Axis In Chronic Kidney Disease Research Articles

SUN-159 RENAL PROTECTIVE EFFECT OF LACTULOSE TARGETING OF GUT-KIDNEY AXIS

With the dramatic development of microbiome research in the last decades, gut-kidney axis which is interaction between intestinal environment and kidney has drawn attention, and it was reported that lubiprostone, a novel laxative, improved the intestinal environment and suppressed deterioration of renal function in renal failure (RF) mice. Chronic kidney disease (CKD) patients frequently suffer from constipation, and their compositions of gut microbiota differ from healthy people; implying that gut-kidney axis is disrupted in CKD patients. The target for improving gut-kidney axis in CKD is relief from constipation, improvement in the intestinal environment, and suppression of uremic toxins accumulation. Lactulose, synthetic disaccharide, alters the intestinal environment by stimulating bowel movements as a disaccharide laxative and prebiotic, therefore, it is expected to affect gut-kidney axis. However, because there are few reports evaluating its effect on renal function, the effectiveness of lactulose on CKD is unclear. Thus, we evaluated the effect of lactulose on renal function in adenine-induced RF rats. Wistar/ST male rats (10-week-old) were fed 0.75% adenine-containing diet for 3 weeks to induce RF. Then, they were fed 3.0% or 7.5% lactulose-containing diets for 4 weeks. The rats were observed for parameters including renal function, uremic toxins and gut microbiota. RF rats exhibited increased serum creatinine and blood urea nitrogen (BUN), renal fibrosis accompanying accumulation of serum uremic toxins, and alteration of the intestinal environment. Lactulose reduced serum uremic toxins such as indoxyl sulfate (IS) and p-cresyl sulfate (PCS), and improved renal fibrosis. Additionally, analysis of the gut microbiota showed the slightly increase in Bifidobacterium, saccharolytic bacteria, and the decrease in Bacteroides which contributed to production of indole is metabolized to IS in the liver. These results suggest that lactulose modifies gut microbiota and ameliorates CKD progression by suppressing uremic toxins accumulation. Our study first discovered the renal protective effect of lactulose via relief from uremia and showed the possibility of lactulose as a gut-kidney axis regulator.

The gut microbiota and the brain–gut–kidney axis in hypertension and chronic kidney disease

Crosstalk between the gut microbiota and the host has attracted considerable attention owing to its involvement in diverse diseases. Chronic kidney disease (CKD) is commonly associated with hypertension and is characterized by immune dysregulation, metabolic disorder and sympathetic activation, which are all linked to gut dysbiosis and altered host-microbiota crosstalk. In this Review, we discuss the complex interplay between the brain, the gut, the microbiota and the kidney in CKD and hypertension and explain our brain-gut-kidney axis hypothesis for the pathogenesis of these diseases. Consideration of the role of the brain-gut-kidney axis in the maintenance of normal homeostasis and of dysregulation of this axis in CKD and hypertension could lead to the identification of novel therapeutic targets. In addition, the discovery of unique microbial communities and their associated metabolites and the elucidation of brain-gut-kidney signalling are likely to fill fundamental knowledge gaps leading to innovative research, clinical trials and treatments for CKD and hypertension.

Changes of insulin-like growth factor 1 axis in chronic kidney disease and its role in skeletal muscle atrophy

Objective: To investigate the changes of insulin-like growth factor 1 (IGF-1) axis in chronic kidney disease (CKD) and its role in skeletal muscle atrophy. Methods: A total of 240 patients with CKD stage 1-5 (without dialysis treatment) were included between August 2016 and February 2017. Serum IGF-1 and IGF-1 binding protein-3 (IGFBP-3) were measured using chemiluminescence, and the influencing factors of serum IGF-1 and IGFBP-3 were analyzed. Besides, male Sprague-Dawley rats (200-250 g) were randomly assigned to the sham-operated control group (Control, n=15) and the 5/6 nephrectomy group (n=15) as CKD animal model. The expressions of local IGF-1 and IGF-1 receptor (IGF-1R) of skeletal muscles were evaluated at the level of transcription and protein by real-time PCR and Western blotting. Results: There was no significant correlation between changes of serum IGF-1 level and estimated glomerular filtration rate (eGFR) (r=-0.066, P=0.307). However, after multivariable adjustment, serum IGFBP-3 increased with decreasing of eGFR (r=-0.181, P=0.005) in adult CKD patients. In multivariate analysis, age, eGFR, serum cholesterol level and 24 h urinary protein quantification were independent factors of serum IGFBP-3 in patients with CKD (R2=0.243, P<0.001). Animal experiments showed that the expression of IGF-1 mRNA and protein decreased in skeletal muscles of CKD rats. Expressions of IGF-1R mRNA and protein were slightly reduced and phosphorylation of IGF-1R was severely impaired in skeletal muscles of CKD rats. Conclusions: IGF-1 levels seem to be independent of renal function, but IGFBP-3 levels increased with decreasing of eGFR, which may cause a low affinity of IGF-1 with IGF-1R in skeletal muscles. Low affinity of IGF-1 with IGF-1R, as well as the decreasing of IGF-1 synthesis could lead to disorders of IGF-1R phosphorylation, and thus cause atrophy of skeletal muscles.

Impairment of the carnitine/organic cation transporter 1–ergothioneine axis is mediated by intestinal transporter dysfunction in chronic kidney disease

Carnitine/organic cation transporter 1 (OCTN1) is a specific transporter of the food-derived antioxidant ergothioneine. Ergothioneine is absorbed by intestinal OCTN1, distributed through the bloodstream, and incorporated into each organ by OCTN1. OCTN1 expression is upregulated in injured tissues, and promotes ergothioneine uptake to reduce further damage caused by oxidative stress. However, the role of the OCTN1-ergothioneine axis in kidney-intestine cross-talk and chronic kidney disease (CKD) progression remains unclear. Here we assessed ergothioneine uptake via intestinal OCTN1 and confirmed the expression of OCTN1. The ability of OCTN1 to absorb ergothioneine was diminished in mice with CKD. In combination with OCTN1 dysfunction, OCTN1 localization on the intestinal apical cellular membrane was disturbed in mice with CKD. Proteomic analysis, RT-PCR, Western blotting, and immunohistochemistry revealed that PDZ (PSD95, Dlg, and ZO1), a PDZK1 domain-containing protein that regulates the localization of transporters, was decreased in mice with CKD. Decreased intestinal ergothioneine uptake from food decreased ergothioneine levels in the blood of mice with CKD. Despite increased OCTN1 expression and ergothioneine uptake into the kidneys of mice with CKD, ergothioneine levels did not increase. To identify the role of the OCTN1-ergothioneine axis in CKD, we evaluated kidney damage and oxidative stress in OCTN1-knockout mice with CKD and found that kidney fibrosis worsened. Oxidative stress indicators were increased in OCTN1-knockout mice. Moreover, ergothioneine levels in the blood of patients with CKD decreased, which were restored after kidney transplantation. Thus, a novel inter-organ interaction mediated by transporters is associated with CKD progression.

FGF23-Klotho axis in CKD

Fibroblast growth factor 23 (FGF23) is a bone-derived hormone regulating phosphate and vitamin D metabolism. FGF23 works by binding to Klotho-FGF receptor (FGFR) complex. FGF23 reduces serum phosphate level by suppressing the expression of type 2a and 2c sodium-phosphate cotransporters in the renal proximal tubules. In addition, FGF23 suppresses intestinal phosphate absorption by reducing 1,25-dihydroxyvitamin D (1,25(OH)2D) level. FGF23 also inhibits the production and secretion of parathyroid hormone. FGF23 starts to increase in the early phase of chronic kidney disease (CKD) and is considered to prevent the development of hyperphosphatemia. With the progression of CKD, the expression of Klotho decreases causing impaired actions of FGF23. It has been reported that FGF23 level is correlated with various adverse events including cardiovascular diseases especially in patients with CKD. It was also shown that FGF23 induces left ventricular hypertrophy by directly acting on cardiomyocytes in a Klotho-independent way. However, there still remain several unanswered questions concerning FGF23-Klotho axis. We hope that further studies elucidate unsolved problems and will be useful for more appropriate management of patients with CKD.

Klotho/FGF23 Axis in CKD.

The sequential bone disorders, serum parameter abnormalities and vascular calcification that are associated with chronic kidney disease (CKD) have come to be generally known as CKD-mineral bone disorder (MBD). Klotho, a causative protein of aging, and fibroblast growth factor 23 (FGF23), a bone-derived phosphaturic factor, have been reported to be involved in CKD-MBD, and their relationship to the pathophysiology of this disease is gradually being elucidated. Klotho functions as a cofactor of FGF receptors and has been reported to cause FGF23 action and specificity in the kidney. In addition, the presence of secreted Klotho in membrane protein fractions has been determined, and its specific actions are now garnering attention. FGF23, in cooperation with Klotho, inhibits phosphate reabsorption and vitamin D production at the kidney. Blood Klotho and FGF23 levels have been reported to increase beginning at the early stages of CKD, and these factors are receiving attention as new surrogate markers that are reported to be related to life expectancy. In this chapter, we summarize and outline the pathophysiology of Klotho and FGF23 in CKD-MBD as well as important points that are starting to influence clinical practice.

Alterations of intestinal barrier and microbiota in chronic kidney disease.

Recent studies have highlighted the close relationship between the kidney and the gastrointestinal (GI) tract--frequently referred to as the kidney--gut axis--in patients with chronic kidney disease (CKD). In this regard, two important pathophysiological concepts have evolved: (i) production and accumulation of toxic end-products derived from increased bacterial fermentation of protein and other nitrogen-containing substances in the GI tract, (ii) translocation of endotoxins and live bacteria from gut lumen into the bloodstream, due to damage of the intestinal epithelial barrier and quantitative/qualitative alterations of the intestinal microbiota associated with the uraemic milieu. In both cases, these gut-centred alterations may have relevant systemic consequences in CKD patients, since they are able to trigger chronic inflammation, increase cardiovascular risk and worsen uraemic toxicity. The present review is thus focused on the kidney-gut axis in CKD, with special attention to the alterations of the intestinal barrier and the local microbiota (i.e. the collection of microorganisms living in a symbiotic coexistence with their host in the intestinal lumen) and their relationships to inflammation and uraemic toxicity in CKD. Moreover, we will summarize the most important clinical data suggesting the potential for nutritional modulation of gut-related inflammation and intestinal production of noxious by-products contributing to uraemic toxicity in CKD patients.

Which outcome in chronic kidney disease-mineral and bone disorder patients?

Dear Editor, Secondary hyperparathyroidism (SHPT) is one the major complications in dialysis patients. Hyperphosphatemia, hypocalcemia, low serum vitamin D levels are greatly involved into the physiopathology of SHPT in chronic kidney disease (CKD), in which the down-regulation of parathyroid Vitamin D Receptor (VDR) and Calcium Sensing Receptor (CaSR) represent a critical step. Moreover, new data demonstrate that the Fibroblast Growth Factor 23 (FGF-23) plays an important role in the regulation of calcium-phosphate-vitamin D axis in CKD. Thus, new insights into the pathogenesis of SHPT give the possibility to have different treatments of this condition in CKD. SHPT causes both bone (osteitis fibrosa) and extra-skeletal disease (cardiovascular and soft-tissue calcifications, altered erythropoiesis, endocrine dysfunctions) (1). Clinical targets for serum phosphate (P), calcium (Ca), and parathyroid hormone (PTH) levels have been elucidated by the Kidney Dialysis Outcomes Quality Initiative (K/DOQI) Working Group (2). Since alterations in mineral and bone metabolism have classically been named renal osteodystrophy and classified based on bone biopsy, recently, KDIGO (Kidney Disease: Improving Global Outcomes) proposed a new definition for this disease: the CKD-Mineral and Bone Disorder (CKD-MBD) (3). In addition to hypocalcemia and hyperphosphatemia, CKD-MBD is characterized by abnormalities of bone volume, turnover, mineralization, and growth as well as vascular calcification (VC). In fact, VC seems to link abnormalities in serum Ca and P levels and the enhanced mortality risk associated with CKD-MBD. Impressively, VC starts early in CKD and patients with CKD-3, -4 and -5 not undergoing hemodialysis present a significant amount of calcium deposition in the coronary arteries (40-80%). During the last decade, many efforts have been made to try to decrease VC progression. The control of serum PTH levels and calcium- and phosphate-load, using aluminum- and calcium phosphate binders, more selective vitamin D receptors activators, and cinacalcet clearly represent our current pharmacological tools to improve quality of life and reduce mortality in CKD (4). In their manuscript, Rostami et al. (5) showed quality of life in dialysis patients affected by CKD-MBD in Iran. Interestingly, quality of like associated with serum Ca levels, serum calcium-phosphate product levels, and serum PTH levels. Furthermore, hospitalizations were associated with serum P levels. Thus, management of CKD-MBD included phosphate binders (both calcium-based and calcium-free), vitamin D, and cinacalcet, even if treatment of this dramatic complication of CKD remains suboptimal for most patients.

The axis AGE-RAGE-soluble RAGE and oxidative stress in chronic kidney disease.

Chronic kidney disease (CKD) has been shown to be associated with high oxidative stress and cardiovascular disease. In this chapter our focus will be on the role of advanced glycation end products (AGE) and their receptor, RAGE in CKD progression and their role on cardiovascular complications. We provide a succinct, yet comprehensive summary of the current knowledge, the challenges and the future therapeutic avenues that are stemming out from novel recent findings. We first briefly review glycation and AGE formation and the role of the kidney in their metabolism. Next, we focus on the RAGE, its signaling and role in oxidative stress. We address the possible role of soluble RAGEs as decoys and the controversy regarding this issue. We then provide the latest information on the specific role of both AGE and RAGE in inflammation and perpetuation of kidney damage in diabetes and in CKD without diabetes, which is the main purpose of the review. Finally, we offer an update on new avenues to target the AGE-RAGE axis in CKD.

Arterial stiffness, vascular calcification and bone metabolism in chronic kidney disease

Patients with chronic kidney disease (CKD) have an extremely poor cardiovascular outcome. Arterial stiffness, a strong independent predictor of survival in CKD, is connected to arterial media calcification. A huge number of different factors contribute to the increased arterial calcification and stiffening in CKD, a process which is in parallel with impaired bone metabolism. This coincidence was demonstrated to be part of the direct inhibition of calcification in the vessels, which is a counterbalancing effect but also leads to low bone turnover. Due to the growing evidence, the definition of "CKD mineral bone disorder" was created recently, underlining the strong connection of the two phenomena. In this review, we aim to demonstrate the mechanisms leading to increased arterial stiffness and the up-to date data of the bone-vascular axis in CKD. We overview a list of the different factors, including inhibitors of bone metabolism like osteoprotegerin, fetuin-A, pyrophosphates, matrix Gla protein, osteopontin, fibroblast growth factor 23 and bone morphogenic protein, which seem to play role in the progression of vascular calcification and we evaluate their connection to impaired arterial stiffness in the mirror of recent scientific results.

Effect of paricalcitol and GcMAF on angiogenesis and human peripheral blood mononuclear cell proliferation and signaling

In addition to its role in calcium homeostasis and bone mineralization, vitamin D is involved in immune defence, cardiovascular function, inflammation and angiogenesis, and these pleiotropic effects are of interested in the treatment of chronic kidney disease. Here we investigated the effects of paricalcitol, a nonhypercalcemic vitamin D analogue, on human peripheral blood mononuclear cell proliferation and signaling, and on angiogenesis. These effects were compared with those of a known inhibitor of angiogenesis pertaining to the vitamin D axis, the vitamin D-binding protein-derived Gc-macrophage activating factor (GcMAF). Since the effects of vitamin D receptor agonists are associated with polymorphisms of the gene coding for the receptor, we measured the effects of both compounds on mononuclear cells harvested from subjects harboring different BsmI polymorphisms. Paricalcitol inhibited mononuclear cell viability with the bb genotype showing the highest effect. GcMAF, on the contrary, stimulated cell proliferation, with the bb genotype showing the highest stimulatory effect. Both compounds stimulated 3'-5'-cyclic adenosine monophosphate formation in mononuclear cells with the highest effect on the bb genotype. Paricalcitol and GcMAF inhibited the angiogenesis induced by proinflammatory prostaglandin E1. Polymorphisms of the vitamin D receptor gene, known to be associated with the highest responses to vitamin D receptor agonists, are also associated with the highest responses to GcMAF. These results highlight the role of the vitamin D axis in chronic kidney disease, an axis which includes vitamin D, its receptor and vitamin D-binding protein-derived GcMAF.

'Dem bones' are made for more than walking

Bone is an endocrine organ that reaches out to other tissues, orchestrating responses that may have a role in pathology and physiology at distant sites. In 'Bench to Bedside', L. Darryl Quarles discusses recent studies showing how a feedback loop between the bone hormone FGF-23 and renal phosphate excretion and vitamin D metabolism is integrated with the classical PTH–vitamin D axis in chronic kidney disease (CKD). This new paradigm may change the diagnosis and treatment of disordered mineral homeostasis of people with CKD. A recent epidemiological study argues a mechanistic link between bone loss and atherosclerosis, maladies usually linked to aging. In 'Bedside to Bench', Sundeep Khosla discusses how this clinical study underpins research showing that mediators of inflammation and oxidative stress share common mechanisms that may lead to this calcium shift during aging.

Statins--beyond lipids in CKD

correlates of prevalent coronary calcification. Int J Cardiol 2005; 98: 325–330 45. Shisen J, Leung DY, Juergens CP. Gender and age differences in the prevalence of coronary artery calcification in 953 Chinese subjects. Hearth Lung Circ 2005; 14: 69–73 46. London GM, Marchais SJ, Guerin AP et al. Association of bone activity, calcium load, aortic stiffness, and calcifications in ESRD. J Am Soc Nephrol 2008; 19: 1827–1835 47. Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group. KDIGO Clinical Practice Guideline for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney DiseaseMineral and Bone Disorder (CKD-MBD). Kidney Int Suppl 2009; 113: S1–S130 48. Stenvinkel P, Wang K, Qureshi AR et al. Low fetuin-A levels are associated with cardiovascular death: impact of variations in the gene encoding fetuin. Kidney Int 2005; 67: 2383–2392 49. Chiu YW, Teitelbaum I, Misra M et al. Pill burden, adherence, hyperphosphatemia, and quality of life in maintenance dialysis patients. Clin J Am Soc Nephrol 2009; 4: 1089–1096 50. Giachelli CM. The emerging role of phosphate in vascular calcification. Kidney Int 2009; 75: 890–897 51. Fan S, Ross C, Mitra S et al. A randomized, crossover design study of sevelamer carbonate powder and sevelamer hydrochloride tablets in chronic kidney disease patients on haemodialysis. Nephrol Dial Transplant 2009; 24: 3794–3799 52. Fishbane S, Delmez J, Suki WN et al. A randomized, parallel, openlabel study to compare once-daily sevelamer carbonate powder dosing with thrice-daily sevelamer hydrochloride tablet dosing in CKD patients on hemodialysis. Am J Kidney Dis 2010; 55: 307–315 53. Oliveira RB, Cancela AL, Graciolli FG et al. Early control of PTH and FGF23 in normophosphatemic CKD patients: a new target in CKD-MBD therapy?. Clin J Am Soc Nephrol 2010; 5: 286–291 54. Brandenburg VM, Jahnen-Dechent W, Ketteler M. Sevelamer and the bone-vascular axis in chronic kidney disease: bone turnover, inflammation, and calcification regulation. Kidney Int Suppl 2009; 114: S26–S33

Osteoprotegerin: A Biomarker With Many Faces

Osteoprotegerin (OPG), a member of the tumor necrosis factor receptor superfamily, is a soluble decoy receptor for the osteoclast differentiation factor receptor-activator of nuclear factor κB ligand (RANKL) that inhibits interaction between RANKL and its membrane-bound receptor RANK (Figure).1 The RANKL/OPG/RANK axis has been shown to regulate bone remodeling2,3 and was more recently found to be involved in carcinogenesis as well as central thermoregulation.4,5 This system has also been linked to the development of atherosclerosis and plaque destabilization.6,7 RANKL exhibits several properties with relevance to atherogenesis, such as promotion of inflammatory responses in T cells and dendritic cells, induction of chemotactic properties in monocytes, induction of matrix metalloproteinase (MMP) activity in vascular smooth muscle cells (SMC), and RANKL has also been found to have prothrombotic properties.2,8 In observational studies, elevated circulating OPG levels have been associated with prevalence and severity of coronary artery disease, cerebrovascular disease, and peripheral vascular disease.2,8 Circulating OPG levels are increased in patients with acute coronary syndrome,9 and enhanced expression has been found within symptomatic carotid plaques.10 Elevated OPG levels have also been associated with the degree of coronary calcification in the general population as a marker of coronary atherosclerosis.11 OPG has been reported to predict survival in patients with heart failure after acute myocardial infarction,12 to predict heart failure hospitalization and mortality in patients with acute coronary syndrome,9 and to be associated with long-term mortality in patients with ischemic stroke.13 There are also a few …

The bone–vascular axis in chronic kidney disease

This review highlights the most recent publications addressing the relationship between bone and vascular calcification in patients with chronic and end-stage kidney disease. The relatively new term 'chronic kidney disease-mineral bone disorder' reflects the growing reach of chronic kidney disease research into the realm of systems physiology, involving a triad of renal, skeletal, and vascular tissues. Recent studies address underlying mechanisms of the bone and vascular complications of chronic kidney disease and point to a variety of biochemical factors, including phosphatonins (fibroblast growth factor-23, matrix extracellular phosphoglycoprotein), bone morphogenetic protein 7, osteoprotegerin, matrix GLA protein, ectonucleotide pyrophosphatase/phosphodiesterase 1, alkaline phosphatase, and lipid oxidation products. Studies also demonstrate that agents used for treatment of one component of the triad often act on the other components of the triad - beneficially or adversely. These findings emphasize the importance of avoiding the subspecialty, single organ viewpoint when treating individual components of chronic kidney disease-mineral bone disorder. The consistent synchrony among chronic kidney disease, aortic calcification, and bone loss offers clues to underlying mechanisms for the systemic abnormalities.

Bone–Vascular Axis in Chronic Kidney Disease

Chronic kidney disease (CKD) is characterized by changes in mineral metabolism associated with alterations of its hormonal regulation and various forms of bone disease. In the past, these associations focused attention on the kidney–bone axis. The last decade has seen renewed interest on interactions among mineral metabolism disorders and extraosseous and cardiovascular calcifications observed in CKD or end-stage renal disease (ESRD). Vascular calcification is an active process similar to bone formation that implicates a variety of proteins involved in bone and mineral metabolism (1,2) and is considered part of a systemic dysfunction defined as CKD–mineral and bone disorder (3). Growing evidence linking bone with different functional and structural characteristics of the arterial tree has contributed to developing the concept of the bone–vascular axis (4). The first observations suggesting the existence of the bone–vascular axis were the frequent associations of osteoporosis and atherosclerotic vascular calcifications observed in postmenopausal women (5–7). Longitudinal population-based studies revealed a relationship between the progression of vascular calcifications and bone demineralization, and others were identified between bone mineral density (BMD) and aortic or central artery calcifications (6), or coronary arteries in type 2 diabetes (8). The osteopenia–osteoporosis association was also linked with arterial functional indexes, such as aortic stiffness and interactions independent of calcifications, suggesting broader biologic interplay (9,10). Relationships between bone and vascular modifications were also observed in CKD and ESRD patients. In dialysis patients, coronary artery calcification score was found to be inversely correlated with vertebral bone mass (11,12). In addition, a high systemic arterial calcification score combined with bone histomorphometry suggestive of low bone activity was observed in hemodialysis patients (13,14). Arterial stiffening and low spine BMD or calcaneal osteopenia were significantly associated in CKD and hemodialysis patients (15–17). …

Potential Role of Growth Factors With Particular Focus on Growth Hormone and Insulin-Like Growth Factor-1 in the Management of Chronic Kidney Disease

Prevention and treatment of chronic kidney disease (CKD) so far primarily has been based on early and aggressive treatment of hypertension. A number of other therapeutic approaches have the potential of being translated to the clinical area within the foreseeable future. In this review, we focus on growth factors and, in particular, on the role of growth hormone (GH) and insulin-like growth factor-1 (IGF-1) in the treatment of CKD and the management of its complications. Disturbances of the GH-IGF-1 axis in CKD have suggested therapeutic roles for both the inhibition, as well as the stimulation, of that axis in CKD. Experimental data have suggested that GH may have a detrimental effect on kidney growth, scarring, and the progression of CKD. Therapies based on the inhibition of GH showed some benefit, but failed to translate to clinical CKD. On the other hand, the administration of IGF-1 has been reported in a number of small studies to have conflicting effects on renal function. In end-stage renal disease, GH has been shown in a number of small-scale studies to modify inflammation, improve lipid profile, and favorably affect cardiovascular parameters. Studies also have shown some benefit of IGF-1 administration on the nutritional parameters of patients on renal replacement therapy. More recently, a larger randomized, double-blind, placebo-controlled, 26-week, proof-of-concept clinical study was conducted to investigate the effect of GH (Norditropin; Novo Nordisk, Bagsvaerd, Denmark) in adult chronic hemodialysis (CHD) patients. Beneficial effects were observed on lean body mass, serum albumin, high-density lipoprotein cholesterol, and homocysteine levels, all known to be associated with mortality and morbidity in CHD. These studies suggested that GH therapy may prove beneficial in reducing morbidity and mortality in CHD patients.

Growth hormone axis in chronic kidney disease

Chronic kidney disease (CKD) in children is associated with dramatic changes in the growth hormone (GH) and insulin-like growth factor (IGF-1) axis, resulting in growth retardation. Moderate-to-severe growth retardation in CKD is associated with increased morbidity and mortality. Renal failure is a state of GH resistance and not GH deficiency. Some mechanisms of GH resistance are: reduced density of GH receptors in target organs, impaired GH-activated post-receptor Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling, and reduced levels of free IGF-1 due to increased inhibitory IGF-binding proteins (IGFBPs). Treatment with recombinant human growth hormone (rhGH) has been proven to be safe and efficacious in children with CKD. Even though rhGH has been shown to improve catch-up growth and to allow the child to achieve normal adult height, the final adult height is still significantly below the genetic target. Growth retardation may persist after renal transplantation due to multiple factors, such as steroid use, decreased renal function and an abnormal GH–IGF1 axis. Those below age 6 years are the ones to benefit most from transplantation in demonstrating acceleration in linear growth. Newer treatment modalities targeting the GH resistance with recombinant human IGF-1 (rhIGF-1), recombinant human IGFBP3 (rhIGFBP3) and IGFBP displacers are under investigation and may prove to be more effective in treating growth failure in CKD.

Fetuin-A, Valve Calcification, and Diabetes

In the current issue of Circulation , Ix et al demonstrate an inverse correlation between mitral and aortic valve calcification and serum fetuin-A levels in a cross-sectional study of 970 patients with coronary artery disease and without renal disease.1 Increased serum fetuin was significantly associated with diabetes mellitus, hypertriglyceridemia, serum albumin, and body mass index, with a weaker association with serum C-reactive protein, low-density lipoprotein cholesterol, and serum calcium. The link between aortic stenosis and fetuin held only in those without diabetes.1 The data highlight the complex interactions of fetuin with inflammation, insulin resistance, and tissue calcification. Furthermore, the results, though intriguing, underscore our lack of understanding of the cellular mechanisms of calcification in diverse pathological substrates, such as the degenerating aortic leaflet and mitral annulus. Article p 2533 Fetuin is a member of the cystatin superfamily of cysteine protease inhibitors, originally discovered as the major component of fetal bovine serum. It is a carrier for growth factors, binds to and inactivates transforming growth factor (TGF)–β and bone morphogenic protein, and is a major component of mineralized bone.2 Fetuin-A is also an acute-phase glycoprotein, produced in adults primarily in the liver, and is a powerful circulating inhibitor of hydroxyapatite formation. Mice that lack fetuin-A exhibit extensive soft-tissue calcification, which is accelerated on a mineral-rich diet, which suggests that fetuin-A acts to inhibit calcification systemically.3 In addition to its effects on mineralization, fetuin-A inhibits insulin receptor autophosphorylation and tyrosine kinase activity in vitro and in vivo. Fetuin-null knockout mice demonstrate improved insulin sensitivity and resistance to diet-induced obesity, and it has been postulated that the absence of fetuin in mice may contribute to the improvement of insulin sensitivity associated with aging.4 Clinically, serum fetuin-A is decreased in patients with moderate to severe chronic kidney disease, especially …

The hypothalamic-pituitary axis in men and women with chronic kidney disease

Although the precise abnormalities that lead to failure of the hypothalamic-pituitary-gonadal axis in men and women with chronic kidney disease (CKD) and end-stage renal disease (ESRD) remains undefined, evidence exists for defects in both the hypothalamus and the pituitary. The lack of appropriate cyclic release of gonadotropin-releasing hormone (GnRH) by the hypothalamus leads to loss of normal pulsatile luteinizing hormone (LH) release by the pituitary, which results in impaired ovulation in women and reduced testosterone and sperm production in men. The cause of impaired cyclic release of GnRH is unclear, but hyperprolactinemia, elevated endorphins, and high levels of GnRH and LH caused by reduced clearance may contribute. Perturbations of the hypothalamic-pituitary-gonadaotropin axis in CKD lead to high rates of infertility, dysfunctional uterine bleeding, and impaired puberty in children. Only through additional study of the complex effects of CKD on the hypothalamic-pituitary-gonadal axis will the precise abnormalities in hormonal control of reproduction be explained. Although the precise abnormalities that lead to failure of the hypothalamic-pituitary-gonadal axis in men and women with chronic kidney disease (CKD) and end-stage renal disease (ESRD) remains undefined, evidence exists for defects in both the hypothalamus and the pituitary. The lack of appropriate cyclic release of gonadotropin-releasing hormone (GnRH) by the hypothalamus leads to loss of normal pulsatile luteinizing hormone (LH) release by the pituitary, which results in impaired ovulation in women and reduced testosterone and sperm production in men. The cause of impaired cyclic release of GnRH is unclear, but hyperprolactinemia, elevated endorphins, and high levels of GnRH and LH caused by reduced clearance may contribute. Perturbations of the hypothalamic-pituitary-gonadaotropin axis in CKD lead to high rates of infertility, dysfunctional uterine bleeding, and impaired puberty in children. Only through additional study of the complex effects of CKD on the hypothalamic-pituitary-gonadal axis will the precise abnormalities in hormonal control of reproduction be explained.