- Email: [email protected]
A powerful new agonist: flooding the system with growth hormone
co m m e nta r y
subsequent careful analysis (for example, by region, ethnic background, and medical system) would lead to better identification of true genotype–phenotype correlations, but also genetic and environmental modifiers responsible for the variability in disease expression. In this regard, the current collaboration between the pan-European Hyperoxaluria Consortium (OxalEurope) and the Mayo Clinic Hyperoxaluria Center (USA) will help by creating a database with significant numbers for genotype – phenotype studies (an estimated > 600 PH cases worldwide), as well as for the development of predictive models. DISCLOSURE The author declared no competing interests. REFERENCES 1. 2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
Hoppe B, Beck BB, Milliner DS. The primary hyperoxalurias. Kidney Int 2009; 75: 1264–1271. Williams EL, Acquaviva C, Amoroso A et al. Primary hyperoxaluria type 1: update and additional mutation analysis of the AGXT gene. Hum Mutat 2009; 30: 910–917. Harambat J, Fargue S, Acquaviva C et al. Genotype–phenotype correlation in primary hyperoxaluria type 1: the p.Gly170Arg AGXT mutation is associated with a better outcome. Kidney Int 2010; 77: 443–449. Van Woerden CS, Groothoff JW, Wanders RJ et al. Primary hyperoxaluria type 1 in The Netherlands: prevalence and outcome. Nephrol Dial Transplant 2003; 18: 273–279. Hoppe B, Langman C. A United States survey on diagnosis, treatment and outcome of patients with primary hyperoxaluria. Pediatr Nephrol 2003; 18: 986–991. Kopp N, Leumann E. Changing pattern of primary hyperoxaluria in Switzerland. Nephrol Dial Transplant 1995; 10: 2224–2227. Herrmann G, Krieg T, Weber M et al. Unusual painful sclerotic like plaques on the legs of a patient with late diagnosis of primary hyperoxaluria type I. Br J Dermatol 2004; 151: 1104–1107. Hoppe B, Danpure CJ, Rumsby G et al. A vertical (pseudodominant) pattern of inheritance in the autosomal recessive disease primary hyperoxaluria type I. Lack of relationship between genotype, enzymic phenotype and disease severity. Am J Kidney Dis 1997; 29: 36–44. Danpure CJ. Molecular aetiology of primary hyperoxaluria type 1. Nephron Exp Nephrol 2004; 98: e39–e44. Rumsby G, Williams E, Coulter-Mackie M. Evaluation of mutation screening as a first line test for the diagnosis of the primary hyperoxalurias. Kidney Int 2004; 66: 959–963. Pirulli D, Marangella M, Amoroso A. Primary hyperoxaluria: genotype-phenotype correlation. J Nephrol 2003; 16: 297–309. Monico CG, Rossetti S, Olson JB et al. Pyridoxine effect in type I primary hyperoxaluria is associated with the most common mutant allele. Kidney Int 2005; 67: 1704–1709. Van Woerden CS, Jaap W, Groothoff F et al. Clinical implications of mutation analysis in
Kidney International (2010) 77
primary hyperoxaluria type 1. Kidney Int 2004; 66: 746–750. 14. Lorenzo V, Alvarez A, Torres A et al. Presentation and role of transplantation in adult patients with type 1 primary hyperoxaluria and the I244T AGXT
mutation: single-center experience. Kidney Int 2006; 70: 1115–1119. 15. Hoppe B, Latta K, von Schnakenburg C et al. Primary hyperoxaluria: the German experience. Am J Nephrol 2005; 25: 276–281.
see original article on page 450
A powerful new agonist: flooding the system with growth hormone Victoria S. Lim1 Niemczyk et al. treated predialysis chronic kidney disease patients with a new growth hormone-releasing hormone agonist, AKL-0707, and noted important changes in body composition characterized by an increase in fat-free mass, a modest rise in bone mineral content, and a reduction in fat mass. These changes were accompanied by a reduction in both serum urea nitrogen and normalized protein nitrogen appearance rate, while dietary protein intake was unchanged. Importantly, there were no serious adverse events. Kidney International (2010) 77, 385–387. doi:10.1038/ki.2009.487
Endocrine dysfunction is common in patients with chronic kidney disease (CKD), especially those near end-stage renal disease and those on renal replacement. One of the dysfunctions is the growth hormone–insulin-like growth factor-1 (GH–IGF-1) axis. Figure 1 is a schematic representation of the physiology of the GH–IGF-1 axis, showing that the hypothalamus produces GH-releasing hormone (GHRH) and somatostatin to, respectively, stimulate and suppress GH secretion. GH acts on many target tissues, but most importantly, it stimulates the liver to synthesize IGF-1, which accounts for most of the circulating IGF-1. GH also stimulates many target tissues to produce IGF-1 that acts locally in an autocrine/paracrine fashion. It appears that the locally made IGF-1 is as important as that produced by the liver, because
1Division of Nephrology , Department of Medicine,
Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA Correspondence: Victoria S. Lim, Department of Medicine, Carver College of Medicine, University of Iowa, 200 Hawkins Drive, T310 GH, Iowa City, Iowa 52242, USA. E-mail: [email protected]
liver IGF-1 knockout mice grew normally. IGF-1 receptors are present ubiquitously in almost all tissue, including cartilage, bone, muscle, liver, kidney, and the nervous system. In circulation, IGF-1 is bound to six binding proteins; 80% of which is IGF-binding protein-3 (IGFBP-3), which is the active moiety. IGF-1 bound to other binding proteins is physiologically inhibitory with regard to its function. The GH– IGF-1 axis regulates statural growth and body composition, the latter through enhanced protein synthesis and lipolysis. The dysfunction in the GH–IGF-1 axis in CKD patients is not due to abnormal central hypothalamic–pituitary regulation but lies in tissue resistance to both molecules. The circulating level of GH is high and that of IGF-1 either normal or low; a normal IGF-1, in the presence of high GH, suggests that the liver is not responding adequately to the GH. In the liver and many target tissues where GH and IGF-1 exert their physiological action, there is a post-receptor defect in the phosphorylation of various tyrosine kinases along the JAK–STAT transduction pathway.1,2 The most prominent clinical consequence of the GH–IGF-1 axis abnormality 385
com m enta r y
Hypothalamus
GHRH
Somatostatin
AKL-0707 Pituitary Ghrelin GH
JAK/STAT
Liver
IGF-1
Target tissues
JAK/STAT
Growth and anabolism
Figure 1 | A diagram of GH–IGF-1 axis physiology. Solid lines indicate stimulatory effects; dotted lines indicate inhibitory effects. Xs represent steps along the axis where chronic kidney disease patients showed defective function. AKL-0707 is the new GH-releasing hormone super-agonist. GHRH, growth hormone–releasing hormone; IGF-1, insulin-like growth factor 1.
in CKD patients is impaired linear bone growth in children, which is underscored by the unequivocal catch-up growth observed with pharmacological doses of recombinant human GH (rhGH).3 In adults, there is, however, no single manifestation that can be attributed to the dysfunction of this system, except for the notion that malnutrition observed in CKD patients may be related to excessive catabolism that could be ameliorated by GH. In the past two decades, there have been multiple studies and trials using rhGH in adult CKD patients, with equivocal and sometimes conflicting results. Garibotto et al., using forearm [3H]phenylalanine flux technique, found that 6 weeks of rhGH treatment resulted in an increase in muscle protein synthesis and a decrease in negative protein balance in the post-absorptive state in hemodialysis patients.4 Kopple and colleagues found that a 2-week subcutaneous administration of rhGH to hemodialysis patients led to a strong and sustained positive nitrogen balance.5 By contrast, Kotzmann and associates wrote that after 3 months of rhGH therapy, hemodialysis patients showed no change in their nutritional and anthropometric parameters 386
even though serum IGF-1 levels were significantly raised.6 Niemczyk et al. 7 (this issue) now report that a 4-week course of treatment with a newly discovered GHRH superagonist, AKL-0707, resulted in an impressive improvement in body composition. This is a phase II randomized, placebo-controlled, double-blind efficacy/toxicity study in which 26 subjects completed the protocols; 12 were given the active agent, and 14 were given placebo. Those who received the active medication showed a gain in body weight and, as demonstrated by dual-energy Xray absorptiometry, an unequivocal increase in fat-free mass, a modest rise in bone mineral content, and, most interestingly, a reduction in fat mass. Therefore, the observed rise in body weight was entirely due to an increase in lean muscle mass. By comparison, weight and body composition remained unchanged in those who received placebo. This is particularly remarkable in that the study subjects were in their 60 s, a time of life when aging tends to favor fat accumulation and reduced muscle mass; thus, it is almost like reversal of the aging process.
The net gain in lean body mass was accompanied by a decrease in serum urea nitrogen concentration and a reduction in normalized protein nitrogen appearance rate as derived from 24-hour urine urea nitrogen excretion. It is noteworthy that these changes in urea nitrogen profile occurred in the presence of an unchanged dietary protein intake. The authors attribute these remarkable anabolic effects to the ability of AKL-0707 to greatly stimulate GH secretion, as serum GH level and GH secretion rate, represented by GH area under the curve, were both strikingly increased whereas no increment was seen in the placebo group. Additionally, AKL-0707 also significantly increased serum IGF-1 levels and completely normalized the circulating IGFBP profile characterized by an increase in IGFBP-3 and a reduction in IGFBP-1; these changes prolonged the half-life of IGF-1 and enhanced its local action. AKL-0707 is an analog of human GHRH resulting from substitution of its levo-amino acids at Ala2, Tyr10, Ala15, and Lys22 by dextro-amino acids of hGHRH (1–29)NH2; this dextro-isoform amino acid–substituted molecule increased its affinity to bind human GHRH receptors in vitro by an incredible magnitude of 900-fold, thus the name super-agonist. It is important to mention here that ghrelin is another naturally occurring peptide that could stimulate GH release. This point is interesting because ghrelin, touted as the ‘hungry hormone,’ has generated lots of interest as a potential therapeutic agent to treat malnutrition. It not only enhances feeding but should also stimulate GH secretion like a GHRH agonist. The study by Niemczyk et al.7 did not measure ghrelin levels, so we do not know whether ghrelin would be suppressed by this new agonist. One disappointing aspect of this study is the failure to demonstrate improved protein synthesis with the whole-body leucine flux technique, as increased protein synthesis is the hallmark of GH-induced anabolism. Perhaps regional kinetics would be the more appropriate technique to demonstrate changes in amino acid turnover at the muscle level. We have observed distinct differences between whole-body and regional amino acid kinetics in CKD Kidney International (2010) 77
co m m e nta r y
patients.8 Measurement of amino acid kinetics in the fed state would be another method to better document enhanced protein synthesis; that would involve the administration of two isotopes, one given orally and the other intravenously. This study also does not explain the mechanism of how excessive GH overcomes target tissue resistance; it is not unlike giving large doses of insulin to patients with type 2 diabetes. We also do not know whether the hormonal changes could be translated to improved physical performance. Why, one might ask, should we be interested in this new analog of GHRH when rhGH and IGF-1 are available and have been used with some success? First, both GH and IGF-1 exert a negative-feedback effect on the hypothalamus and the pituitary and thus downregulate endogenous production of these two hormones. In using a GHRH agonist, one can keep the endogenous production upregulated. Second, treatment with a GHRH agonist maintains the pulsatile nature of GH secretion, and this rhythmicity is of important physiological consequence. Third, no previous studies using rhGH had documented any solid increase in fatfree mass in CKD patients; most reports showed only short-term effects such as enhanced protein synthesis during isotope infusion, increased amino acid uptake, or positive nitrogen balance. Niemczyk et al. 7 found no serious adverse events with the new agonist. However, there are many potential side effects from prolonged GH therapy, including fluid retention, arthralgia, carpal tunnel syndrome, hyperglycemia, and maybe some features of acromegaly. The new agonist, in this study, was found to increase both fasting insulin and glucose, suggesting insulin resistance. While GH confers a state of insulin resistance,9 IGF-1 enhances glucose clearance and did not increase serum insulin.10 Thus, it appears that, in the study by Niemczyk et al.,7 GH exerted a dominant effect on glucose metabolism. It is comforting to know that the hormonal changes returned to baseline level after discontinuation of treatment. If further studies confirm the same anabolic phenomenon in CKD patients, the new drug could conceivably be tried in many other population groups. Kidney International (2010) 77
DISCLOSURE The author declared no competing interests. REFERENCES 1.
2.
3.
4.
5.
Mak RH, Cheung WW, Roberts Jr CT. The growth hormone-insulin-like growth factor-I axis in chronic kidney disease. Growth Horm IGF Res 2008; 18: 17–25. Tonshoff B, Kiepe D, Ciarmatori S. Growth hormone/insulin-like growth factor system in children with chronic renal failure. Pediatr Nephrol 2005; 20: 279–289. Haffner D, Schaeffer F, Nissel R et al. Effect of growth hormone treatment on the adult height of children with chronic renal failure. N Engl J Med 2000; 343: 923–930. Garibotto G, Barreca A, Sofia A et al. Effects of recombinant human growth hormone on muscle protein turnover in malnourished hemodialysis patients. J Clin Invest 1997; 99: 97–105. Kopple JD, Brunori G, Leiserowitz M et al. Growth hormone induces anabolism in malnourished maintenance haemodialysis patients. Nephrol Dial Transplant 2005; 20: 952–958.
6.
Kotzmann H, Yilmaz N, Lercher P et al. Differential effects of growth hormone therapy in malnourished hemodialysis patients. Kidney Int 2001; 60: 1578–1585. 7. Niemczyk S, Sikorska H, Więcek A et al. A superagonist of growth hormone–releasing hormone causes rapid improvement of nutritional status in patients with chronic kidney disease. Kidney Int 2010; 77: 450–458. 8. Lim VS, Ikizler TA, Raj DS et al. Does hemodialysis increase protein breakdown? Dissociation between whole-body amino acid turnover and regional muscle kinetics. J Am Soc Nephrol 2005; 6: 862–868. 9. Bratusch-Marrain PR, Smith D, DeFronzo RA. The effect of growth hormone on glucose metabolism and insulin secretion in man. J Clin Endocrinol Metab 1982; 55: 973–982. 10. Douglas RG, Gluckman PD, Bell K et al. The effects of infusion of insulin-like growth factor (IGF)-I IGF-II and insulin on glucose and protein metabolism in fasted lambs. J Clin Invest 1991; 88: 614–622.
see original article on page 407
ROCK inhibition facilitates tissue reconstitution from embryonic kidney cell suspensions Kai M. Schmidt-Ott1 Explanted embryonic kidney tissues, when placed in organ culture, recapitulate key aspects of nephron formation. Yet attempts to dissociate these tissues into single cells to make them more accessible for genetic manipulation and tissue recombination have been disappointing. Now it is reported that inhibitors of Rho-associated kinase (ROCK) facilitate tissue reconstitution and nephron differentiation from single-cell suspensions of the embryonic kidney. This finding illustrates an unexpected potential for self-organization in these cells and introduces a window of single-cell accessibility to the organ culture system. Kidney International (2010) 77, 387–389. doi:10.1038/ki.2009.488
During mid-embryogenesis (embryonic day 10.5 of mouse development), the ureteric bud emanates from the nephric duct and contacts the adjacent metanephric 1Experimental and Clinical Research Center,
Charité–Universitätsmedizin Berlin, Max Delbrück Center for Molecular Medicine, Berlin, Germany Correspondence: Kai M. Schmidt-Ott, Max Delbrück Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany. E-mail: [email protected]
mesenchyme. This process constitutes the first step of definitive nephrogenesis. The ureteric bud undergoes branching morphogenesis and eventually gives rise to the ureter, the renal pelvis, and the collecting duct system. The metanephric mesenchyme contains committed progenitors that, as a result of interactions with the ureteric bud, differentiate to generate the nephron. These processes are critical for kidney development and, when perturbed, 387
subsequent careful analysis (for example, by region, ethnic background, and medical system) would lead to better identification of true genotype–phenotype correlations, but also genetic and environmental modifiers responsible for the variability in disease expression. In this regard, the current collaboration between the pan-European Hyperoxaluria Consortium (OxalEurope) and the Mayo Clinic Hyperoxaluria Center (USA) will help by creating a database with significant numbers for genotype – phenotype studies (an estimated > 600 PH cases worldwide), as well as for the development of predictive models. DISCLOSURE The author declared no competing interests. REFERENCES 1. 2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
Hoppe B, Beck BB, Milliner DS. The primary hyperoxalurias. Kidney Int 2009; 75: 1264–1271. Williams EL, Acquaviva C, Amoroso A et al. Primary hyperoxaluria type 1: update and additional mutation analysis of the AGXT gene. Hum Mutat 2009; 30: 910–917. Harambat J, Fargue S, Acquaviva C et al. Genotype–phenotype correlation in primary hyperoxaluria type 1: the p.Gly170Arg AGXT mutation is associated with a better outcome. Kidney Int 2010; 77: 443–449. Van Woerden CS, Groothoff JW, Wanders RJ et al. Primary hyperoxaluria type 1 in The Netherlands: prevalence and outcome. Nephrol Dial Transplant 2003; 18: 273–279. Hoppe B, Langman C. A United States survey on diagnosis, treatment and outcome of patients with primary hyperoxaluria. Pediatr Nephrol 2003; 18: 986–991. Kopp N, Leumann E. Changing pattern of primary hyperoxaluria in Switzerland. Nephrol Dial Transplant 1995; 10: 2224–2227. Herrmann G, Krieg T, Weber M et al. Unusual painful sclerotic like plaques on the legs of a patient with late diagnosis of primary hyperoxaluria type I. Br J Dermatol 2004; 151: 1104–1107. Hoppe B, Danpure CJ, Rumsby G et al. A vertical (pseudodominant) pattern of inheritance in the autosomal recessive disease primary hyperoxaluria type I. Lack of relationship between genotype, enzymic phenotype and disease severity. Am J Kidney Dis 1997; 29: 36–44. Danpure CJ. Molecular aetiology of primary hyperoxaluria type 1. Nephron Exp Nephrol 2004; 98: e39–e44. Rumsby G, Williams E, Coulter-Mackie M. Evaluation of mutation screening as a first line test for the diagnosis of the primary hyperoxalurias. Kidney Int 2004; 66: 959–963. Pirulli D, Marangella M, Amoroso A. Primary hyperoxaluria: genotype-phenotype correlation. J Nephrol 2003; 16: 297–309. Monico CG, Rossetti S, Olson JB et al. Pyridoxine effect in type I primary hyperoxaluria is associated with the most common mutant allele. Kidney Int 2005; 67: 1704–1709. Van Woerden CS, Jaap W, Groothoff F et al. Clinical implications of mutation analysis in
Kidney International (2010) 77
primary hyperoxaluria type 1. Kidney Int 2004; 66: 746–750. 14. Lorenzo V, Alvarez A, Torres A et al. Presentation and role of transplantation in adult patients with type 1 primary hyperoxaluria and the I244T AGXT
mutation: single-center experience. Kidney Int 2006; 70: 1115–1119. 15. Hoppe B, Latta K, von Schnakenburg C et al. Primary hyperoxaluria: the German experience. Am J Nephrol 2005; 25: 276–281.
see original article on page 450
A powerful new agonist: flooding the system with growth hormone Victoria S. Lim1 Niemczyk et al. treated predialysis chronic kidney disease patients with a new growth hormone-releasing hormone agonist, AKL-0707, and noted important changes in body composition characterized by an increase in fat-free mass, a modest rise in bone mineral content, and a reduction in fat mass. These changes were accompanied by a reduction in both serum urea nitrogen and normalized protein nitrogen appearance rate, while dietary protein intake was unchanged. Importantly, there were no serious adverse events. Kidney International (2010) 77, 385–387. doi:10.1038/ki.2009.487
Endocrine dysfunction is common in patients with chronic kidney disease (CKD), especially those near end-stage renal disease and those on renal replacement. One of the dysfunctions is the growth hormone–insulin-like growth factor-1 (GH–IGF-1) axis. Figure 1 is a schematic representation of the physiology of the GH–IGF-1 axis, showing that the hypothalamus produces GH-releasing hormone (GHRH) and somatostatin to, respectively, stimulate and suppress GH secretion. GH acts on many target tissues, but most importantly, it stimulates the liver to synthesize IGF-1, which accounts for most of the circulating IGF-1. GH also stimulates many target tissues to produce IGF-1 that acts locally in an autocrine/paracrine fashion. It appears that the locally made IGF-1 is as important as that produced by the liver, because
1Division of Nephrology , Department of Medicine,
Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA Correspondence: Victoria S. Lim, Department of Medicine, Carver College of Medicine, University of Iowa, 200 Hawkins Drive, T310 GH, Iowa City, Iowa 52242, USA. E-mail: [email protected]
liver IGF-1 knockout mice grew normally. IGF-1 receptors are present ubiquitously in almost all tissue, including cartilage, bone, muscle, liver, kidney, and the nervous system. In circulation, IGF-1 is bound to six binding proteins; 80% of which is IGF-binding protein-3 (IGFBP-3), which is the active moiety. IGF-1 bound to other binding proteins is physiologically inhibitory with regard to its function. The GH– IGF-1 axis regulates statural growth and body composition, the latter through enhanced protein synthesis and lipolysis. The dysfunction in the GH–IGF-1 axis in CKD patients is not due to abnormal central hypothalamic–pituitary regulation but lies in tissue resistance to both molecules. The circulating level of GH is high and that of IGF-1 either normal or low; a normal IGF-1, in the presence of high GH, suggests that the liver is not responding adequately to the GH. In the liver and many target tissues where GH and IGF-1 exert their physiological action, there is a post-receptor defect in the phosphorylation of various tyrosine kinases along the JAK–STAT transduction pathway.1,2 The most prominent clinical consequence of the GH–IGF-1 axis abnormality 385
com m enta r y
Hypothalamus
GHRH
Somatostatin
AKL-0707 Pituitary Ghrelin GH
JAK/STAT
Liver
IGF-1
Target tissues
JAK/STAT
Growth and anabolism
Figure 1 | A diagram of GH–IGF-1 axis physiology. Solid lines indicate stimulatory effects; dotted lines indicate inhibitory effects. Xs represent steps along the axis where chronic kidney disease patients showed defective function. AKL-0707 is the new GH-releasing hormone super-agonist. GHRH, growth hormone–releasing hormone; IGF-1, insulin-like growth factor 1.
in CKD patients is impaired linear bone growth in children, which is underscored by the unequivocal catch-up growth observed with pharmacological doses of recombinant human GH (rhGH).3 In adults, there is, however, no single manifestation that can be attributed to the dysfunction of this system, except for the notion that malnutrition observed in CKD patients may be related to excessive catabolism that could be ameliorated by GH. In the past two decades, there have been multiple studies and trials using rhGH in adult CKD patients, with equivocal and sometimes conflicting results. Garibotto et al., using forearm [3H]phenylalanine flux technique, found that 6 weeks of rhGH treatment resulted in an increase in muscle protein synthesis and a decrease in negative protein balance in the post-absorptive state in hemodialysis patients.4 Kopple and colleagues found that a 2-week subcutaneous administration of rhGH to hemodialysis patients led to a strong and sustained positive nitrogen balance.5 By contrast, Kotzmann and associates wrote that after 3 months of rhGH therapy, hemodialysis patients showed no change in their nutritional and anthropometric parameters 386
even though serum IGF-1 levels were significantly raised.6 Niemczyk et al. 7 (this issue) now report that a 4-week course of treatment with a newly discovered GHRH superagonist, AKL-0707, resulted in an impressive improvement in body composition. This is a phase II randomized, placebo-controlled, double-blind efficacy/toxicity study in which 26 subjects completed the protocols; 12 were given the active agent, and 14 were given placebo. Those who received the active medication showed a gain in body weight and, as demonstrated by dual-energy Xray absorptiometry, an unequivocal increase in fat-free mass, a modest rise in bone mineral content, and, most interestingly, a reduction in fat mass. Therefore, the observed rise in body weight was entirely due to an increase in lean muscle mass. By comparison, weight and body composition remained unchanged in those who received placebo. This is particularly remarkable in that the study subjects were in their 60 s, a time of life when aging tends to favor fat accumulation and reduced muscle mass; thus, it is almost like reversal of the aging process.
The net gain in lean body mass was accompanied by a decrease in serum urea nitrogen concentration and a reduction in normalized protein nitrogen appearance rate as derived from 24-hour urine urea nitrogen excretion. It is noteworthy that these changes in urea nitrogen profile occurred in the presence of an unchanged dietary protein intake. The authors attribute these remarkable anabolic effects to the ability of AKL-0707 to greatly stimulate GH secretion, as serum GH level and GH secretion rate, represented by GH area under the curve, were both strikingly increased whereas no increment was seen in the placebo group. Additionally, AKL-0707 also significantly increased serum IGF-1 levels and completely normalized the circulating IGFBP profile characterized by an increase in IGFBP-3 and a reduction in IGFBP-1; these changes prolonged the half-life of IGF-1 and enhanced its local action. AKL-0707 is an analog of human GHRH resulting from substitution of its levo-amino acids at Ala2, Tyr10, Ala15, and Lys22 by dextro-amino acids of hGHRH (1–29)NH2; this dextro-isoform amino acid–substituted molecule increased its affinity to bind human GHRH receptors in vitro by an incredible magnitude of 900-fold, thus the name super-agonist. It is important to mention here that ghrelin is another naturally occurring peptide that could stimulate GH release. This point is interesting because ghrelin, touted as the ‘hungry hormone,’ has generated lots of interest as a potential therapeutic agent to treat malnutrition. It not only enhances feeding but should also stimulate GH secretion like a GHRH agonist. The study by Niemczyk et al.7 did not measure ghrelin levels, so we do not know whether ghrelin would be suppressed by this new agonist. One disappointing aspect of this study is the failure to demonstrate improved protein synthesis with the whole-body leucine flux technique, as increased protein synthesis is the hallmark of GH-induced anabolism. Perhaps regional kinetics would be the more appropriate technique to demonstrate changes in amino acid turnover at the muscle level. We have observed distinct differences between whole-body and regional amino acid kinetics in CKD Kidney International (2010) 77
co m m e nta r y
patients.8 Measurement of amino acid kinetics in the fed state would be another method to better document enhanced protein synthesis; that would involve the administration of two isotopes, one given orally and the other intravenously. This study also does not explain the mechanism of how excessive GH overcomes target tissue resistance; it is not unlike giving large doses of insulin to patients with type 2 diabetes. We also do not know whether the hormonal changes could be translated to improved physical performance. Why, one might ask, should we be interested in this new analog of GHRH when rhGH and IGF-1 are available and have been used with some success? First, both GH and IGF-1 exert a negative-feedback effect on the hypothalamus and the pituitary and thus downregulate endogenous production of these two hormones. In using a GHRH agonist, one can keep the endogenous production upregulated. Second, treatment with a GHRH agonist maintains the pulsatile nature of GH secretion, and this rhythmicity is of important physiological consequence. Third, no previous studies using rhGH had documented any solid increase in fatfree mass in CKD patients; most reports showed only short-term effects such as enhanced protein synthesis during isotope infusion, increased amino acid uptake, or positive nitrogen balance. Niemczyk et al. 7 found no serious adverse events with the new agonist. However, there are many potential side effects from prolonged GH therapy, including fluid retention, arthralgia, carpal tunnel syndrome, hyperglycemia, and maybe some features of acromegaly. The new agonist, in this study, was found to increase both fasting insulin and glucose, suggesting insulin resistance. While GH confers a state of insulin resistance,9 IGF-1 enhances glucose clearance and did not increase serum insulin.10 Thus, it appears that, in the study by Niemczyk et al.,7 GH exerted a dominant effect on glucose metabolism. It is comforting to know that the hormonal changes returned to baseline level after discontinuation of treatment. If further studies confirm the same anabolic phenomenon in CKD patients, the new drug could conceivably be tried in many other population groups. Kidney International (2010) 77
DISCLOSURE The author declared no competing interests. REFERENCES 1.
2.
3.
4.
5.
Mak RH, Cheung WW, Roberts Jr CT. The growth hormone-insulin-like growth factor-I axis in chronic kidney disease. Growth Horm IGF Res 2008; 18: 17–25. Tonshoff B, Kiepe D, Ciarmatori S. Growth hormone/insulin-like growth factor system in children with chronic renal failure. Pediatr Nephrol 2005; 20: 279–289. Haffner D, Schaeffer F, Nissel R et al. Effect of growth hormone treatment on the adult height of children with chronic renal failure. N Engl J Med 2000; 343: 923–930. Garibotto G, Barreca A, Sofia A et al. Effects of recombinant human growth hormone on muscle protein turnover in malnourished hemodialysis patients. J Clin Invest 1997; 99: 97–105. Kopple JD, Brunori G, Leiserowitz M et al. Growth hormone induces anabolism in malnourished maintenance haemodialysis patients. Nephrol Dial Transplant 2005; 20: 952–958.
6.
Kotzmann H, Yilmaz N, Lercher P et al. Differential effects of growth hormone therapy in malnourished hemodialysis patients. Kidney Int 2001; 60: 1578–1585. 7. Niemczyk S, Sikorska H, Więcek A et al. A superagonist of growth hormone–releasing hormone causes rapid improvement of nutritional status in patients with chronic kidney disease. Kidney Int 2010; 77: 450–458. 8. Lim VS, Ikizler TA, Raj DS et al. Does hemodialysis increase protein breakdown? Dissociation between whole-body amino acid turnover and regional muscle kinetics. J Am Soc Nephrol 2005; 6: 862–868. 9. Bratusch-Marrain PR, Smith D, DeFronzo RA. The effect of growth hormone on glucose metabolism and insulin secretion in man. J Clin Endocrinol Metab 1982; 55: 973–982. 10. Douglas RG, Gluckman PD, Bell K et al. The effects of infusion of insulin-like growth factor (IGF)-I IGF-II and insulin on glucose and protein metabolism in fasted lambs. J Clin Invest 1991; 88: 614–622.
see original article on page 407
ROCK inhibition facilitates tissue reconstitution from embryonic kidney cell suspensions Kai M. Schmidt-Ott1 Explanted embryonic kidney tissues, when placed in organ culture, recapitulate key aspects of nephron formation. Yet attempts to dissociate these tissues into single cells to make them more accessible for genetic manipulation and tissue recombination have been disappointing. Now it is reported that inhibitors of Rho-associated kinase (ROCK) facilitate tissue reconstitution and nephron differentiation from single-cell suspensions of the embryonic kidney. This finding illustrates an unexpected potential for self-organization in these cells and introduces a window of single-cell accessibility to the organ culture system. Kidney International (2010) 77, 387–389. doi:10.1038/ki.2009.488
During mid-embryogenesis (embryonic day 10.5 of mouse development), the ureteric bud emanates from the nephric duct and contacts the adjacent metanephric 1Experimental and Clinical Research Center,
Charité–Universitätsmedizin Berlin, Max Delbrück Center for Molecular Medicine, Berlin, Germany Correspondence: Kai M. Schmidt-Ott, Max Delbrück Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany. E-mail: [email protected]
mesenchyme. This process constitutes the first step of definitive nephrogenesis. The ureteric bud undergoes branching morphogenesis and eventually gives rise to the ureter, the renal pelvis, and the collecting duct system. The metanephric mesenchyme contains committed progenitors that, as a result of interactions with the ureteric bud, differentiate to generate the nephron. These processes are critical for kidney development and, when perturbed, 387