kidneys, is a `tradeoff' for the efficient urinary concentrating mechanism provided by the loop of Henle and countercurrent exchanger. Medullary hypoxaemia renders the kidney disproportionately vulnerable to ischaemic injury. Such vulnerability may be considered as a `tradeoff' for the kidney's ability to conserve free water [24].

A coordinated homeostatic mechanism is present within the kidney to allow an efficient urinary concentrating mechanism and to reduce the risk of medullary injury during hypoperfusion. This can be accomplished by increasing medullary blood flow or decreasing transport work in order to preserve oxygen sufficiency [24]. However, homeostasis can be rendered insufficient by excessive blood loss or dehydration or by exposure to renal toxins. The development of ARF would result in death or chronic renal insufficiency if the vulnerable parts of the kidney were incapable of regeneration. However, ARF is usually reversible provided that fluid and electrolyte balance can be maintained until renal repair takes place [5].

The rat has provided a useful experimental model for ARF in humans [5]. Ischaemic renal injury in the rat results in damage to the most distal (S3) segment of the proximal tubule, which is vulnerable to hypoxaemia for the reasons detailed above. Recovery is dependent on the ability of the tubular cells to regenerate and reline the damaged areas along the nephron [5,24].

The rationale for the use of exogenous IGF I as a therapeutic agent in ARF is provided by observations in animal models indicating that IGF I mediates renal self-repair: (i) the proximal tubule cell has receptors for and is responsive to IGF I [1,2,5]; and (ii) IGF I, normally expressed in the renal collecting duct [1], is transiently expressed in regenerating proximal tubule cells beginning 2–3 days following acute renal injury in rats [25,26].

We have shown that IGF I administered prior to acute ischaemic injury to rats, immediately following acute ischaemic injury or 24 h after injury accelerates the recovery of normal renal function and the regeneration of damaged proximal tubular epithelium, and reduces mortality [5,27,28]. Similar findings were reported by many others using animal models of ischaemic and toxic injury [2934]. Several explanations for the effectiveness of IGF I when administered following ischaemic renal injury in rats have been proposed.

First, IGF I increases the glomerular filtration rate via a direct action on the glomerular vasculature. In rats, infusion of IGF I decreases renal glomerular afferent and efferent arteriolar resistances and increases the glomerular ultrafiltration coefficient [3,35]. The action of IGF I in dilating pre-glomerular vessels is probably mediated via local production of nitric oxide and vasodilatory prostaglandins, since, in blood-perfused rat juxtamedullary nephron preparations: (i) IGF I induces a rapid increase of nitric oxide concentration in intact renal microvessels; (ii) the vasodilatory action of IGF I is abrogated by nitric oxide synthase inhibitors; and (iii) IGF I-induced vasodilation is inhibited by indomethacin [36]. Enhancement of the glomerular filtration rate (GFR) by IGF I could alter the course of ARF, possibly by limiting the extent of injury due to obstruction of tubules by cellular debris.

Second, IGF I reduces protein breakdown and exerts a generalized anabolic action [37]. This action attenuates weight loss in the setting of the catabolism that accompanies acute ischaemic injury in the rat [28,29].

Third, although IGF I has little or no mitogenic action on cells in the proximal tubule, when administered to normal adult rats [38], it enhances DNA synthesis in regenerating proximal tubule cells following ischaemia/reperfusion injury [39].

The successful use of IGF I in rats has led to clinical trials in humans. We showed that IGF I administered post-operatively to patients undergoing surgery during which blood flow to the kidneys is interrupted is well tolerated, and eliminates the fall in GFR that occurs in placebo-treated subjects [9] (Figure 3Go). The incidence of ARF in our study population was too low to permit any conclusions regarding an action of IGF I in ameliorating the course of post-operative ARF. However, IGF I was well tolerated and significantly enhanced GFRs post-operatively.



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Fig. 3. Creatinine clearances in patients who received IGF I or placebo post-operatively. Data are expressed as a percentage of baseline creatine clearance (100)±SE. *IGF I>placebo, P<0.05, Student's t-test. Reproduced with permission [9].

 
A second clinical trial conducted to test the efficacy of IGF I in established ARF was terminated after an interim analysis demonstrated no beneficial effect. It was suggested that the severity of systemic illness, heterogeneity of causes for ARF (surgery, trauma, hypertension, sepsis or drugs) or a delay in starting IGF I after the onset of ARF might have contributed to the negative outcome [10].

The explanation for the effectiveness of IGF I when administered prior to the induction of ischaemic injury in rats (IGF I pre-treatment) [28] is less clear than for its effectiveness following injury. IGF I pre-treated rats do not manifest elevated GFRs or renal plasma flow, increased body weights or increased DNA synthesis in the renal cortex compared with vehicle-pretreated animals [38]. Therefore, a difference in one or more of these parameters that precedes induction of acute renal injury cannot explain the action of IGF I pre-treatment in accelerating recovery. The explanation for the efficacy of IGF I administered prior to the induction of acute renal injury could reflect an action to `pre-condition' the kidney.

The so-called `pre-conditioning effect' in rat myocardium is the protection afforded by a short period of ischaemia prior to a more sustained period. The molecular basis for myocardial pre-conditioning is undefined [40]. However, it is proposed that a short period of ischaemia protects the myocardium by `pre-activating' genes that are important in protecting it from ischaemic injury [40]. Like the heart, the kidney can be protected from ischaemia by a prior ischaemic episode. Rats that are at the height of ARF following ischaemic injury are relatively resistant to subsequent ischaemic insults [41].

No `pre-activated' gene that protects the ischaemic kidney from subsequent injury has been identified definitively. However, one gene, the expression of which is enhanced in kidney at the site of tubular regeneration, following the peak of renal dysfunction, is IGF I [2528]. If IGF I were protective for the kidney, one might expect that its administration to rats prior to ischaemic injury could substitute for its renal `pre-activation' and ameliorate the subsequent injury.

We have demonstrated a more rapid and more intense activation of the osteopontin gene in kidneys from IGF I pre-treated rats subsequently rendered ischaemic. Osteopontin is a protein with a myriad of actions in renal and in other cellular systems, many of which are thought to regulate tissue repair. Its expression is markedly enhanced in rat kidney following acute ischaemic injury [38]. IGF I pre-treatment has no effect on osteopontin expression in rats not rendered ischaemic. Rather, IGF I pre-treatment accelerates the onset [38] and increases the extent (Figure 4Go) of renal osteopontin expression only in kidneys from rats in which ischaemia is induced [38].



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Fig. 4. Northern assay for osteopontin mRNA. Levels of osteopontin mRNA extracted from kidneys originating from sham-operated rats or rats rendered ischaemic (ARF) 24 h previously. Rats were pre-treated with vehicle or with IGF I. Shown is a representative autoradiogram of a Northern blot. The size of the RNA species (1.5 kb) is shown.

 
The significance of increased osteopontin expression in the setting of acute renal injury and its enhancement by IGF I pre-treatment has yet to be completely defined. However, a protective role for osteopontin has been suggested by recent observations. Mice with a targeted mutation of the osteopontin gene manifest augmented expression of inducible nitric oxide synthase and prevalence of potentially toxic nitrotyrosine residues relative to wild-type counterparts post-ischaemia, and do not recover normally from ischaemic renal injury [42].

IGF I, ischaemia and compensatory renal growth

Compensatory renal growth after reduction of renal mass involves mainly hypertrophy, although, in younger animals or in animals with extreme reductions of renal mass, hyperplasia also contributes [43]. The identity of the stimulus for compensatory renal growth, probably humoral, remains unknown [42,43]. It does not appear to be IGF I because levels of circulating IGF I do not increase following unilateral nephrectomy of rats, and the Bmax and KD values for IGF I binding to glomerular or proximal tubule membranes do not change [44]. Furthermore, levels of IGF I extractable from remaining kidneys and IGF I mRNA in remaining kidneys are not increased following unilateral nephrectomy in adult rats [45] prior to the time when the renal growth response is well underway [43].

In contrast to reduction in renal mass, ischaemia appears to be a stimulus to enhance renal IGF I expression. This is illustrated in Figure 5Go which shows levels of IGF I mRNA extracted 3 days after surgery from left kidneys of rats that underwent: (i) right unilateral nephrectomy, (ii) sham surgery; (iii) right unilateral nephrectomy and partial contralateral renal infarction induced by permanent ligation of one-half of the renal arterial blood supply; or (iv) partial left kidney infarction only; or from right kidneys of rats after partial infarction of left kidneys. Levels of IGF I mRNA do not correlate with the extent in reduction of renal mass, but rather with the presence of ischaemia induced by arterial ligation [45]. Levels of IGF I protein extractable from partially infarcted kidneys are also increased [45]. The increases in renal IGF I expression observed following renal infarction may be stimulated by the same factors that enhance local IGF I expression after ischaemia/reperfusion injury [25,26].



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Fig. 5. Levels of IGF I mRNA extracted 3 days after surgery from the left kidneys of rats that underwent left unilateral nephrectomy (UNX), sham surgery, left unilateral nephrectomy and partial contralateral renal infarction (11/2 NX), partial left renal infarction (1/2 NX), or from contralateral right kidneys of rats after 1/2 NX (contra). Top: autoradiography of a solution hybridization, nuclease protection experiment using total RNA extracted from liver or kidneys. Bottom: ethidium bromide-stained agarose–formaldehyde gel. Reproduced with permission [45].

 
If IGF I is not the stimulus for compensatory renal growth, one would expect that the effects of reduction of renal mass and administration of IGF I would be additive. In fact, this is the case. The administration of high dose (2.2 mg/kg body weight/day), but not low dose (0.9 mg/kg body weight/day), IGF I for 7 days to young male rats that underwent unilateral nephrectomy and partial contralateral renal infarction 16 days previously increases renal weights [46]. In young female rats, unilateral nephrectomy and partial contralateral renal infarction is mitogenic for the proximal tubule. The administration of IGF I (4 mg/kg body weight/day for 4 days) to these young rats, further increases the number of mitoses/mm2 in proximal tubules [47].

GH, IGF I and chronic renal failure

One rationale for the use of growth factors 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 undergoing dialysis and was shown to reduce urea generation and improve the efficiency of dietary protein utilization in these individuals [4850]. GH administration results in increased circulating IGF I, and the actions of GH in this setting are thought to be mediated via IGF I [4850]. Patients with chronic renal failure are not GH deficient. Therefore, the anabolic effect of GH/IGF I in this setting represents a pharmacological action.

The potential for the use of IGF I as a therapeutic agent to enhance kidney function in the setting of chronic renal failure is based upon clinical and experimental observations relating to actions of GH on the kidney [51]. In short, conditions of GH deficiency in man and in experimental animals are associated with a reduction of kidney size, GFR and renal plasma flow, and conditions of GH excess are associated with an increase in kidney size and enhancement of GFR and renal plasma flow.

The actions of GH in increasing kidney size and enhancing GFR and renal plasma flow are not mediated by GH directly, but rather through IGF I. One mechanism by which IGF I exerts these actions is via rapid alterations of glomerular haemodynamics (see above). It is of interest that although IGF I dilates pre-glomerular vessels, renal autoregulatory capacity is not reduced by the growth factor [36]. The preserved renal autoregulatory capacity is an important consideration relating to the safety of IGF I administration in ARF and in ESRD.

Given their abilities to increase the GFR, the potential use of either GH or IGF I as therapeutic agents in the setting of ESRD was suggested decades ago [51]. However, the definitive testing of their efficacy required the development and availability of recombinant preparations. Early investigations into their utility were disappointing. For example, Haffner et al. found that GH had no effect on glomerular filtration rates in seven patients with chronic renal insufficiency even though it was anabolic and the identical dosage increased the GFRs of individuals with normal renal function [49]. The administration of GH to children with chronic renal insufficiency and growth failure has been found to have no significant effect on renal function despite its beneficial action in enhancing somatic growth [52]. It was suggested, on the basis of the evidence detailed above, that the uraemic state is one of relative renal resistance to the actions of GH [2,49].

The literature relating to IGF I resistance in uraemia recently has been reviewed [6]. Resistance was first suggested by the observation that IGF I bioactivity in the serum of patients with ESRD is less than that predicted by IGF I immunoactivity. It was shown subsequently that the actions of IGF I in lowering levels of amino acids, insulin and C-peptide are blunted in patients receiving haemodialysis or peritoneal dialysis compared with controls [6]. The actions of IGF I in stimulating protein synthesis and inhibiting protein degradation in skeletal muscle isolated from rats with reduced functional renal mass is reduced compared with its action in muscle from control rats, consistent with IGF I resistance in this experimental model of ESRD [6]. Relating to the effects of GH and IGF I on GFRs, the increases of inulin clearance that follow the administration of either GH or IGF I to normal rats are not observed following administration of the same doses of peptides to rats with reduced renal function [53].

To address the question directly as to whether humans with ESRD are responsive to the renal effects of IGF I, we administered IGF I to individuals whose baseline inulin clearances were at a level such that dialysis was contemplated, and evaluated its effects on inulin and p-aminohippurate (PAH) clearances. IGF I administered by subcutaneous injection (100 µg/kg, b.i.d.) increases both when administered to individuals with ESRD over a 4 day period. However, at this dose level, patients become refractory to its action within 1–2 weeks and the incidence of serious side effects is high [12].

We assessed the use of a lower IGF I dose to reduce side effects, and intermittent administration to eliminate refractoriness. To this end, patients with ESRD (inulin clearances 5.6–15.4 ml/min/1.73 m2) were enrolled in an open-label 24-day trial or a 31-day double-blinded, placebo-controlled, randomized trial. Patients received subcutaneous IGF I, 50 µg/kg/day, or vehicle, on an intermittent schedule of 4 days on drug followed by 3 days off drug.

Treatment with IGF I resulted in significantly increased GFRs during the third and fourth weeks of therapy in both open-label and double-blind studies. Vehicle had no effect. No patient required discontinuation of drug secondary to side effects. Several patients studied prospectively remained off dialysis for 4–18 months after beginning IGF I. Our study shows that IGF I effects sustained improvement of renal function in patients with ESRD, and is well tolerated. Clearances in patients receiving IGF I are comparable with those generally achieved by dialysis [13].

Shown in Figure 6Go are the results of our double-blinded, placebo-controlled, randomized trial. Inulin clearances in patients who received IGF I were significantly higher than those who received placebo on days 17, 28 and 31 of the study. IGF I or placebo was stopped after 31 days, and inulin clearances were measured after 14 days off therapy. At that time (day 45), clearances of patients who received IGF I remained significantly elevated compared with clearances of patient who received placebo. Since the effects of IGF I on glomerular haemodynamics would be expected to have dissipated within 14 days after cessation of therapy, this observation suggests that the action of IGF I in enhancing inulin clearance may reflect IGF I-induced renal hypertrophy [1,2] in addition to changes in glomerular perfusion [35].



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Fig. 6. Inulin clearances over time in patients receiving IGF I or placebo. Reproduced with permission [13].

 
Summary and conclusions

The use of renal allotransplantation to treat ESRD in the US is limited by lack of organ availability [54]. A possible solution is the transplantation of developing kidneys (metanephric allograft or xenografts). We have conducted studies that demonstrate the feasibility of such a strategy [23] and have shown that IGF I may be useful to accelerate the growth and development of these transplanted organs. The rationale for the use of IGF I in this setting grew from a basic understanding of the role that the growth factor plays in kidney development.

ARF in humans is the most costly kidney-related disease requiring hospitalization. Its incidence is increasing. Despite many advances in dialytic therapy, the mortality rate for patients with ARF has not changed in the last several decades. Strategies for treatment of ARF are directed toward supportive care to permit renal regeneration to occur. There exists a need for new therapeutic approaches that can speed recovery and reduce mortality [5]. Although IGF I may not prove to be the `magic bullet' for ARF, its proposal and testing as a potential therapeutic agent has provided a paradigm for the development of treatment modalities to accelerate renal regeneration based upon a basic understanding of the injury/repair process. The basis for development of a `growth factor' therapy for ARF will probably evolve, at least in part, out of the testing and use of IGF I in rat models and in humans.

The use of GH to treat ESRD was proposed shortly after its isolation and the demonstration of its action in increasing the rate of glomerular filtration. Later, it was discovered that the actions of GH on kidney are mediated by IGF I, and the means by which IGF I enhances glomerular filtration was elucidated [1,2]. We have shown that humans with ESRD are not resistant to the actions of IGF I in enhancing the GFR, establishing the potential for use of IGF I as a pharmacological agent for ESRD. There is no effective drug therapy to enhance renal function in ESRD. Although much work remains to be done, and clearly caution is advised, our observations establish the potential for the use of IGF I as a therapeutic agent in this setting and justify continued study of IGF I as a medical therapy to delay the need for dialysis.

Acknowledgments

We are grateful for useful collaborations with Dr David Basile, Ms Nancy Hammerman, Mr Daniel Martin, Dr Steven Miller, Ms Sharon Rogers and Dr Babu Padanilam (Washington University) and Dr Lyn Powell-Braxton (Genentech Inc.). M.R.H. was supported by NIH grants DK-27600, DK-42958, DK-45181, DK20579, DK 53497 and RR-00036, by the D. D. Dunlop Kidney Grant Fund from the Fraternal Order of Eagles, Kennett MO, and by Genentech Inc. (S. San Francisco, CA) and the Bayer Corporation (Berkeley, CA).

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