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New concepts: growth hormone, insulin-like growth factor-I and the kidney
Growth Hormone & IGF Research 14 (2004) 270–276 www.elsevier.com/locate/ghir
Review
New concepts: growth hormone, insulin-like growth factor-I and the kidney Ralph Rabkin a
a,*
, Franz Schaefer
b
Veterans Affairs Palo Alto Health Care System and Department of Medicine, Stanford University, 3801 Miranda Avenue, Palo Alto, CA 94304, USA b Division of Pediatric Nephrology, Department of Pediatrics, University of Heidelberg, Germany Received 20 January 2004; accepted 4 February 2004
Abstract Both growth hormone (GH) and IGF-1 have major effects on normal kidney growth, structure and function and participate in the pathogenesis of certain kidney diseases. Furthermore when the kidneys fail there are profound changes in the circulating GHIGF-1 system and the renal and systemic responses to these hormones. In this brief review we address the advances that have been made in our understanding of the relationship between growth hormone GH and IGF-1 and the kidney in health and the systemic and local perturbations that occur in kidney disease and identify key unanswered questions. Published by Elsevier Ltd. Keywords: Somatotropin; IGF-1; Kidney; Uremia; IGF binding proteins
1. Introduction Growth hormone (GH) and insulin-like growth factor-I (IGF-I) have profound effects on kidney growth, structure and function. This has led to a large number of studies directed at advancing our understanding of the properties of these growth factors with the ultimate goal of utilizing knowledge gained for therapeutic purposes. In this article, we will briefly review the advances achieved in this area over the past few years and identify important unanswered questions. For a comprehensive overview of the literature dealing with the renal GH/ IGF-I axis and the impact of renal failure on GH and IGF-I in general, the reader is referred to several excellent reviews [1–5]. In the following, a short overview of the renal GH/IGF axis will be given before describing the latest developments in this field. The GH/IGF/IGFBP system, comprising the receptors for GH and IGF-I, IGF-I and the six major insulinlike growth factor (IGFBPs) as well as the acid-labile
*
Corresponding author. Tel.: +1-650-858-3985; fax: +1-650-8490213. E-mail address: [email protected] (R. Rabkin). 1096-6374/$ - see front matter. Published by Elsevier Ltd. doi:10.1016/j.ghir.2004.02.001
subunit (ALS) of the IGFBP-3 complex, is expressed in a complicated manner within the kidney [1,4]. This complexity reflects the structural heterogeneity of the kidney, which consists of a vascular network from which the glomeruli and peritubular vessels arise, tubules composed of epithelial cells which vary in structure and function along the nephron, and an interstitial compartment. Most but not all actions of GH are mediated through IGF-I, which is either derived from the circulation or synthesized locally. In the rat, IGF-I mRNA is expressed in the loop of Henle and possibly the collecting ducts. GH receptors are also expressed in the loop of Henle and to a lesser extent in the proximal tubule; IGF-I is only transiently expressed at this latter site after acute injury. It is notable that the thick ascending loop of Henle is the only nephron segment where IGF-I, the IGF-I receptor, the GH receptor and IGFBP-1 colocalize, suggesting that this may be a site where GH induces IGF-I expression and where IGF-I binds to its receptor, perhaps after first being trapped locally by IGFBP-1. Apart from this scenario, given the complexity and anatomical heterogeneity of the renal GH/IGF-I system and the large number of physiological and nutritional factors that regulate renal IGF-I expression, it is difficult to conceive how the different
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components of the IGF axis interact to induce their functional and structural effects.
2. Renal disposal of GH, IGF-I and the IGFBPs in health and disease The kidney is a major site of removal of low molecular weight proteins from the circulation. Following passage out of the glomerulus into the tubules, small proteins are captured by endocytosis by the proximal tubular cells, degraded in lysosomes and the constituent amino acids transported back into the circulation [6]. This is a highly efficient process and usually <1–2% of filtered protein enters the urine. However, even mild tubular injury affects the absorptive process and urinary protein excretion increases, making monitoring of urinary excretion of protein hormones an unreliable estimate of circulating hormone turnover. Hormones such as GH and IGF-I are also taken up from the renal peritubular circulation after binding to their specific receptors in basolateral tubular cell membranes, though this is quantitatively far less important than the glomerular filtration pathway and mainly serves to deliver each hormone to its site of action [6]. Growth hormone, MW 20–22 kDa, passes through the glomerular filtration barrier with relative ease (sieving coefficient 0.7), and the kidney accounts for approximately half of the total metabolic clearance rate (MCR) of the hormone. Thus, when renal function declines so does GH disposal, and serum GH levels are often elevated in advanced renal failure. The renal handling of IGF-I is more complex because >98% of circulating IGF-I is bound to IGFBPs. The formation of 45 kDa and more commonly 150 kDa IGF-IGFBP complexes restricts the passage of IGF-I through the glomerular filtration barrier, with negligible amounts of the IGFBP-3/ALS/ IGF-I ternary complex crossing the barrier in healthy individuals [1,4]. Thus, the kidney plays a minor role in removing IGF-I from the circulation. Consequently, the MCR of IGF-I in patients with advanced renal failure does not differ from that observed in normal controls [7]. However, because of the increase in circulating IGFBPs the volume of distribution of IGF-I is decreased and following the administration of IGF-I higher serum levels of IGF-I are attained. Urinary excretion of IGF-I tends to be higher in the young, in line with their higher serum levels, and excretion falls with age. In patients with acromegaly, urinary IGF-I excretion increases several fold. Normally small amounts of IGFBPs also appear in the urine with IGFBP-1, IGFBP-2 and IGFBP-3 being the predominant binding proteins present [4]. In patients with extensive damage to the glomerulus, the permeability of the glomerular filtration barrier increases and this often leads to heavy proteinuria, hypercholesterolemia, hy-
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poalbuminemia and clinical edema, features of the nephrotic syndrome. In patients with this syndrome and in animal models, filtration of the smaller IGF-IGFBP complexes increases and a larger amount of IGF-I is excreted in the urine [1,2]. Urinary excretion of IGFBP1, -2 and -3 and ALS excretion also increases. This has lead to the thesis that the increased tubular cell exposure to filtered IGF-I may contribute to the tubulointerstitial disease that develops in most heavy proteinuric states [8]. In contrast to the increase in urinary IGF-I levels, serum IGF-I levels are usually reduced in nephrotic patients. This is mainly due to the protein malnutrition caused by heavy proteinuria, with urinary IGF-I losses playing a lesser role. Circulating IGFBP levels are also perturbed in the nephrotic syndrome [1,2]. The abundance of intact IGFBP-3 and the 150 kDa ternary complex falls while immunoreactive IGFBP-3 levels rise secondary to accumulation of IGFBP-3 fragments. Reduced levels of intact IGFBP-3 may be caused in part by increased losses through the damaged glomerular filtration barrier, though it has been suggested that increased serum proteolysis of IGFBP-3 also may occur. In contrast to the reduced concentrations of IGFBP-3, serum IGFBP2 levels are increased and this may reflect a compensatory rise in hepatic production of IGFBP-2 in response to protein malnutrition. The net effect of these changes in the serum IGFBP profile is to increase the proportion of IGF-I bound to IGFBP-2, which is more readily filtered than the larger ternary IGF-I/IGFBP3/ALS complex. As might be anticipated, with remission of the nephrotic syndrome serum IGF-I and the IGFBP levels return to normal.
3. Renal actions of GH, IGF-I and the IGFBPs Growth hormone and IGF-I have profound effects on renal growth, glomerular hemodynamics and tubular function [1–4,9]. Administration of IGF-I to animals promotes renal growth through a process of cellular hypertrophy and hyperplasia, and induces a rapid increase in renal blood flow and glomerular filtration, and a reduction in renal vascular resistance. The hemodynamic effects appear to be mediated by metabolites of cyclooxygenase activity and the generation of nitrous oxide which together induce glomerular arteriolar vasodilatation, a fall in efferent and afferent arteriolar resistance, and an increase in the glomerular ultrafiltration coefficient [4]. In humans IGF-I increases renal blood flow and GFR by 25% and causes sodium retention and volume expansion [9]. Sodium retention occurs by a direct action on the renal tubules, by stimulation of renin release and by suppression of atrial natriuretic peptide secretion. IGF-I administered to GH deficient rats or to patients with GH receptor defects normalizes
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the low GFR as does GH replacement in GH deficiency. The effects of GH on kidney function are similar to those observed with IGF-I, except that the functional response to GH is delayed several days and correlates with the increase in serum IGF-I levels, indicating that the GH effects are mediated by IGF-I. GH receptors are present in the proximal tubule, a site where IGF-I mRNA is not normally expressed, suggesting that GH also may have direct actions on tubular function. More recently it has become evident that mesangial cells are an important target for IGF-I action and this is discussed later in the context of diabetes. As is true for other tissues, circulating and locally produced IGFBPs have profound effects on the delivery of IGF-I to its target cells and on its actions in the kidney, and also may exert some IGF-independent effects [3]. In general, because of the formation of high affinity IGF-I/IGFBP complexes the exposure of kidney cells to IGF-I is limited. However, individual IGFBPs may have a modulating effect on the exposure of nephron segments to IGF-I. For example, when IGF-I–IGFBP-3 complexes are infused into rodents, the amount of IGF-I localized to the glomerulus increases [10]. Interestingly, when IGF-I and IGFBP-3 are together incubated with cultured renal tubular cells there is a reduction in IGF-I receptor binding and internalization. Furthermore, IGFBP-3 alone inhibits tubular cell DNA synthesis in an IGF-I independent manner [11] and when added to growth factor deficient cells induces apoptosis [12]. IGFBP-5 also may exhibit IGF-I independent actions. IGFBP-5 is able to inhibit the migration of mesangial cells by binding to a serine kinase receptor [13] . IGFBP-1 also appears able to act in the kidney. In several conditions that cause renal hypertrophy such as compensatory renal growth, diabetes, metabolic acidosis and hypokalemia, renal IGFBP-1 expression is increased. Enhanced IGFBP-1 expression in turn may be the cause of the rise in renal IGF-I levels that occurs in these conditions without a concomitant increase in IGFI gene expression [14,15,19]. Indeed infusion of IGFBP1 into GH deficient dwarf mice stimulates renal but not body growth [16]. However, excessive levels of IGFBP-1 appear to have an adverse effect on the kidney, as transgenic mice over-expressing IGFBP-1 have a reduced number of nephrons and develop glomerulosclerosis [17,18].
4. The GH–IGF-I axis in renal disease There is a growing body of evidence implicating the GH–IGF-I axis in the pathogenesis of progressive gomerular disease. Most compelling are studies examining the potential roles of GH and IGF-I in diabetic kidney disease [8,19]. In the early stages of diabetes in humans the kidney hypertrophies, and renal blood flow and
GFR increase. Later, in patients who develop diabetic kidney disease, typical structural changes occur and there is a slow fall in GFR over time. In rats with experimental diabetes there is an early increase in renal IGF-I content during the first few days of diabetes, starting before renal hypertrophy is apparent. In most reports this rise in kidney IGF-I occurs in the absence of changes in gene expression, but is accompanied by increases in local IGFBP levels, especially IGFBP-1, and it is thought that the accumulation of IGF-I likely reflects increased trapping by IGFBPs. IGF-I appears to be synthesized and secreted by mesangial cells isolated from non-obese type 1 diabetic (NOD) mice, leading to activation of the IGF-I receptor and its signaling pathways, including those involving phosphatidinylinositol-3 kinase and ERKs [20]. The activity of matrix metalloprotein-2 released by these diabetic mesangial cells is reduced, but may be increased by blocking IGF-I or the IGF-I receptor. These same cells exhibit an upregulation of IGF-I receptor expression as do mesangial cells isolated from db/db mice [20,21]. Exposing mesangial cells to IGF-I increases cell proliferation and matrix production while inhibiting matrix degradation and blocking mesangial cell motility. Lipid accumulation is enhanced, leading to a foam cell appearance, which also contributes to impaired mesangial cell migration and phagocytic function [22,23]. Exposure to high glucose levels increases the sensitivity of mesangial cells to IGF-I possibly by decreasing mesangial cell IGFBP-2 secretion [24]. Furthermore, high glucose levels stimulate secretion of IGF-I, connective tissue growth factor, and collagen by cultured renal fibroblasts [25]. Taken together these findings support the notion that local IGF-I may participate in the development and progression of diabetic glomerular disease and possibly other forms of progressive glomerular disease. In support of this concept, administration of an IGF-I receptor antagonist inhibits early renal hypertrophy in diabetic rats, and also blocks compensatory renal growth following loss of renal mass [26]. Compensatory renal growth also may be inhibited by GH receptor blockade [27], but renal hypertrophy induced by a high protein intake is GH independent [28]. While most reports appear to implicate IGF-I as a potential mediator of pathological changes in the diabetic kidney, IGF-I also is protective against oxidative stress and apoptosis induced by high levels of glucose in cultured mesangial cells. This protection appears to be mediated by activation via the IGF-I receptor of the Akt/PKB and MAP kinase signalling pathways [29], and it has been suggested that stimulation of this survival pathways may be turned to therapeutic advantage for protection against cell death and progression of nephropathy. Another mechanism whereby IGF-I may participate in the pathogenesis of diabetic nephropathy is through
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increased tubular cell exposure to growth factor because of increased permeability of the diseased glomerulus to large proteins, including IGF-IGFBP complexes. It has been suggested that filtered IGF-I may contribute to the sodium retention and progressive tubulo-interstitial disease present in diabetic nephropathy [8]. With respect to GH there is strong evidence from animal studies that it also plays a role in the pathogenesis of diabetic nephropathy, and possibly in other progressive non-diabetic kidney diseases. For example, chronically elevated GH levels in GH transgenic mice or in dogs receiving GH therapy is associated with renal hypertrophy, glomerular hypertrophy with mesangial matrix expansion, and glomerulosclerosis. Administration of GH to diabetic rats [30] worsens the diabetic kidney disease, while treatment with a GH receptor antagonist or somatostatin analog inhibits the development of glomerular hypertrophy, hyper-filtration, and proteinuria [27,31]. Additionally, mice with targeted deficiency of the GH receptor are protected against diabetic kidney disease, which develops in heterozygous and normal controls [32]. It is noteworthy that mice over-expressing IGF-I via a transgene develop enlarged kidneys with hypertrophied glomeruli but not glomerulosclerosis, suggesting that the presence of excessive GH is required for the development of glomerulosclerosis, even though many of the actions of GH are mediated by IGF-I [4]. In an important study, Thirone et al. [33] recently showed that in diabetic rats the renal signaling response to GH is exaggerated. After treatment with GH, phosphorylation of Janus kinase 2 (JAK2), insulin receptor substrate-1 (IRS-1), Shc, ERKs and Akt was more pronounced in diabetic rats compared to normal controls. Of note, administration of a GH receptor antagonist normalized the exaggerated GH mediated signal transduction and prevented the renal hypertrophy of diabetes. Gowri et al. [34] recently explored the mechanism in diabetes accounting for the resistance to GH induced linear growth and hepatic IGF-I expression while renal sensitivity to GH is retained. They showed that GH receptor expression is reduced in the liver but enhanced in the kidney. It is conceivable that this increase in kidney GH receptor expression accounts for the enhanced GH mediated signal transduction observed by Thirone et al. [33]. With respect to clinical diabetes, the data in humans are not as convincing as in experimental animals, but results do suggest that GH may participate in the development of diabetic nephropathy. For example, in poorly controlled diabetes GH levels are elevated and the glomerular filtration rate is high, but when glycemia is tightly controlled elevated plasma GH levels normalize and glomerular hyperfiltration declines in parallel [6,19]. Moreover, administration of a somatostatin analogue to diabetic patients reduces renal hypertrophy
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and glomerular hyperfiltration in the absence of a change in glycemic control [27]. Thus, taken together with the animal studies these results provide support for a role for GH in development of diabetic nephropathy and suggest that GH receptor blockade may offer an approach to disease prevention.
5. Impact of renal failure on GH and IGF-I action Resistance to GH and IGF-I are well-recognized complications of uremia. As discussed earlier serum GH levels tend to be normal or even elevated in renal failure, but despite this linear growth is impaired in uremic children [1,3,35]. Serum IGF-I levels are usually in the normal range, but in malnourished patients levels are low and have been used to monitor the nutritional status of patients maintained by regular dialysis treatment [36]. In animals with chronic renal failure (CRF) tissue IGF-I mRNA levels are reduced and this is largely caused by impaired dietary intake [1,4]. GH resistance has been attributed to a reduction in GH receptor levels, impaired signal transduction with attenuated IGF-I expression and resistance to IGF-I [1,3]. Regarding GH receptor expression animal studies have yielded inconsistent findings. Some reports have demonstrated reduced receptor levels in the liver and at the growth plate in bone, while other studies suggest that the diminished GH receptor expressions reflect decreased food consumption and utilization [1,4]. In the clinical setting, most studies have reported that serum GH binding protein (GHBP) levels are reduced in CRF [37]. As the GHBP is derived by proteolytic cleavage of the extracellular domain of the GH receptor, it has been assumed that the low serum GHBP levels reflect reduced tissue GH receptor protein expression. However, this notion has been challenged by our recent study of adult hemodialysis patients in whom, despite significantly reduced GHBP levels, GH receptor expression in peripheral blood mononuclear cells was not different from normal controls [38]. Interestingly, the low serum GHBP levels could not be accounted for by malnutrition or inflammation and appear to be a consequence of the uremic state per se. On the other hand, it is conceivable that the low serum levels might be a reflection of reduced GH receptor expression in other tissues. There is now convincing evidence from animal studies that the GH resistance acquired in uremia is partly due to a post-receptor signaling defect. In the liver and in skeletal muscle of uremic rats, despite normal GH receptor protein levels, downstream phosphorylation of janus kinase 2 (JAK2) and signal transducer and activator of transcription 5 (STAT5) is reduced, as is the nuclear translocation of phosphorylated STAT5 [39,40]. As STAT5 has been implicated in the transcription of IGF-I and as a mediator of body growth [41], this
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signaling defect presumably contributes to the attenuated increase in IGF-I expression in response to GH and the impaired body growth and muscle wasting in uremia. One potential mechanism accounting for the impaired JAK2–STAT phosphorylation in uremia is overexpression of suppressors of cytokine signaling (SOCS), which serve as negative feedback regulators of GH-induced JAK–STAT5 signaling [42]. In rats with CRF SOCS-2 and -3 mRNA levels are indeed increased [39]. SOCS expression normally is stimulated by GH, but it is not clear how this occurs in uremia when GH action is impaired. One possibility is that the increase in SOCS-2 and -3 is caused by inflammatory cytokines that act through other members of the JAK family such as JAK1, JAK3 and Tyk2. Chronic sub-clinical inflammation is common in patients with end stage renal failure and this may contribute to the GH resistant state. It is also conceivable that the increase in SOCS expression is induced by GH through a non-STAT mediated pathway. GH resistance also arises because of insensitivity to IGF-I and this has largely been attributed to the accumulation of circulating IGFBPs [1,3,43]. Serum IGFBP1, -2, -4 and -6 levels are elevated, and this may lead to a reduction in bioavailable IGF-I. Indeed it has been suggested that administration of an inactive IGF-I analog might be used to displace IGF-I from IGFBPs in renal failure and thus restore IGF-I bioactivity [3]. Immunoreactive IGFBP-3 levels are also increased, but this is largely the result of accumulation of immunoreactive fragments with reduced IGF-I affinity; intact IGFBP-3 levels are not elevated [8]. Animal studies indicate that skeletal muscle IGF-I resistance also may be secondary to end organ insensitivity caused by a post-receptor signal transduction defect [44,45]. Tissue resistance also may arise because of changes in local IGFBP production.
6. Therapeutic use of GH and IGF-I in kidney failure It is well accepted that GH is effective and relatively safe for the treatment of growth retardation in children with renal failure [3,35,46], however, it remains to be established whether GH is effective in the management of muscle wasting in uremic adults [5,46,47]. Several small studies have shown that GH induces an anabolic response in the adult end-stage renal disease patient, but large scale studies are required to evaluate its clinical utility. IGF-I also has been shown to be anabolic in CRF [48], but these studies are more limited and results are generally less promising than the GH studies. Because of its renotropic actions, several investigators have studied the use of IGF-I for the treatment of acute renal failure (ARF) and remarkably good results were obtained in animal studies [4]. In contrast, two double
blind studies in human ARF yielded negative results, even when IGF-I was given early in the course of disease [49,50]. Limited studies also have also been performed to see whether IGF-I can augment renal function in patients with advanced CRF. Increments in GFR by 14% to 45% have been reported, suggesting the need for large scale prolonged double blinded studies [5,51]. If proven to be effective in augmenting GFR, then there may well be a role for the use of IGF-I in advanced CRF to delay the need for dialysis. In many instances this might permit the elective placement of a permanent vascular access for dialysis under optimal conditions.
7. Summary and concluding thoughts Within the last few years there has been steady progress in our understanding of the physiology of the GHIGF-I system in the kidney, its role in the pathogenesis of progressive kidney disease and the impact of renal failure on the actions and metabolism of GH and IGF-I. The efficacy and safety of GH in the management of uremic growth failure has been reassuringly confirmed and the outcome of studies evaluating GH therapy for uremic sarcopenia in adults remains to be completed. Worth consideration is an examination of the use of GH in combination with recombinant IGF-I and exercise; the latter to stimulate local GH independent IGF-I production [52]. A major disappointment has been the failure of IGF-I administration to modify the course of clinical ARF. This may reflect the multi-factorial nature of ARF and the repeated insults that occur in the clinical setting rather than an intrinsic failure of IGF-I to promote regeneration of the injured human kidney. With respect to chronic renal disease there is growing evidence suggesting that GH and IGF-I are involved in the pathogenesis of diabetic nephropathy. It appears that GH and IGF-I mediated signal transduction is augmented in the diabetic kidney and that by promoting an increase in extracellular matrix production and accumulation contribute to the pathological changes. Thus, prevention of GH action by blockade either at the receptor level or along its signal transduction pathway offers the potential for effective therapeutic opportunities. Similarly, interrupting IGF-I action also may offer a way to inhibit the development or progression of kidney pathology. To achieve these goals better studies are needed to specifically define the roles of GH and IGF-I in the genesis of diabetic kidney disease. Paradoxically, while exaggerated GH and IGF-I mediated signal transduction may be involved in the pathogenesis of the structural and functional changes that occur in progressive kidney disease, in advanced kidney failure GH and IGF-I mediated signal transduction are depressed as a consequence of the uremic state. Again a deeper understanding of the alterations induced in these
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signal transduction pathways by uremia could provide an opportunity to develop new therapeutic strategies to improve the management of the patient with advanced kidney failure.
Acknowledgements This work was supported by a Merit Review Grant from the Research Service of the Department of Veterans Affairs, and by funding from the American Heart Association and the Norman S. Coplon Grant from Satellite Research. Apologies are extended in advance to those papers that are not referenced in this review because of its brevity.
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R. Rabkin, F. Schaefer / Growth Hormone & IGF Research 14 (2004) 270–276 induced diabetic animals: effect of a growth hormone receptor antagonist, Diabetes 51 (2002) 2270–2281. P.M. Gowri, J.H. Yu, A. Shaufl, M.A. Sperling, R.K. Menon, Recruitment of a repressosome complex at the growth hormone receptor promoter and its potential role in diabetic nephropathy, Mol. Cell. Biol. 23 (2003) 815–825. E. W€ uhl, F. Schaefer, Effects of growth hormone in patients with chronic renal failure: experience in children and adults, Horm. Res. 58 (Suppl. 3) (2002) 35–38. T. Sanaka, Nutritional effect of dialysis therapy, Artif. Organs 27 (2003) 224–226. G. Baumann, Growth hormone binding protein 2001, J. Pediatr. Endocrinol. Metab. 14 (2001) 355–375. J.S. Greenstein, S. Guest, P. Tummala, J. Tan, R. Rabkin, Peripheral blood mononuclear cell growth hormone receptor expression and growth hormone binding protein levels in uremia. J. Am. Soc. Nephrol. 2003 (abstract). F. Schaefer, Y. Chen, T. Tsao, P. Nouri, R. Rabkin, Impaired JAK-STAT signal transduction contributes to growth hormone resistance in chronic uremia, J. Clin. Invest. 108 (2001) 467–475. D. Sun, L. Zheng, P. Tummala, J. Oh, F. Schaefer, R. Rabkin, Growth hormone mediated signaling is impaired in skeletal muscle in uremia. J. Am. Soc. Nephrol. 2003 (abstract). J. Woelfle, D.J. Chia, P. Rotwein, Mechanisms of Growth Hormone (GH) Action: identification of conserved Stat5 binding sites that mediate GH-induced insulin-like growth factor-I gene activation, J. Biol. Chem. 278 (2003) 51261–51266. L. Larsen, C. Ropke, Suppressors of cytokine signalling: SOCS, Apmis 110 (2002) 833–844. D.R. Powell, F. Liu, B.K. Baker, et al., Effect of chronic renal failure and growth hormone therapy on the insulin-like growth factors and their binding proteins, Pediatr. Nephrol. 14 (2000) 579–583.
[44] H. Ding, X.L. Gao, R. Hirschberg, J.V. Vadgama, J.D. Kopple, Impaired actions of insulin-like growth factor 1 on protein synthesis and degradation in skeletal muscle of rats with chronic renal failure. Evidence for a postreceptor defect, J. Clin. Invest. 97 (1996) 1064–1075. [45] T. Tsao, F. Fervenza, M. Friedlaender, Y. Chen, R. Rabkin, Effect of prolonged uremia on insulin-like growth factor-I receptor autophosphorylation and tyrosine kinase activity in kidney and muscle, Exp. Nephrol. 10 (2002) 285–292. [46] G. Johannsson, J. Ahlmen, End-stage renal disease: endocrine aspects of treatment, Growth Horm. IGF Res. 13 (Suppl A) (2003) S94–S101. [47] Y. Chen, F.C. Fervenza, R. Rabkin, Growth factors in the treatment of wasting in kidney failure, J. Ren. Nutr. 11 (2001) 62– 66. [48] D. Fouque, S.C. Peng, E. Shamir, J.D. Kopple, Recombinant human insulin-like growth factor-1 induces an anabolic response in malnourished CAPD patients, Kidney Int. 57 (2000) 646–654. [49] R. Hirschberg, J. Kopple, P. Lipsett, et al., Multicenter clinical trial of recombinant human insulin-like growth factor I in patients with acute renal failure, Kidney Int. 55 (1999) 2423–2432. [50] M.A. Hladunewich, G. Corrigan, G.C. Derby, et al., A randomized, placebo-controlled trial of IGF-I for delayed graft function: a human model to study postischemic ARF, Kidney Int. 64 (2003) 593–602. [51] A. Vijayan, S.C. Franklin, T. Behrend, M.R. Hammerman, S.B. Miller, Insulin-like growth factor I improves renal function in patients with end-stage chronic renal failure, Am. J. Physiol. 276 (1999) R929–R934. [52] P. Rotwein, Insulin-like growth factor action and skeletal muscle growth, an in vivo perspective, Growth Horm. IGF Res. 13 (2003) 303–305.
Review
New concepts: growth hormone, insulin-like growth factor-I and the kidney Ralph Rabkin a
a,*
, Franz Schaefer
b
Veterans Affairs Palo Alto Health Care System and Department of Medicine, Stanford University, 3801 Miranda Avenue, Palo Alto, CA 94304, USA b Division of Pediatric Nephrology, Department of Pediatrics, University of Heidelberg, Germany Received 20 January 2004; accepted 4 February 2004
Abstract Both growth hormone (GH) and IGF-1 have major effects on normal kidney growth, structure and function and participate in the pathogenesis of certain kidney diseases. Furthermore when the kidneys fail there are profound changes in the circulating GHIGF-1 system and the renal and systemic responses to these hormones. In this brief review we address the advances that have been made in our understanding of the relationship between growth hormone GH and IGF-1 and the kidney in health and the systemic and local perturbations that occur in kidney disease and identify key unanswered questions. Published by Elsevier Ltd. Keywords: Somatotropin; IGF-1; Kidney; Uremia; IGF binding proteins
1. Introduction Growth hormone (GH) and insulin-like growth factor-I (IGF-I) have profound effects on kidney growth, structure and function. This has led to a large number of studies directed at advancing our understanding of the properties of these growth factors with the ultimate goal of utilizing knowledge gained for therapeutic purposes. In this article, we will briefly review the advances achieved in this area over the past few years and identify important unanswered questions. For a comprehensive overview of the literature dealing with the renal GH/ IGF-I axis and the impact of renal failure on GH and IGF-I in general, the reader is referred to several excellent reviews [1–5]. In the following, a short overview of the renal GH/IGF axis will be given before describing the latest developments in this field. The GH/IGF/IGFBP system, comprising the receptors for GH and IGF-I, IGF-I and the six major insulinlike growth factor (IGFBPs) as well as the acid-labile
*
Corresponding author. Tel.: +1-650-858-3985; fax: +1-650-8490213. E-mail address: [email protected] (R. Rabkin). 1096-6374/$ - see front matter. Published by Elsevier Ltd. doi:10.1016/j.ghir.2004.02.001
subunit (ALS) of the IGFBP-3 complex, is expressed in a complicated manner within the kidney [1,4]. This complexity reflects the structural heterogeneity of the kidney, which consists of a vascular network from which the glomeruli and peritubular vessels arise, tubules composed of epithelial cells which vary in structure and function along the nephron, and an interstitial compartment. Most but not all actions of GH are mediated through IGF-I, which is either derived from the circulation or synthesized locally. In the rat, IGF-I mRNA is expressed in the loop of Henle and possibly the collecting ducts. GH receptors are also expressed in the loop of Henle and to a lesser extent in the proximal tubule; IGF-I is only transiently expressed at this latter site after acute injury. It is notable that the thick ascending loop of Henle is the only nephron segment where IGF-I, the IGF-I receptor, the GH receptor and IGFBP-1 colocalize, suggesting that this may be a site where GH induces IGF-I expression and where IGF-I binds to its receptor, perhaps after first being trapped locally by IGFBP-1. Apart from this scenario, given the complexity and anatomical heterogeneity of the renal GH/IGF-I system and the large number of physiological and nutritional factors that regulate renal IGF-I expression, it is difficult to conceive how the different
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components of the IGF axis interact to induce their functional and structural effects.
2. Renal disposal of GH, IGF-I and the IGFBPs in health and disease The kidney is a major site of removal of low molecular weight proteins from the circulation. Following passage out of the glomerulus into the tubules, small proteins are captured by endocytosis by the proximal tubular cells, degraded in lysosomes and the constituent amino acids transported back into the circulation [6]. This is a highly efficient process and usually <1–2% of filtered protein enters the urine. However, even mild tubular injury affects the absorptive process and urinary protein excretion increases, making monitoring of urinary excretion of protein hormones an unreliable estimate of circulating hormone turnover. Hormones such as GH and IGF-I are also taken up from the renal peritubular circulation after binding to their specific receptors in basolateral tubular cell membranes, though this is quantitatively far less important than the glomerular filtration pathway and mainly serves to deliver each hormone to its site of action [6]. Growth hormone, MW 20–22 kDa, passes through the glomerular filtration barrier with relative ease (sieving coefficient 0.7), and the kidney accounts for approximately half of the total metabolic clearance rate (MCR) of the hormone. Thus, when renal function declines so does GH disposal, and serum GH levels are often elevated in advanced renal failure. The renal handling of IGF-I is more complex because >98% of circulating IGF-I is bound to IGFBPs. The formation of 45 kDa and more commonly 150 kDa IGF-IGFBP complexes restricts the passage of IGF-I through the glomerular filtration barrier, with negligible amounts of the IGFBP-3/ALS/ IGF-I ternary complex crossing the barrier in healthy individuals [1,4]. Thus, the kidney plays a minor role in removing IGF-I from the circulation. Consequently, the MCR of IGF-I in patients with advanced renal failure does not differ from that observed in normal controls [7]. However, because of the increase in circulating IGFBPs the volume of distribution of IGF-I is decreased and following the administration of IGF-I higher serum levels of IGF-I are attained. Urinary excretion of IGF-I tends to be higher in the young, in line with their higher serum levels, and excretion falls with age. In patients with acromegaly, urinary IGF-I excretion increases several fold. Normally small amounts of IGFBPs also appear in the urine with IGFBP-1, IGFBP-2 and IGFBP-3 being the predominant binding proteins present [4]. In patients with extensive damage to the glomerulus, the permeability of the glomerular filtration barrier increases and this often leads to heavy proteinuria, hypercholesterolemia, hy-
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poalbuminemia and clinical edema, features of the nephrotic syndrome. In patients with this syndrome and in animal models, filtration of the smaller IGF-IGFBP complexes increases and a larger amount of IGF-I is excreted in the urine [1,2]. Urinary excretion of IGFBP1, -2 and -3 and ALS excretion also increases. This has lead to the thesis that the increased tubular cell exposure to filtered IGF-I may contribute to the tubulointerstitial disease that develops in most heavy proteinuric states [8]. In contrast to the increase in urinary IGF-I levels, serum IGF-I levels are usually reduced in nephrotic patients. This is mainly due to the protein malnutrition caused by heavy proteinuria, with urinary IGF-I losses playing a lesser role. Circulating IGFBP levels are also perturbed in the nephrotic syndrome [1,2]. The abundance of intact IGFBP-3 and the 150 kDa ternary complex falls while immunoreactive IGFBP-3 levels rise secondary to accumulation of IGFBP-3 fragments. Reduced levels of intact IGFBP-3 may be caused in part by increased losses through the damaged glomerular filtration barrier, though it has been suggested that increased serum proteolysis of IGFBP-3 also may occur. In contrast to the reduced concentrations of IGFBP-3, serum IGFBP2 levels are increased and this may reflect a compensatory rise in hepatic production of IGFBP-2 in response to protein malnutrition. The net effect of these changes in the serum IGFBP profile is to increase the proportion of IGF-I bound to IGFBP-2, which is more readily filtered than the larger ternary IGF-I/IGFBP3/ALS complex. As might be anticipated, with remission of the nephrotic syndrome serum IGF-I and the IGFBP levels return to normal.
3. Renal actions of GH, IGF-I and the IGFBPs Growth hormone and IGF-I have profound effects on renal growth, glomerular hemodynamics and tubular function [1–4,9]. Administration of IGF-I to animals promotes renal growth through a process of cellular hypertrophy and hyperplasia, and induces a rapid increase in renal blood flow and glomerular filtration, and a reduction in renal vascular resistance. The hemodynamic effects appear to be mediated by metabolites of cyclooxygenase activity and the generation of nitrous oxide which together induce glomerular arteriolar vasodilatation, a fall in efferent and afferent arteriolar resistance, and an increase in the glomerular ultrafiltration coefficient [4]. In humans IGF-I increases renal blood flow and GFR by 25% and causes sodium retention and volume expansion [9]. Sodium retention occurs by a direct action on the renal tubules, by stimulation of renin release and by suppression of atrial natriuretic peptide secretion. IGF-I administered to GH deficient rats or to patients with GH receptor defects normalizes
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the low GFR as does GH replacement in GH deficiency. The effects of GH on kidney function are similar to those observed with IGF-I, except that the functional response to GH is delayed several days and correlates with the increase in serum IGF-I levels, indicating that the GH effects are mediated by IGF-I. GH receptors are present in the proximal tubule, a site where IGF-I mRNA is not normally expressed, suggesting that GH also may have direct actions on tubular function. More recently it has become evident that mesangial cells are an important target for IGF-I action and this is discussed later in the context of diabetes. As is true for other tissues, circulating and locally produced IGFBPs have profound effects on the delivery of IGF-I to its target cells and on its actions in the kidney, and also may exert some IGF-independent effects [3]. In general, because of the formation of high affinity IGF-I/IGFBP complexes the exposure of kidney cells to IGF-I is limited. However, individual IGFBPs may have a modulating effect on the exposure of nephron segments to IGF-I. For example, when IGF-I–IGFBP-3 complexes are infused into rodents, the amount of IGF-I localized to the glomerulus increases [10]. Interestingly, when IGF-I and IGFBP-3 are together incubated with cultured renal tubular cells there is a reduction in IGF-I receptor binding and internalization. Furthermore, IGFBP-3 alone inhibits tubular cell DNA synthesis in an IGF-I independent manner [11] and when added to growth factor deficient cells induces apoptosis [12]. IGFBP-5 also may exhibit IGF-I independent actions. IGFBP-5 is able to inhibit the migration of mesangial cells by binding to a serine kinase receptor [13] . IGFBP-1 also appears able to act in the kidney. In several conditions that cause renal hypertrophy such as compensatory renal growth, diabetes, metabolic acidosis and hypokalemia, renal IGFBP-1 expression is increased. Enhanced IGFBP-1 expression in turn may be the cause of the rise in renal IGF-I levels that occurs in these conditions without a concomitant increase in IGFI gene expression [14,15,19]. Indeed infusion of IGFBP1 into GH deficient dwarf mice stimulates renal but not body growth [16]. However, excessive levels of IGFBP-1 appear to have an adverse effect on the kidney, as transgenic mice over-expressing IGFBP-1 have a reduced number of nephrons and develop glomerulosclerosis [17,18].
4. The GH–IGF-I axis in renal disease There is a growing body of evidence implicating the GH–IGF-I axis in the pathogenesis of progressive gomerular disease. Most compelling are studies examining the potential roles of GH and IGF-I in diabetic kidney disease [8,19]. In the early stages of diabetes in humans the kidney hypertrophies, and renal blood flow and
GFR increase. Later, in patients who develop diabetic kidney disease, typical structural changes occur and there is a slow fall in GFR over time. In rats with experimental diabetes there is an early increase in renal IGF-I content during the first few days of diabetes, starting before renal hypertrophy is apparent. In most reports this rise in kidney IGF-I occurs in the absence of changes in gene expression, but is accompanied by increases in local IGFBP levels, especially IGFBP-1, and it is thought that the accumulation of IGF-I likely reflects increased trapping by IGFBPs. IGF-I appears to be synthesized and secreted by mesangial cells isolated from non-obese type 1 diabetic (NOD) mice, leading to activation of the IGF-I receptor and its signaling pathways, including those involving phosphatidinylinositol-3 kinase and ERKs [20]. The activity of matrix metalloprotein-2 released by these diabetic mesangial cells is reduced, but may be increased by blocking IGF-I or the IGF-I receptor. These same cells exhibit an upregulation of IGF-I receptor expression as do mesangial cells isolated from db/db mice [20,21]. Exposing mesangial cells to IGF-I increases cell proliferation and matrix production while inhibiting matrix degradation and blocking mesangial cell motility. Lipid accumulation is enhanced, leading to a foam cell appearance, which also contributes to impaired mesangial cell migration and phagocytic function [22,23]. Exposure to high glucose levels increases the sensitivity of mesangial cells to IGF-I possibly by decreasing mesangial cell IGFBP-2 secretion [24]. Furthermore, high glucose levels stimulate secretion of IGF-I, connective tissue growth factor, and collagen by cultured renal fibroblasts [25]. Taken together these findings support the notion that local IGF-I may participate in the development and progression of diabetic glomerular disease and possibly other forms of progressive glomerular disease. In support of this concept, administration of an IGF-I receptor antagonist inhibits early renal hypertrophy in diabetic rats, and also blocks compensatory renal growth following loss of renal mass [26]. Compensatory renal growth also may be inhibited by GH receptor blockade [27], but renal hypertrophy induced by a high protein intake is GH independent [28]. While most reports appear to implicate IGF-I as a potential mediator of pathological changes in the diabetic kidney, IGF-I also is protective against oxidative stress and apoptosis induced by high levels of glucose in cultured mesangial cells. This protection appears to be mediated by activation via the IGF-I receptor of the Akt/PKB and MAP kinase signalling pathways [29], and it has been suggested that stimulation of this survival pathways may be turned to therapeutic advantage for protection against cell death and progression of nephropathy. Another mechanism whereby IGF-I may participate in the pathogenesis of diabetic nephropathy is through
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increased tubular cell exposure to growth factor because of increased permeability of the diseased glomerulus to large proteins, including IGF-IGFBP complexes. It has been suggested that filtered IGF-I may contribute to the sodium retention and progressive tubulo-interstitial disease present in diabetic nephropathy [8]. With respect to GH there is strong evidence from animal studies that it also plays a role in the pathogenesis of diabetic nephropathy, and possibly in other progressive non-diabetic kidney diseases. For example, chronically elevated GH levels in GH transgenic mice or in dogs receiving GH therapy is associated with renal hypertrophy, glomerular hypertrophy with mesangial matrix expansion, and glomerulosclerosis. Administration of GH to diabetic rats [30] worsens the diabetic kidney disease, while treatment with a GH receptor antagonist or somatostatin analog inhibits the development of glomerular hypertrophy, hyper-filtration, and proteinuria [27,31]. Additionally, mice with targeted deficiency of the GH receptor are protected against diabetic kidney disease, which develops in heterozygous and normal controls [32]. It is noteworthy that mice over-expressing IGF-I via a transgene develop enlarged kidneys with hypertrophied glomeruli but not glomerulosclerosis, suggesting that the presence of excessive GH is required for the development of glomerulosclerosis, even though many of the actions of GH are mediated by IGF-I [4]. In an important study, Thirone et al. [33] recently showed that in diabetic rats the renal signaling response to GH is exaggerated. After treatment with GH, phosphorylation of Janus kinase 2 (JAK2), insulin receptor substrate-1 (IRS-1), Shc, ERKs and Akt was more pronounced in diabetic rats compared to normal controls. Of note, administration of a GH receptor antagonist normalized the exaggerated GH mediated signal transduction and prevented the renal hypertrophy of diabetes. Gowri et al. [34] recently explored the mechanism in diabetes accounting for the resistance to GH induced linear growth and hepatic IGF-I expression while renal sensitivity to GH is retained. They showed that GH receptor expression is reduced in the liver but enhanced in the kidney. It is conceivable that this increase in kidney GH receptor expression accounts for the enhanced GH mediated signal transduction observed by Thirone et al. [33]. With respect to clinical diabetes, the data in humans are not as convincing as in experimental animals, but results do suggest that GH may participate in the development of diabetic nephropathy. For example, in poorly controlled diabetes GH levels are elevated and the glomerular filtration rate is high, but when glycemia is tightly controlled elevated plasma GH levels normalize and glomerular hyperfiltration declines in parallel [6,19]. Moreover, administration of a somatostatin analogue to diabetic patients reduces renal hypertrophy
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and glomerular hyperfiltration in the absence of a change in glycemic control [27]. Thus, taken together with the animal studies these results provide support for a role for GH in development of diabetic nephropathy and suggest that GH receptor blockade may offer an approach to disease prevention.
5. Impact of renal failure on GH and IGF-I action Resistance to GH and IGF-I are well-recognized complications of uremia. As discussed earlier serum GH levels tend to be normal or even elevated in renal failure, but despite this linear growth is impaired in uremic children [1,3,35]. Serum IGF-I levels are usually in the normal range, but in malnourished patients levels are low and have been used to monitor the nutritional status of patients maintained by regular dialysis treatment [36]. In animals with chronic renal failure (CRF) tissue IGF-I mRNA levels are reduced and this is largely caused by impaired dietary intake [1,4]. GH resistance has been attributed to a reduction in GH receptor levels, impaired signal transduction with attenuated IGF-I expression and resistance to IGF-I [1,3]. Regarding GH receptor expression animal studies have yielded inconsistent findings. Some reports have demonstrated reduced receptor levels in the liver and at the growth plate in bone, while other studies suggest that the diminished GH receptor expressions reflect decreased food consumption and utilization [1,4]. In the clinical setting, most studies have reported that serum GH binding protein (GHBP) levels are reduced in CRF [37]. As the GHBP is derived by proteolytic cleavage of the extracellular domain of the GH receptor, it has been assumed that the low serum GHBP levels reflect reduced tissue GH receptor protein expression. However, this notion has been challenged by our recent study of adult hemodialysis patients in whom, despite significantly reduced GHBP levels, GH receptor expression in peripheral blood mononuclear cells was not different from normal controls [38]. Interestingly, the low serum GHBP levels could not be accounted for by malnutrition or inflammation and appear to be a consequence of the uremic state per se. On the other hand, it is conceivable that the low serum levels might be a reflection of reduced GH receptor expression in other tissues. There is now convincing evidence from animal studies that the GH resistance acquired in uremia is partly due to a post-receptor signaling defect. In the liver and in skeletal muscle of uremic rats, despite normal GH receptor protein levels, downstream phosphorylation of janus kinase 2 (JAK2) and signal transducer and activator of transcription 5 (STAT5) is reduced, as is the nuclear translocation of phosphorylated STAT5 [39,40]. As STAT5 has been implicated in the transcription of IGF-I and as a mediator of body growth [41], this
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signaling defect presumably contributes to the attenuated increase in IGF-I expression in response to GH and the impaired body growth and muscle wasting in uremia. One potential mechanism accounting for the impaired JAK2–STAT phosphorylation in uremia is overexpression of suppressors of cytokine signaling (SOCS), which serve as negative feedback regulators of GH-induced JAK–STAT5 signaling [42]. In rats with CRF SOCS-2 and -3 mRNA levels are indeed increased [39]. SOCS expression normally is stimulated by GH, but it is not clear how this occurs in uremia when GH action is impaired. One possibility is that the increase in SOCS-2 and -3 is caused by inflammatory cytokines that act through other members of the JAK family such as JAK1, JAK3 and Tyk2. Chronic sub-clinical inflammation is common in patients with end stage renal failure and this may contribute to the GH resistant state. It is also conceivable that the increase in SOCS expression is induced by GH through a non-STAT mediated pathway. GH resistance also arises because of insensitivity to IGF-I and this has largely been attributed to the accumulation of circulating IGFBPs [1,3,43]. Serum IGFBP1, -2, -4 and -6 levels are elevated, and this may lead to a reduction in bioavailable IGF-I. Indeed it has been suggested that administration of an inactive IGF-I analog might be used to displace IGF-I from IGFBPs in renal failure and thus restore IGF-I bioactivity [3]. Immunoreactive IGFBP-3 levels are also increased, but this is largely the result of accumulation of immunoreactive fragments with reduced IGF-I affinity; intact IGFBP-3 levels are not elevated [8]. Animal studies indicate that skeletal muscle IGF-I resistance also may be secondary to end organ insensitivity caused by a post-receptor signal transduction defect [44,45]. Tissue resistance also may arise because of changes in local IGFBP production.
6. Therapeutic use of GH and IGF-I in kidney failure It is well accepted that GH is effective and relatively safe for the treatment of growth retardation in children with renal failure [3,35,46], however, it remains to be established whether GH is effective in the management of muscle wasting in uremic adults [5,46,47]. Several small studies have shown that GH induces an anabolic response in the adult end-stage renal disease patient, but large scale studies are required to evaluate its clinical utility. IGF-I also has been shown to be anabolic in CRF [48], but these studies are more limited and results are generally less promising than the GH studies. Because of its renotropic actions, several investigators have studied the use of IGF-I for the treatment of acute renal failure (ARF) and remarkably good results were obtained in animal studies [4]. In contrast, two double
blind studies in human ARF yielded negative results, even when IGF-I was given early in the course of disease [49,50]. Limited studies also have also been performed to see whether IGF-I can augment renal function in patients with advanced CRF. Increments in GFR by 14% to 45% have been reported, suggesting the need for large scale prolonged double blinded studies [5,51]. If proven to be effective in augmenting GFR, then there may well be a role for the use of IGF-I in advanced CRF to delay the need for dialysis. In many instances this might permit the elective placement of a permanent vascular access for dialysis under optimal conditions.
7. Summary and concluding thoughts Within the last few years there has been steady progress in our understanding of the physiology of the GHIGF-I system in the kidney, its role in the pathogenesis of progressive kidney disease and the impact of renal failure on the actions and metabolism of GH and IGF-I. The efficacy and safety of GH in the management of uremic growth failure has been reassuringly confirmed and the outcome of studies evaluating GH therapy for uremic sarcopenia in adults remains to be completed. Worth consideration is an examination of the use of GH in combination with recombinant IGF-I and exercise; the latter to stimulate local GH independent IGF-I production [52]. A major disappointment has been the failure of IGF-I administration to modify the course of clinical ARF. This may reflect the multi-factorial nature of ARF and the repeated insults that occur in the clinical setting rather than an intrinsic failure of IGF-I to promote regeneration of the injured human kidney. With respect to chronic renal disease there is growing evidence suggesting that GH and IGF-I are involved in the pathogenesis of diabetic nephropathy. It appears that GH and IGF-I mediated signal transduction is augmented in the diabetic kidney and that by promoting an increase in extracellular matrix production and accumulation contribute to the pathological changes. Thus, prevention of GH action by blockade either at the receptor level or along its signal transduction pathway offers the potential for effective therapeutic opportunities. Similarly, interrupting IGF-I action also may offer a way to inhibit the development or progression of kidney pathology. To achieve these goals better studies are needed to specifically define the roles of GH and IGF-I in the genesis of diabetic kidney disease. Paradoxically, while exaggerated GH and IGF-I mediated signal transduction may be involved in the pathogenesis of the structural and functional changes that occur in progressive kidney disease, in advanced kidney failure GH and IGF-I mediated signal transduction are depressed as a consequence of the uremic state. Again a deeper understanding of the alterations induced in these
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signal transduction pathways by uremia could provide an opportunity to develop new therapeutic strategies to improve the management of the patient with advanced kidney failure.
Acknowledgements This work was supported by a Merit Review Grant from the Research Service of the Department of Veterans Affairs, and by funding from the American Heart Association and the Norman S. Coplon Grant from Satellite Research. Apologies are extended in advance to those papers that are not referenced in this review because of its brevity.
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