Brenner and Rector's The Kidney, 8th ed.

CHAPTER 50. Endocrine Aspects of Kidney Disease

Ajay K. Singh   Jean Mulder   Biff F. Palmer



Endocrine Aspects Underlying Sexual Dysfunction in Chronic Kidney Disease, 1744



Hypothalamic-Pituitary-Gonadal Axis in Uremic Men, 1744



Testicular Function, 1744



Sex Steroids, 1744



Hypothalamic-Pituitary Function, 1745



Prolactin Metabolism, 1745



Gynecomastia, 1746



Treatment, 1746



Hypothalamic-Pituitary-Gonadal Axis Abnormalities in Uremic Women, 1746



Normal Menstrual Cycle, 1747



Hormonal Disturbances in Uremic Premenopausal Women, 1747



Prolactin and Galactorrhea, 1747



Hormonal Disturbances in Uremic Postmenopausal Women, 1747



Treatment, 1747



Thyroid Function in Chronic Renal Failure, 1748



Thyroid Hormone Metabolism, 1748



Hypothalamic-Pituitary Dysfunction, 1748



Clinical Manifestations, 1748



Disturbances in Carbohydrate Metabolism, 1749



Insulin Resistance in Dialysis Patients, 1749



Insulin Resistance in Transplant Patients, 1750



Insulin Resistance in Patients with Chronic Kidney Disease Not on Dialysis, 1750



Insulin Resistance in Patients with Chronic Kidney Disease and Thiazolidinediones, 1750



Growth Hormone and Kidney Disease, 1751



Growth Failure in Children, 1751



Adult Patients with Chronic Kidney Disease and Growth Hormone, 1753

Endocrine aspects of kidney disease encompass a wide variety of syndromes and clinical disorders. The kidney is both a potent endocrine organ as well as an important target for hormonal action. The kidney produces key hormones such as erythropoietin, renin, as well as activating vitamin D through the action of 1-alpha hydroxylase. On the other hand, hormones such as vasopressin, the atrial natriuretic peptides, and angiotensin II target the kidney and play key roles in fluid and electrolyte physiology. However, the kidney during disease is also a key modulator of endocrine function. The uremic state is associated with abnormalities in the synthesis or action of many hormones, including the pituitary (e.g., prolactin, growth hormone) as well as pancreatic hormones (e.g., insulin). The purpose of this chapter is to focus on endocrine abnormalities that manifest during different phases of kidney disease.


Disturbances in the hypothalamic-pituitary-gonadal axis are common in patients with chronic kidney disease and play an important role in the development of sexual dysfunction ( Table 50-1 ). In uremic men the most prominent abnormalities are in gonadal function while disturbances in the hypothalamic-pituitary axis are more subtle. By contrast, central disturbances predominate in uremic women.

TABLE 50-1   -- Endocrine Factors Involved in the Pathogenesis of Sexual Dysfunction in Men and Women with Chronic Kidney Disease


 ↓ Gonadal function

  Decreased production of testosterone

↓ Hypothalamic-pituitary function

  Blunted increase in serum luteinizing hormone (LH) levels

  Decreased amplitude of LH secretory burst

  Variable increase in serum follicle stimulating hormone levels

  Increased prolactin levels


Anovulatory menstrual cycles

Lack of mid-cycle surge in LH

↑ prolactin




Hypothalamic-Pituitary-Gonadal Axis in Uremic Men

In men with chronic kidney disease disturbances in the pituitary-gonadal axis can be detected with only moderate reductions in the glomerular filtration rate and progressively worsen as kidney failure progresses. These disorders rarely normalize with initiation of hemodialysis or peritoneal dialysis and, in fact, often progress. By comparison, a well-functioning kidney transplant is much more likely to restore normal sexual activity, although some features of reproductive function may remain impaired. [1] [2]

Testicular Function

Chronic kidney failure is associated with impaired spermatogenesis and testicular damage, often leading to infertility.[3] Semen analysis typically shows a decreased volume of ejaculate, either low or complete azoospermia, and a low percentage of motility. These abnormalities are often apparent prior to the need for dialysis and then deteriorate further once dialytic therapy is initiated. Histologic changes in the testes show evidence of decreased spermatogenic activity with the greatest changes in the hormonally dependent later stages of spermatogenesis. The number of spermatocytes is reduced and there is little evidence of maturation to the stage of mature sperm. In most instances the number of spermatogonia is normal but on occasion complete aplasia of germinal elements may also be present. Other findings include damage to the seminiferous tubules, interstitial fibrosis, and calcifications. Interstitial fibrosis and calcification also develop in the epididymis and corpora cavernosa particularly as the time on maintenance hemodialysis becomes prolonged. [4] [5]

Unlike other causes of severe primary testicular lesions, the Leydig and Sertoli cells show little evidence of hypertrophy or hyperplasia. This later finding suggests a defect in the hormonal regulation of the Leydig and Sertoli cells as might occur with gonadotropin deficiency or resistance, rather than a cytotoxic effect of uremia where spermatogonia would be most affected.[6] The factors responsible for testicular damage in uremia are not well understood. It is possible that plasticizers in dialysis tubing, such as phthalate, may play a role in propagating the abnormalities once patients are initiated onto maintenance hemodialysis.

Sex Steroids

In addition to impaired spermatogenesis, the testes show evidence of impaired endo crine function. Total and free testosterone levels are typically reduced, although the binding capacity and concentration of sex hormone-binding globulin are normal.[7] Acute stimulation of testosterone secretion with administration of human chorionic gonadotropin (HCG), a compound with luteinizing hormone-like actions, produces only a blunted response in uremic men. Lower free testosterone levels and impaired Leydig cell sensitivity to HCG are first detectable with only moderate reductions in the glomerular filtration rate and before basal levels of testosterone fall. Recent studies have shown evidence of a factor in uremic serum capable of blocking the luteinizing hormone receptor thus providing an explanation for the sluggish response of the Leydig cell to infusion of HCG.[8] This blocking activity is inversely correlated with glomerular filtration rate and largely disappears following transplantation.

In comparison to testosterone, the total plasma estrogen concentration is often elevated in advanced kidney failure. However, the physiologically important estradiol levels are typically in the normal range. As with the lack of hypertrophy and hyperplasia of Leydig cells, normal levels of estradiol suggest a functional gonadotropin deficiency or resistance in uremia because increased luteinizing hormone levels should enhance the testicular secretion of estradiol.[6]

Hypothalamic-Pituitary Function

The plasma concentration of the pituitary gonadotropin, luteinizing hormone (LH), is elevated in uremic men. Elevated levels are found early in kidney insufficiency and progressively rise with deteriorating kidney function. The excess LH secretion in this setting is thought to result from the diminished release of testosterone from the Leydig cells because testosterone normally leads to feedback inhibition of LH release. In addition, the metabolic clearance rate of LH is reduced as a result of decreased kidney clearance.

The increase in serum LH is variable and modest when compared to that observed in castrate nonuremic subjects. The lack of a more robust response of LH to low levels of circulating testosterone suggests a derangement in the central regulation of gonadotropin release. Infusion of gonadotropin-releasing hormone (GnRH) increases LH levels to the same degree as in normals; however, the peak value and return to baseline may be delayed. Because the kidney contributes importantly to the clearance of GnRH and LH, decreased metabolism of these hormones may explain the observed variations. The abnormal LH response to GnRH precedes and is not corrected by dialytic therapy.

In addition to decreased metabolism, subtle disturbances in LH secretion have also been described. Under normal circumstances, LH is secreted in a pulsatile fashion. In uremic subjects the number of secretory bursts remains normal but the amount of LH released per secretory burst is reduced.[9] It is not known whether this decrease in amplitude is the result of a change in the pattern of GnRH release from the hypothalamus or a change in the responsiveness of the pituitary. Under normal circumstances GnRH release is pulsatile in nature. This pattern of release is critical for normal function of gonadotropin cells and reproductive capability. Uremia, with contributions from inadequate nutrient intake, stress, and systemic illness, is associated with alterations in the pulsatile release of GnRH leading to a hypogonadal state.[10] The secretory pattern of GnRH and LH returns to normal following the placement of a well-functioning allograft.

Follicle stimulating hormone (FSH) secretion is also increased in men with chronic kidney failure, although to a more variable degree such that the LH/FSH ratio is typically increased. FSH release by the pituitary normally responds to feedback inhibition by a peptide product of the Sertoli cells called inhibin. The plasma FSH concentration tends to be highest in those uremic patients with the most severe damage to seminiferous tubules and presumably the lowest levels of inhibin. It has been suggested that increased FSH levels may portend a poor prognosis for recovery of spermatogenic function following kidney transplantation. [3] [11]

Clomiphene is a compound that acts by competing with estrogen or testosterone for receptors at the level of the hypothalamus and prevents the negative feedback of gonadal steroids on the release of GnRh and subsequently the release of pituitary gonadotropins. When administered to chronic kidney failure patients there is an appropriate rise in the levels of both LH and FSH suggesting that the negative feedback control of testosterone on the hypothalamus is intact and that the storage and release of gonadotropins by the pituitary is normal.

In summary, a number of observations suggest that gonadal failure is an important consequence of chronic kidney failure. The finding that LH levels are typically increased is consistent with the presence of testicular damage. However, the lack of Leydig cell hypertrophy and normal estradiol levels also raise the possibility of functional hypogonadism. The finding that LH levels are only modestly increased in chronic kidney failure suggests a diminished response of the hypothalamic-pituitary axis to lowered testosterone levels and impaired regulation of gonadotropin secretion. One explanation for the blunted rise in LH in response to low levels of testosterone is that the hypothalamic-pituitary axis in chronic kidney failure is reset in such a way that it is more sensitive to the negative feedback inhibition of testosterone. In this manner, the axis begins to assume a similar characteristic as seen in the prepubertal state where there is extreme sensitivity to the inhibitory effect of gonadal steroids.[6]

Prolactin Metabolism

Elevated plasma prolactin levels are commonly found in dialyzed men. Increased production is primarily responsible because the kidney plays little, if any, role in the catabolism of this hormone. Prolactin release is normally under dopaminergic inhibitory control. Its secretion in chronic kidney disease, however, appears autonomous and resistant to stimulatory or suppressive maneuvers. As an example, dopamine infusion or the administration of oral L-dopa fails to decrease basal prolactin levels. On the other hand, procedures that normally increase prolactin secretion such as arginine infusion, insulin-induced hypoglycemia, or thyrotropin-releasing hormone infusion elicit either no or only a blunted response. These abnormalities resolve following a successful kidney transplant.

Increased prolactin secretion in chronic kidney disease may be related in part to the development of secondary hyperparathyroidism. An infusion of parathyroid hormone (PTH) in normal men enhances prolactin release, a response that can be suppressed by the administration of L-dopa. In one study decreased levels of PTH in response to the administration of calcitriol was associated with increased plasma testosterone levels, a reduction in plasma gonadotropin concentrations, and improved sexual function.[12] However, this benefit of vitamin D therapy could not be confirmed in a controlled trial.[13] Depletion of total body zinc stores may also play an etiologic role in uremic hyperprolactinemia.[14]

The clinical significance of enhanced prolactin release in uremic men is incompletely understood. Extreme hyperprolactinemia is associated with infertility, loss of libido, low circulating testosterone levels, and inappropriately low LH levels in men with normal kidney function. These observations led to the evaluation of therapy with bromocriptine, which reduces prolactin secretion. Although it can lower prolactin levels to near normal in men with advanced kidney disease, there has been an inconsistent effect on sexual potency and libido. In addition, the drug has numerous side effects to include hypotension.


Gynecomastia occurs in approximately 30% of men on maintenance hemodialysis. This problem most often develops during the initial months of dialysis and then tends to regress as dialysis continues. The pathogenesis of gynecomastia in this setting is unclear. Although elevated prolactin levels and an increased estrogen-to-androgen ratio seem attractive possibilities, most data fail to support a primary role for abnormal hormonal function. Alternatively, a mechanism similar to that responsible for gynecomastia following refeeding of malnourished patients may be involved.


Erectile dysfunction, decreased libido, and marked declines in the frequency of intercourse are common manifestation of sexual dysfunction in men with chronic kidney disease. For example, the prevalence of erectile dysfunction has been reported to be as high as 70% to 80% and is similar between patients on hemodialysis and peritoneal dialysis. [15] [16] The treatment of sexual dysfunction in the uremic man is initially of a general nature. One must ensure optimal delivery of dialysis and adequate nutritional intake. One area that deserves further investigation is the impact of slow nocturnal hemodialysis on sexual function. In a pilot study of 5 patients undergoing dialysis 6 nights per week for 8 hours each night serum testosterone levels increased in three patients over an 8-week period.[17] Levels of LH and FSH remained unchanged. In a separate study the percentage of patients who felt that sexual function was a problem declined from 80% to 29% after 3 months of nightly nocturnal hemodialysis.[18]

Administration of recombinant human erythropoietin has been shown to enhance sexual function in chronic kidney failure. The improvement in well being that typically accompanies correction of anemia probably accounts for at least a part of this response. However, in some studies erythropoietin therapy has been reported to cause normalization of the pituitary-gonadal feedback mechanism with reduced plasma concentrations of LH and FSH and increases in plasma testosterone levels. [19] [20] Reductions in elevated plasma prolactin levels have also been noted.[21] It is controversial as to whether these endocrinologic changes are solely the result of correction of the anemia or a direct effect of erythropoietin. As mentioned previously, controlling the degree of secondary hyperparathyroidism with 1,25 (OH)2 vitamin D may be of benefit in lowering prolactin levels and improving sexual function in some patients.

For those patients who continue to manifest erectile dysfunction despite optimal delivery of dialysis, it has become common clinical practice to give a therapeutic trial of phosphodiesterase inhibitors such as sildenafil. [22] [23]Approximately 60% to 80% of patients have a satisfactory response to these drugs.[15] In those patients who fail to respond an endocrinologic workup can be initiated. Because hypogonadism is frequently present in this setting it is tempting to implicate decreased circulating levels of testosterone and expect significant improvement with replacement therapy. Unfortunately the management of sexual dysfunction in men tends to be much more difficult. Administration of testosterone to uremic men usually fails to restore libido or potency, despite increased testosterone levels and reduced release of LH and FSH. In one study of 27 male dialysis patients with biochemically proven hypogonadism, administration of depot testosterone fully restored sexual function in only three patients.[24] In two of the restored patients, the benefit was short lived. A trial of testosterone may be warranted in hypogonadal patients whose primary complaint is decreased libido. In very limited studies administration of clomiphene citrate has also been reported to cause a normalization of plasma testo-sterone levels associated with some improvement in sexual function.

Patients found to have increased circulating levels of prolactin may benefit from a trial of bromocriptine. This agent is a dopaminergic agonist that has shown some efficacy in improving sexual function presumably by reducing elevated prolactin levels. However, its usefulness has been limited by a relatively high frequency of side effects. Other dopaminergic agonists, such as Parlodel and lisuride, seem to be better tolerated but have only been used in small short-term studies.

Zinc deficiency has also been suggested as a cause of gonadal failure. Uremic patients are often deficient in zinc, probably due to reduced dietary intake, zinc malabsorption, and/or possible leaching of zinc by dialysis equipment. In a controlled trial, supplemental zinc resulted in significant increases in the plasma testosterone concentration and sperm counts, as well as significant declines in LH and FSH levels as compared to a control group.[25] Potency, libido, and frequency of intercourse also improved in those patients given zinc. It is possible that normalization of total body zinc may also be effective in correcting uremic hyperprolactinemia.[14] Thus, the aggregate data suggest that the administration of zinc in a zinc-deficient man is a reasonable therapeutic option.


Disturbances in menstruation and fertility are commonly encountered in women with chronic kidney failure, usually leading to amenorrhea by the time the patient reaches end-stage renal disease. The menstrual cycle typically remains irregular with scanty flow after the initiation of maintenance dialysis, although normal menses is restored in some women.[26] In others, hyper menorrhagia develops, potentially leading to significant blood loss and increased transfusion requirements.

The major menstrual abnormality in uremic women is anovulation, with affected patients being infertile.[27] Women on chronic dialysis also tend to complain of decreased libido and reduced ability to reach orgasm.[28]

Pregnancy can rarely occur in advanced kidney failure, but fetal wastage is markedly increased. Some residual kidney function is usually present in the infrequent pregnancy that can be carried to term. The subject of pregnancy in chronic kidney insufficiency has recently been reviewed.[29]

Normal Menstrual Cycle

The normal menstrual cycle is divided into a follicular or proliferative phase and a luteal or secretory phase. Normal follicular maturation and subsequent ovulation require appropriately timed secretion of the pituitary gonadotropins. Follicle stimulating hormone (FSH) secretion exhibits typical negative feedback, with hormone levels falling as the plasma estrogen concentration rises. In contrast, luteinizing hormone (LH) secretion is suppressed maximally by low concentrations of estrogen but exhibits positive feedback control in response to a rising and sustained elevation of estradiol. Thus, high levels of estradiol in the late follicular phase trigger a surging elevation in LH secretion, which is responsible for ovulation. Following ovulation, progesterone levels increase due to production by the corpus luteum. Progesterone is responsible for the transformation of the endometrium into the luteal phase.

Hormonal Disturbances in Uremic Premenopausal Women

Indirect determination of ovulation suggests that anovulatory cycles are the rule in uremic women.[30] For example, endometrial biopsies show an absence of progestational effects and there is a failure to increase basal body temperature at the time when ovulation would be expected. In addition the preovulatory peak in LH and estradiol concentrations are frequently absent. The failure of LH to rise in part reflects a disturbance in the positive estradiol feedback pathway because the administration of exogenous estrogen to mimic the preovulatory surge in estradiol fails to stimulate LH release.[30] In contrast, feedback inhibition of gonadotropin release by low doses of estradiol remains intact. This can be illustrated by the ability of the antiestrogen clomiphene to enhance LH and FSH secretion. It remains unclear whether the disturbances in cyclic gonadotropin production originate in the hypothalamus (via impaired production of gonadotropin-releasing hormone (GnRH)) or in the anterior pituitary.[27] It is possible, for example, that endorphins are involved. Circulating endorphin levels are increased in chronic kidney failure due primarily to reduce renal opioid clearance and endorphins can inhibit ovulation, perhaps by reducing the release of GnRH.

Prolactin and Galactorrhea

Women with chronic kidney failure commonly have elevated circulating prolactin levels. As in men with chronic kidney failure, the hypersecretion of prolactin in this setting appears to be autonomous, as it is resistant to maneuvers designed to stimulate or inhibit its release. It has been suggested that the elevated prolactin levels may impair hypothalamic-pituitary function and contribute to sexual dysfunction and galactorrhea in these patients. In this regard nonuremic females with prolactin-producing pituitary tumors commonly present with amenorrhea, galactorrhea, and low circulating gonadotropin levels. However, uremic women treated with bromocriptine rarely resume normal menses and continue to complain of galactorrhea (if present), despite normalization of the plasma prolactin concentration. Thus, factors other than hyperprolactinemia must be important in this setting.

Hormonal Disturbances in Uremic Postmenopausal Women

Postmenopausal uremic women have gonadotropin levels as high as those seen in nonuremic women of similar age.[30] As mentioned earlier, the negative feedback of estrogen on LH and FSH release is intact in premenopausal uremic women. Presumably low estrogen levels in the postmenopausal state lead to the increased gonadotropin levels. The age at which menopause begins in chronic kidney failure tends to be decreased when compared to normal women.


The high frequency of anovulation leads sequentially to lack of formation of the corpus luteum and failure of progesterone secretion. Because progesterone is responsible for transforming the endometrium into the luteal phase, lack of progesterone is associated with amenorrhea. For patients who desire to resume menses, administration of a progestational agent during the final days of the monthly cycle will usually be successful. On the other hand, ongoing menses can contribute significantly to the anemia of chronic kidney disease, particularly in those patients with hypermenorrhagia. In this setting, administration of a progestational agent during the entire monthly cycle will terminate menstrual flow. Rarely, a patient may require hysterectomy for refractory uterine bleeding.

It is not known whether the usual absence of menses in women with chronic kidney failure predisposes to the development of endometrial hyperplasia and possible carcinoma. Because these patients are often anovulatory, there is no disruption of the proliferative effect of estrogen by the release of progesterone. It is therefore recommended that women with chronic kidney failure be monitored closely by a gynecologist; it may be desirable in at least some cases to administer a progestational agent several times per year to interrupt the proliferation induced by unopposed estrogen release.

Although pregnancy can rarely occur in women on chronic dialysis, restoration of fertility as a therapeutic goal should be discouraged. In comparison, the abnormalities in ovulation can usually be reversed and successful pregnancy achieved in women with a well-functioning kidney transplant. Uremic women who are menstruating normally should be encouraged to use birth control.

Studies addressing the therapy of decreased libido and sexual function in uremic women are lacking. Amenorrheic hemodialysis patients may have low estradiol levels that can secondarily lead to vaginal atrophy and dryness and result in discomfort during intercourse. Such patients may benefit from local estrogen therapy or vaginal lubricants. Low-dose testosterone may be effective in increasing sexual desire but is rarely used secondary to potential toxicity. Use of a testosterone patch has been shown to be effective in surgically menopausal women with hypoactive sexual disorder and deserves further investigation as to its use in uremic women.[31] Bromocriptine therapy in hyperprolactinemic patients may help in restoring sexual function but has not been well studied. Estrogen supplementation may improve sexual function in those patients with low circulating estradiol levels. Successful transplantation is clearly the most effective means to restore normal sexual desire in women with chronic kidney failure.

Amenorrheic women on hemodialysis may also be at increased risk for metabolic bone disease.[32] In a recent study of 74 women on hemodialysis trabecular bone mineral density was found to be lower in amenorrheic patients as compared to those with regular menses. Although the total serum estradiol concentration was normal in the amenorrheic women when compared with nonuremic women, the values were significantly lower than those in regularly menstruating women. Whether such patients would benefit from estrogen therapy deserves further study. With regard to estrogen therapy it has been noted that woman on hemodialysis are often not treated in the same manner as nonuremic women. In three separate trials only 4.8%, 6%, and 11.3% of post menopausal females were noted to be receiving hormone replacement therapy. [33] [34] [35] Given the potential benefits of estrogen therapy on bone disease and cardiovascular morbidity, it is likely that such therapy is being underutilized in this patient population.


The kidney normally plays an important role in the metabolism, degradation, and excretion of several thyroid hormones. It is not surprising therefore that impairment in kidney function leads to disturbed thyroid physiology. All levels of the hypothalamic-pituitary-thyroid axis may be involved, including alterations in hormone production, distribution, and excretion. As a result, abnormalities in thyroid function tests are frequently encountered in uremia (Table 50-2 ). However, the overlap in symptomatology between the uremic syndrome and hypothyroidism requires a cautious interpretation of these tests. Nevertheless, it is ordinarily possible in the individual uremic patient to assess thyroid status accurately by physical diagnosis and thyroid function testing.

TABLE 50-2   -- Thyroid Abnormalities in Chronic Kidney Disease

↓ T3, normal rT3, T4 either low or normal

TSH normal, rises appropriately in hypothyroidism

Slight ↑ incidence of goiter


TSH, thyroid stimulating hormone.




Thyroid Hormone Metabolism

The kidney normally contributes to the clearance of iodide, primarily by glomerular filtration. Thus, iodide excretion is diminished in advanced renal failure, leading sequentially to an elevated plasma inorganic iodide concentration and an initial increment in thyroidal iodide uptake. The ensuing marked increase in the intrathyroidal iodide pool results in diminished uptake of radiolabeled iodide by the thyroid in uremic patients.[36] Increases in total body inorganic iodide can potentially block thyroid hormone production (the Wolff-Chaikoff effect). Such a change may explain the slightly higher frequency of goiter and hypothyroidism in patients with chronic renal failure. [37] [38]

Most patients with end-stage renal disease have decreased plasma levels of free triiodothyronine (T3), which reflect diminished conversion of T4 (thyroxine) to T3 in the periphery. [39] [40] [41] [42] This abnormality is not associated with increased conversion of T4 to the metabolically inactive reverse T3 (rT3) because plasma rT3 levels are typically normal. This finding differentiates the uremic patient from patients with chronic illness.[42] In the latter setting, the conversion of T4 to T3 is similarly reduced; however, generation of rT3 from T4 is enhanced. Reduced protein binding can contribute to the low levels of total T3. Circulating thyroid hormones are normally bound to thyroid hormone-binding globulin (TBG) and, to a lesser extent, to prealbumin and albumin. Although circulating TBG and albumin levels are typically normal in uremia (in the absence of the nephrotic syndrome), retained substances in renal failure may inhibit hormone binding to these proteins. As examples, urea, creatinine, indoles, and phenols all strongly inhibit protein binding of T4. This inhibition may explain why some patients with chronic renal failure have low serum T4 levels. Another possible contributing factor is that binding inhibitors may inhibit T4 binding to solid phase matrices such as resin and activated charcoal used in measuring T4 levels.[43] Free fatty acids and heparin also interfere with T4 binding to TBG; thus, the routine use of heparin to prevent clotting in the dialysis tubing may explain the transient elevation in plasma T4 levels that commonly occur during hemodialysis.

Low T3 levels have also been linked to the malnutrition-inflammation syndrome, which is frequently present in patients with chronic kidney disease and associated with increased cytokine levels. In a recent report, a strong inverse relationship was found between free T3 levels and interleukin-6 and C-reactive protein.[44] A decrease in the degree of systemic inflammation as occurs during the successful treatment of an infection leads to an increase in T3 levels. The administration of Na-citrate to correct the low level metabolic acidosis frequently present in dialysis patients also leads to an increase in T3 levels.[45] This beneficial effect occurs without a measurable change in cytokine levels.

Hypothalamic-Pituitary Dysfunction

The plasma concentration of thyroid stimulating hormone (TSH) is usually normal in chronic renal failure. [39] [40] However, the TSH response to exogenous thyroid releasing hormone (TRH) is often blunted and delayed, with a prolonged time required to return to baseline levels.[46] Reduced renal clearance may contribute to delayed recovery because TSH and TRH are normally cleared by the kidney. However, the blunted hormone response also suggests disordered function at the hypothalamic-pituitary level that may be induced by uremic toxins. When compared to normals, patients with chronic renal failure have an attenuated rise in TSH levels during the evening hours[47] and the normally pulsatile secretion of TSH is smaller in amplitude.[48] Despite these perturbations, TSH release responds appropriately to changes in the circulating level of thyroid hormones. Exogenous T3 lowers TSH levels and can totally suppress the secretory response to exogenous TRH. On the other hand, TSH production increases appropriately in response to thyroid ablation. The latter response is important clinically because TSH levels should rise (as in normals) when a uremic patient develops hypothyroid.[40]

Clinical Manifestations

There is substantial clinical overlap between chronic renal failure and hypothyroidism. In addition to low total and free plasma T3 levels, there are a number of symptoms that are common to both conditions including cold intolerance, puffy appearance, dry skin, lethargy, fatigability, and constipation. Thyroid gland size is often increased in patients with chronic kidney disease to include patients with a well-functioning allograft. [49] [50] In addition, the frequency of goiter is increased in end-stage renal disease. [40] [51] These patients may also have a slightly higher frequency of thyroid nodules and thyroid cancer. [39] [52] Why this might occur is not known. Despite these findings, most uremic patients are considered to be euthyroid as evidenced by normal TSH levels, basal metabolic rate, and tendon relaxation time. [40] [41] The latter observations are important because they suggest that some of the clinical findings used to diagnose hypothyroidism in subjects with normal renal function can also be applied to patients with renal failure. Hypothyroidism can occur in patients with renal disease, with a frequency that may be slightly greater than that in the general population. [40] [52] The diagnosis can be established by the demonstration of an elevated plasma TSH concentration, usually associated with a reduced plasma T4 concentration and normal TBG levels. Delayed deep tendon relaxation may be a confirmatory clinical finding.

Despite the euthyroid status of most uremic patients, there is some evidence for blunted tissue responsiveness of T3. Although basal oxygen utilization is normal in renal failure, the expected increase following the administration of T3 is not seen. It has also been suggested that decreased responsiveness to T3 may have a protective effect by minimizing protein catabolism. Recent evidence suggest a dialyzable factor in uremic plasma may interfere in the binding of thyroid hormone receptors to thyroid response elements in the genome.[53] This inhibitory effect could contribute to a decrease in transcriptional activation induced by T3.

To summarize, chronic renal failure is associated with multiple disturbances in thyroid metabolism that are manifested in the plasma by low free and total T3 levels and normal rT3 and T4 concentrations (unless the latter is reduced by low TBG or albumin levels). Nevertheless, the plasma TSH concentration is normal and most patients are euthyroid.


Disturbances in carbohydrate metabolism, especially glucose intolerance, are common in CKD patients, particularly in patients on dialysis. [54] [55] [56] [57] [58] [59] [60] [61] One major factor behind the reduced glucose tolerance in uremia is an impaired sensitivity to insulin (insulin resistance, IR) in peripheral tissues, mainly in skeletal muscle. In non-dialyzed uremic patients the insulin dose-response curve is characterized by a decreased maximal response and by a rightward shift. The most common manifestation of IR is glucose intolerance. However, in addition to abnormalities in carbohydrate metabolism, as has been pointed out,[62] the IR syndrome is accompanied by an elevation in non-esterified fatty acids, abnormalities in visceral fat metabolism, elevated uric acid, elevated hematocrit, endothelial dysfunction, and abnormalities in glucocorticoids. In addition, there appear to be differences in the phenotypic expression of the syndrome between men and women and associated abnormalities in fat distribution.[62] Elevations in non-esterified fatty acids, in turn, appear to contribute to glucose intolerance, hypertension, and increased arteriosclerosis. The abnormalities in glucocorticoid metabolism include abnormally increased cortisol levels as well as abnormalities in the hypothalamic-pituitary-adrenal axis. In women, adipose cells express fewer glucocorticoid receptors and less of the enzyme that metabolizes cortisol, 11 beta-hydroxysteroid dehydrogenase.

The characterization of IR in dialysis patients dates back to classic studies from the late 1950s. [63] [64] [65] [66] [67] [68] [69] [70] [71] [72] [73] Defronzo and colleagues,[63] in experiments using the euglycemic insulin clamp technique. They demonstrated that in 17 chronically uremic and 36 control subjects, IR reflected tissue insensitivity to insulin rather than suppression of hepatic glucose production by physiologic hyperinsulinemia or abnormalities in insulin-mediated glucose uptake by the liver. Since these classic studies in uremic patients, other work has demonstrated abnormalities in insulin/carbohydrate metabolism in patients with early kidney disease. [58] [59] [61] [74] [75] [76] [77]Furthermore, IR has also been documented among patients with nephrotic syndrome, polycystic kidney disease,[78] and in kidney transplant and diabetic patients. [79] [80] [81] The management of IR among patients with kidney disease presents some challenges because both the underlying disease process and the various treatment modalities conspire to modulate the IR state.

Insulin Resistance in Dialysis Patients

Insulin resistance may have an important role in the development of atherosclerosis, which is the most common cause of morbidity and mortality in hemodialysis patients. [82] [83] [84] IR and concomitant hyperinsulinemia occur regardless of underlying etiology of the kidney disease. Once insulin production begins to fail in dialysis patients, glucose intolerance develops particularly in the context of prevailing insulin resistance. Evidence suggests that reduced insulin production results from beta cell insensitivity to glucose rather than functional exhaustion of beta cells.[85] Both hemodialysis and peritoneal dialysis treatment improve insulin resistance. The mechanism of IR in dialysis patients is multifactorial. [86] [87] [88] [89] [90] Accumulation of nitrogenous wastes, reduced excretion of adiponectin, the concomitant presence of inflammation and heightened expression of pro-inflammatory cytokines such as TNF-alpha, hyperparathyroidism,[91] and erythropoietin, as well as other hitherto obscure factors are thought to play a role. Notably, resistin, a recently discovered protein that is important in adipogenesis, has been reported to not be elevated in IR, [92] [93] although this is controversial.[94] Kraus and co-workers have reported that in uremia, urea-derived cyanate reacts with amino groups irreversibly forming carbamoyl amino acids (C-AA) and carbamoyl proteins.[95] These carbamoylated molecules can affect binding and trafficking and alter metabolic pathways. N-carbamoyl-L-asparagine (N-C-Asn) was able to reduce insulin-sensitive glucose uptake by 34%, although it did not affect insulin binding.

Insulin resistance in patients on peritoneal dialysis (CAPD) merits discussion because the dialysis procedure itself, in addition to the uremic state, appears to modulate the magnitude of IR.[96] Indeed, there is evidence that IR may be exacerbated by the intraperitoneal presence of dialysate. [97] [98] Comparing the effect of PD versus HD treatment, PD has significantly higher insulin sensitivity than HD—this may reflect the presence of dextrose based dialysate in the peritoneal cavity because it is reduced with the use of icodextran dialysate. [99] [100] Recent evidence, including an open label study has demonstrated efficacy for rosiglitazone (RSG), a thiazolidinedione, in improving insulin resistance in peritoneal dialysis patients. [101] [102]

Management of IR in dialysis patients is multifaceted, although definitive evidence for the efficacy of some of these interventions on clinical outcomes such as cardiovascular end points or mortality is still lacking.[103] Calcium and phosphate disturbances, including vitamin D therapy, significantly reduces insulin resistance in uremia, suggesting a role for hyperparathyroidism. [60] [104] This issue is controversial because it has been suggested that low phosphorous in patients with primary hyperparathyroidism could explain IR,[105] or that increased weight associated with hyperparathyroidism rather than hyperparathyroidism per se accounts for IR.[106] Treatment with recombinant human erythropoietin (EPO) also appears to improve insulin sensitivity, although the mechanism is not well established. [107] [108] [109] Angiotensin-converting enzyme inhibitors have been shown to improve insulin resistance, hyperinsulinemia, and glucose intolerance in uremic patients.[110] The Diabetes Reduction Assessment with ramipril and rosiglitazone Medication trial (DREAM trial) results were recently published. In this study with over 5000 patients rosiglitazone reduced the risk of developing type 2 diabetes by 62% (P < 0.0001) relative to placebo among people at high risk of developing type 2 diabetes. Treatment with the ACE inhibitor ramipril, however, did not prevent or reduce the likelihood of progression to diabetes.[111] Two other trials named ONTARGET and NAVIGATOR are underway to evaluate whether angiotensin blockade wither with or without treatment with an adjunctive Thiazolidinedione (TZDs), such as roglitazone, could prevent diabetes mellitus. [112] [113]

Insulin Resistance in Transplant Patients

Insulin resistance has been extensively documented in renal transplant recipients, both adults and children. [114] [115] [116] [117] [118] [119] [120] IR improves with kidney transplantation in part because of better clearance of factors such as adiponectin, a protein secreted exclusively by adipocytes.[121] On the other hand, steroids have been implicated in inducing an insulin-resistant state. These drugs plus declining graft function together enhance insulin resistance.[114] [116] [122] Studies have suggested that steroids induce abnormalities in nonoxidative glucose disposal.[116] The reduction in nonoxidative glucose disposal appears to be associated with reduced lean body mass and the incapacity to release energy as heat after infusion of insulin (i.e., a thermogenic effect).[116] The role of steroids has been recently explored by Midtvedt and colleagues in some elegant studies. They tested the hypothesis that steroid withdrawal 1 year post transplantation improves insulin sensitivity. They also explored whether complete withdrawal (i.e., discontinuing even low dose (5 mg/day) of prednisone) would have an even further beneficial effect on insulin sensitivity.[122] Using an hyperinsulinemic euglycemic glucose clamp procedure and measuring an insulin sensitivity index (the glucose disposal rate divided by mean serum insulin the last 60 minutes of the clamp), they showed a significant increase in insulin sensitivity (by 24%). However, complete withdrawal of prednisone did not improve insulin sensitivity any further. On the other hand, the effect of tacrolimus and cyclosporine on carbohydrate metabolism in renal transplant recipients appears to be on pancreatic islet cell function rather than insulin resistance. [123] [124] However, this is controversial because other workers have documented enhanced IR at least among tacrolimus treated patients. [125] [126] In fact, Teutonico reported on the effect of calcineurin inhibitor withdrawal and conversion to sirolimus on IR and glucose metabolism. IR is reduced on CNI withdrawal but increases dramatically with the introduction of sirolimus.[127] A recent study, however, suggests that this effect is transient.[128] Interestingly, patients who undergo both pancreatic-kidney transplantation manifest quite severe insulin resistance. This is marked by insulin receptor down-regulation and impaired anti-lipolytic action of insulin. This explanation for this observation, made over 10 years ago, remains obscure.[129]

In addition to withdrawal of steroids and the modulation of CNI dosing, the insulin sensitizer rosiglitazone has been found effective in the management of disordered carbohydrate metabolism in renal transplant recipients; 16 of 22 patients with NODM after renal transplantation responded successfully to rosiglitazone therapy.[130] There were no changes either in serum creatinine concentrations, or cyclosporine and tacrolimus blood levels, respectively. Other workers have confirmed the efficacy and safety of rosiglitazone in this population. [131] [132] It has also been argued that IR may be an important factor in causing chronic allograft dysfunction, although this opinion has not gained much traction in terms of supportive evidence.[133]

Insulin Resistance in Patients with Chronic Kidney Disease Not on Dialysis

Insulin resistance has been postulated as an important factor in modulating the excess risk of cardiovascular disease. IR manifests with hyperinsulinemia, glucose intolerance, hyperglycemia, and dyslipidemia.[134] IR may also indirectly result in renal damage.[135] Several other possible factors have been implicated ( Table 50-3 ). The impact of accumulating nitrogenous waste products in the context of a progressively uremic environment over time in a patient with CKD has been supported by several studies. Both renal replacement therapy and a low protein diet improve insulin resistance. As well, the ingestion of an oral carbonaceous adsorbent reduces plasma glucose and insulin needs in uremic diabetic rats, pointing to a role for uremic toxins in the gastrointestinal tract.[55] An insulin resistance inducing peptide in uremic serum has been isolated and showed initial promise (reviewed in Ref. 55). Accumulation of uric acid in renal failure also appears to be associated with insulin resistance, although causality remains to be proven. Pseudouridine, a nucleotide that accumulates in patients with progressive kidney failure, has been observed in rats to reduce glucose utilization in muscles isolated. N-carbamoyl-L-asparagine has been observed to selectively reduce insulin-mediated glucose uptake in adipocytes.[95] N-carbamoyl-L-asparagine, one of 15 carbamoylated amino acids, selectively reduced insulin-mediated glucose uptake in adipocytes. Carbamoylation of insulin also reduces its activity.

TABLE 50-3   -- Possible Causes of Insulin Resistance in Patients with Chronic Kidney Disease

Kidney related

 Accumulation of nitrogenous wastes

 Uric acid



Kidney unrelated



 Pro-inflammatory cytokines (e.g., TNF-alpha)

 Free fatty acids




It is postulated that IR results in compensatory hyperinsulinism and that excessive insulin promotes the proliferation of renal cells and stimulates the production of other important growth factors such as insulin-like growth factor-1 and transforming growth factor beta. [55] [62] [135] It has also been suggested that insulin up-regulates the expression of angiotensin II type 1 receptor in mesangial cells, enhancing the deleterious effects of angiotensin II in the kidney, and stimulating production and renal action of endothelin-1. Moreover, insulin resistance and hyperinsulinemia are associated with decreased endothelial production of nitric oxide and increased oxidative stress, which has been also implicated in the progression of diabetic nephropathy.[136] In addition, among patients with diabetic kidney disease, the diabetes state is obviously the most plausible reason for insulin resistance in these patients. Type 1 and type 2 diabetes have both been associated with insulin resistance, although the mechanistic factors accounting for insulin resistance are likely to be different. [137] [138] [139] [140] [141] [142] A role for insulin resistance in the pathogenesis of microalbuminuria has been suggested, because the severity of IR appears to correlate with the severity of microalbuminuria.[138] Indeed, data suggests that endothelial-dependent vasodilatation is abnormal in microalbuminuric type 2 diabetic patients, and this is linked with insulin resistance. [139] [141]

Insulin Resistance in Patients with Chronic Kidney Disease and Thiazolidinediones

Thiazolidinediones (TZDs) are insulin sensitizers that act through reduction in IR. TZDs bind a nuclear receptor, called peroxisome proliferators activated receptor gamma (PPARg) and are a member of the ligand-activated nuclear receptor superfamily. [143] [144] [145] [146] [147] [148] [149] [150] There are two other PPAR isoforms, designated PPARalpha and -beta/delta.[145] These receptors play an important role in lipid metabolism and glucose homeostasis; indeed, enormous attention has been focused on their role in regulating adipogenesis, lipid metabolism, insulin sensitivity, inflammation, and blood pressure. [145] [146] PPAR isoforms are widely distributed—principally expressed in adipose tissue, but also highly expressed in the kidney. PPAR expression has also been documented in vascular endothelial cells, vascular smooth muscle cells, macrophages, and colonic epithelial cells. [148] [149]

There is differential expression in the kidney of PPAR. PPAR-alpha is predominantly expressed in renal proximal tubules and medullary thick ascending limbs.[148] PPAR-gamma is mainly localized in renal medullary collecting duct with lower expression in renal glomeruli and renal microvasculature. Unlike PPAR-alpha and -gamma, PPAR-beta/delta is ubiquitously expressed in every segment along the nephron. In ureter and urinary bladder, all PPAR isoforms are mainly localized in urothelium of ureter and bladder. Varied physiological and pathophysiological roles of PPARs in tissues along urinary tract have been suggested. PPAR-alpha plays a major role in triggering fatty acid utilization and the adaptive response to dietary lipids in the kidney. PPAR-beta/delta contributes to cell survival of renal interstitial cell in medullary hyperosmality. PPAR-gamma is involved in regulating renal hemodynamic and water and sodium transport.

The importance of PPARg receptors has been elegantly emphasized by studies that have either induced PPAR deficiency using knockouts, or using agonists including TZDs in animal (largely on rats and mice) and human studies.[151] PPAR deficiency appears to aggravate the severity of diabetic nephropathy through an increase in extracellular matrix formation, inflammation, and circulating free fatty acid and triglyceride concentrations. [152] [153] Several studies show that TZDs are renoprotective by reducing blood pressure, urine albumin excretion, reducing glomerular hyperfiltration, preventing intrarenal arteriosclerosis, and preventing glomerulosclerosis and tubulointerstitial fibrosis (reviewed in Ref. 151). These actions appear to be mediated through reduced endothelial dysfunction, [154] [155] [156] [157] reduced proliferation through stimulating apoptosis of renal proximal tubular cells, [158] [159] and reduced TGF-beta expression, [160] [161] and through the effects on matrix production (by effects on matrix metalloproteinases[162] and plasminogen activator inhibitor type 1 (PAI-1). [163] [164] TZDs have also been postulated to be anti-inflammatory by attenuating oxidative injury in the kidney and lipid mediated mesangial injury. [166] [167] [168]

In summary, IR has emerged as an important consequence of kidney disease but also a potentially important conspirator in inducing further kidney damage, whether in association with obesity and diabetes mellitus, or as a consequence of the kidney disease itself. Indeed, it has been postulated that the excess cardiovascular mortality that heralds and then subsequently accompanies the development of kidney failure may have at least part of its origins in the insulin resistant that develops.

Growth Hormone and Kidney Disease

Resistance to growth hormone (GH) is a significant complication of advanced CKD, particularly among children.[169] Circulating GH levels may be normal or even elevated in uremia, but resistance to the hormone leads to stunting of body growth in children and contributes to muscle wasting in adults.[170] Insensitivity to GH is the consequence of multiple defects in the GH/insulin-like growth factor-1 (IGF-1) system including, at a molecular level, in JAK/STAT-dependent gene regulation[171] ( Fig. 50-1 ). However, the clinical implications of reduced GH activity may extend beyond “growth” per se and could have cardiovascular implications because growth hormone is required for maintaining normal cardiac structure and function and remodeling.[172] As well, IR (discussed earlier) and abnormalities in GH physiology in uremic patients may be linked because some evidence suggests that hyperinsulinism (as observed in IR) could inhibit GH action via inhibition of GH-induced JAK2 phosphorylation.[173]

FIGURE 50-1  Deranged somatotropic axis in chronic renal failure. The GH/IGF-I axis in chronic kidney disease (CKD) is changed markedly compared with the normal axis. In CKD, the total concentrations of the hormones in the GH/IGF-I axis are not reduced, but there is reduced effectiveness of endogenous GH and IGF-I, which probably plays a major role in reducing linear bone growth. The reduced effectiveness of endogenous IGF-I likely is due to decreased levels of free, bioactive IGF-I as levels of circulating inhibitory IGFBP are increased.  (Redrawn from Roelfsema V, Clark RG: The growth hormone and insulin-like growth factor axis: Its manipulation for the benefit of growth disorders in renal failure. J Am Soc Nephrol 12(6): 1297–1306, 2001.)



The defects in the somatotropic hormone axis that lead to GH insensitivity have been extensively investigated.[174] Serum levels of IGF-I and IGF-II are normal in CKD patients not receiving dialysis, whereas in end-stage renal disease (ESRD) patients IGF-I levels are slightly decreased and IGF-II levels slightly increased. These serum IGF-I levels appear inadequately low and likely reflects decreased hepatic production of IGF-I in kidney failure. In turn, this hepatic insensitivity to the action of GH is likely to be the result of both abnormal GH receptor signaling and reduced GH receptor expression in liver tissue. The actions and metabolism of IGFs are modulated by specific high-affinity IGF binding proteins (IGFBPs). IGFBP levels are high in kidney failure because of two factors: increased hepatic production of IGFBPs (IGBP-1 and IGBP-2) and reduced excretion of IGBPs (serum levels have a 7-fold to 10-fold higher IGFBP level than normal) leading to reduced IGF bioactivity despite normal total IGF levels. Excessive levels of circulating high-affinity IGFBPs in kidney failure patients results in inhibition of IGF action on growth plate chondrocytes by competition with the type 1 IGF receptor for IGF binding contributing to growth retardation.

The clinical implications of inadequate GH function in children with kidney failure are growth failure, with accompanying potential psychological, educational, and quality of life problems.[177] Indeed, data suggests that children with growth failure have a higher rate of hospitalization and higher mortality.[178] In adults, reduced muscle mass and malnutrition [179] [180] as well postulated renal and cardiovascular sequelae.[181]

Growth Failure in Children

Growth failure is usually easily recognized in children with kidney disease because growth is monitored by both the pediatric nephrologists or the general pediatrician, or both. [182] [183] [184] However, occasionally, growth failure is the presenting symptom leading to a diagnosis of an underlying kidney disorder, such as renal tubular acidosis. Factors that contribute to the severity of growth failure in patients with CKD include: age at onset, primary renal disease, caloric deficiency, abnormal protein metabolism, metabolic acidosis, renal osteodystrophy, anemia, as well as other co-morbidities.[183] Identifying and addressing growth failure early on is vital to treating the child with CKD. Presently, although most patients with CKD receive treatment for their anemia, acidosis and renal osteodystrophy, which can improve their growth, data suggests that most pediatric CKD patients in the United States are not treated with growth hormone for their growth failure.[184] Other aspects of managing growth failure are also quite complex. Psychological, [186] [187] psychosocial,[187] cognitive,[188] and quality of life issues [190] [191] require monitoring and management. Routine growth assessments, monitoring of laboratory data, and psycho-social assessments are part of the multifaceted approach. The initial evaluation of the child with growth failure associated with CKD should include obtaining appropriate laboratory and radiographic studies. These allow for assessment of pubertal stage and bone age. A detailed nutritional evaluation,[191] as well as assessment of the child's growth pattern including calculation of growth velocity, assessment of height potential by calculating mid-parental height, and tanner staging are an important and necessary part of the work-up. If growth failure continues without significant improvement in growth velocity, further laboratory work-up is indicated. Unusual causes for poor growth in the CKD population, such as hypothyroidism should be screened for. [193] [194] If this work-up is negative, and especially if there is a downward crossing of growth percentiles on their growth curve, or an annualized growth rate that is falling. Growth hormone therapy should be strongly considered in patients who have a standardized height less than 2 SDS below the mean.

Recombinant growth hormone (rhGH) is reviewed extensively elsewhere. [195] [196] [197] Recombinant growth hormone (rhGH) is used in approximately 15% of all children on dialysis.[184] There is strong evidence to indicate that rhGH can increase growth velocity and final adult height in pediatric ESRD patients.[196] It is estimated that on average, 1 year of 28 IU/m(2)/wk hGH in children with CRF results in a 4 cm/yr increase in height velocity above that of untreated controls.[197] In addition, rhGH improves head circumference.[198] Evidence suggests that early institution is likely to improve the final height achieved.[199] However, other important factors include, age, GFR, target height, and the pretreatment growth rate.[200] rhGH is administered as a daily subcutaneous injection. Once treatment is initiated, the patient should be monitored closely and regularly, to determine if growth is adequate, and if dose adjustments in treatment are needed. Monitoring of height, weight, and pubertal stage, as well as a nutritional evaluation, funduscopic examination, assessment of blood chemistries and PTH levels should occur every 3 to 4 months. Patients under the age of 3 should have their head circumference monitored routinely. On a yearly basis, bone films should be obtained to evaluate for renal osteodystrophy and bone age should be determined. Recombinant human GH (rhGH) is approved for the treatment of growth failure in children with kidney failure. A daily dosage of 0.05 mg/kg body wt given by subcutaneous injection is recommended. [203] [204] Using this dose, two large multicenter clinical trials in kidney failure patients have shown that rhGH treatment can improve statural growth. [205] [206] Recent studies showed that rhGH treatment is most effective when it is started at an early age and that the growth response is affected by the degree of renal impairment.[196] RhGH is well tolerated and not associated with a higher incidence of glucose intolerance, pancreatitis, progressive deterioration of renal function, acute allograft rejection, and fluid retention. [207] [208] New formulations of rhGH, to allow more convenient administration regimens, have been tested in animals. One form, an injectable sustained-release formulation of rhGH in erodible polylactate polyglycolate microspheres, was approved recently by the FDA for use in pediatric GH-deficient patients. Indeed, there is evidence that these new formulations of rhGH result in significant catch-up growth.

Adult Patients with Chronic Kidney Disease and Growth Hormone

Malnutrition and a high catabolic rate is a major problem in dialysis patients. Indeed, malnutrition is an important risk factor for poor outcome in dialysis patients. In patients with CKD not on dialysis, GH itself does not increase GFR.[208] Similarly, in children with CKD and growth failure, the administration of GH does not influence kidney function.[208] However, in an interesting prospective open-labeled trial Vijayan and colleagues showed that IGF-1 increases glomerular filtration rates.[209] On the other hand, among CKD patients receiving dialysis, evidence suggests that growth hormone improves anabolic function[210]; (reviewed extensively in Ref. 211). Furthermore, the administration of recombinant human growth hormone stimulates protein synthesis, decreases urea generation, and improves nitrogen balance. The anabolic effects of growth hormone appear to be due to Gh-stimulated hepatic production of insulin-like growth factor-I (IGF-1) (GH stimulates the production and secretion of IGF-I in a variety of organs: bone, muscle and kidney, in addition to the liver).[208] In turn, IGF-1 enhances intracellular transport of glucose and amino acids, stimulates protein synthesis, suppresses protein degradation, and stimulates bone growth and enlargement of many organs.[208]

The use of rhGH or rhGH plus rhIGF-I in dialysis patients has been generally well tolerated. [213] [214] [215] [216] [217] [218] However, in trials testing the efficacy and safety of rhGH in critically ill catabolic patients, a twofold increase in overall mortality of critically ill patients from approximately 20% to 40% occurred.[218] Of note, though, the dosage of rhGH in the critically ill patients was double the recommended dosage for growth disorders in pediatric dialysis patients. Therefore, based on this experience, the current recommendation is that rhGH treatment not be initiated in patients with an acute critical illness.[219] The cause of the increase in mortality is unknown; therefore, it seems reasonable that caution must be exercised in the use of rhGH in adults outside the currently approved use in GH deficiency. Other adverse reactions to GH treatment in CRF include an increased risk of benign intracranial hypertension.[220] The recent suggestion of an increased incidence of type II diabetes mellitus in children who are treated with GH also indicates that rhGH-treated patients deserve close monitoring.[221]

No drug has been approved for use in patients with CKD and ESRD to stimulate renal function or to delay the need for dialysis.[208] Preliminary studies from Hammerman's group using high doses of rhIGF-I (100 mg/kg twice a day) suggest promising results in improvement in renal function but a high rate of adverse effects. Vijayan and colleagues, also from Hammerman's group,[209] showed in patients with ESRD that efficacy could be maintained and side effects could be reduced with the use of an intermittent treatment regimen (4 d on treatment, 3 d off treatment) for rhIGF-I (50 mg/kg per d). This approach was well tolerated and resulted in a sustained improvement in renal function, which may be related to the IGFBPs being relatively unaffected by this mode of delivery.

Therefore, in summary, although the role of GH in children with CKD for the treatment of short stature and growth failure or both is well accepted, the role of GH in adult CKD patients either on or before starting dialysis has not become established. The higher risk of GH in critically ill patients has raised some concerns and more studies will be necessary.


1. Diemont WL, Vruggink PA, Meuleman EJ, et al: Sexual dysfunction after kidney replacement therapy.  Am J Kidney Dis  2000; 35:845-851.

2. Russo D, Musone D, Alteri V, et al: Erectile dysfunction in kidney transplanted patients: efficacy of sildenafil.  J Nephrol  2004; 17:291-295.

3. Prem AR, Punekar SV, Kalpana M, et al: Male reproductive function in uraemia: Efficacy of haemodialysis and kidney transplantation.  Br J Urol  1996; 78:635-638.

4. Guvel S, Pourbager M, Torun D, et al: Calcification of the epididymis and the tunica albuginea of the corpora cavernosa in patients on maintenance hemodialysis.  J Androl  2004; 25:752-756.

5. Bellinghieri G, Santoro G, Santoro D, et al: Ultrastructural changes of corpora cavernosa in men with erectile dysfunction and chronic renal failure.  Semin Nephrol  2004; 24:488-491.

6. Handelsman DJ: Hypothalamic-pituitary gonadal dysfunction in kidney failure, dialysis and kidney transplantation.  Endocr Rev  1985; 6:151-182.

7. Levitan D, Moser SA, Goldstein DA, et al: Disturbances in the hypothalamic-pituitary-gonadal axis in male patients with acute kidney failure.  Am J Nephrol  1984; 4:99-106.

8. Dunkel L, Raivio T, Laine J, Holmberg C: Circulating luteinizing hormone receptor inhibitor(s) in boys with chronic kidney failure.  Kidney Int  1997; 51:777-784.

9. Schaefer F, Veldhuis JD, Robertson WR, et al: The Cooperative Study Group on Pubertal Development in Chronic Kidney Failure: Immunoreactive and bioactive luteinizing hormone in pubertal patients with chronic kidney failure.  Kidney Int  1994; 45:1465-1476.

10. Ayub W, Fletcher S: End-stage kidney disease and erectile dysfunction. Is there any hope?.  Nephrol Dial Transplant  2000; 15:1525-1528.

11. Phocas I, Sarandakou A, Rizos D, Kapetanaki A: Serum α-immunoreactive inhibition in males with kidney failure, under haemodialysis and after successful kidney transplantation.  Andrologia  1995; 27:253-258.

12. Massry SG, Goldstein DA, Procci WR, Kletzky OA: Impotence in patients with uremia: A possible role for parathyroid hormone.  Nephron  1977; 19:305-310.

13. Blumberg A, Wildbolz A, Descoeudres C, et al: Influence of 1,25 dihydroxycholecalciferol on sexual dysfunction and related endocrine parameters in patients on maintenance hemodialysis.  Clin Nephrol  1980; 13:208-214.

14. Caticha O, Norato DYJ, Tambascia MA, et al: Total body zinc depletion and its relationship to the development of hyperprolactinemia in chronic kidney insufficiency.  J Endocrinol Invest  1996; 19:441-448.

15. Palmer BF: Sexual dysfunction in men and women with chronic kidney disease and end-stage renal disease.  Adv Ren Replace Ther  2003; 10:48-60.

16. Palmer BF: Outcomes associated with hypogonadism in men with chronic kidney disease.  Adv Chronic Kidney Dis  2004; 11:342-347.

17. O'Sullivan DA, McCarthy JT, Kumar R, Williams AW: Improved biochemical variables, nutrient intake, and hormonal factors in slow nocturnal hemodialysis: A pilot study.  Mayo Clin Proc  1998; 73:1035-1045.

18. McPhatter LL, Lockridge Jr RS, Albert J, et al: Nightly home hemodialysis: Improvement in nutrition and quality of life.  Adv Ren Replace Ther  1999; 6:358-365.

19. Kokot F, Wiecek , Schmidt-Gayk H, et al: Function of endocrine organs in hemodialyzed patients of long-term erythropoietin therapy.  Artif Org  1995; 19:428-435.

20. Schaefer F, van Kaick B, Veldhuis JD, et al: Changes in the kinetics and biopotency of luteinizing hormone in hemodialyzed men during treatment with recombinant human erythropoietin.  J Am Soc Nephrol  1994; 5:1208-1215.

21. Schaefer RM, Kokot F, Wernze H, et al: Improved sexual function in hemodialysis patients on recombinant erythropoietin: A possible role for prolactin.  Clin Nephrol  1989; 31:1-5.

22. Palmer BF: Management of sexual dysfunction: Responsibility of the primary care physician or the specialist? An Editorial. NKF Website.  Adv Ren Replace Ther  1999; 6(4):

23. Bellinghieri G, Santoro D, Lo Forti B, et al: Erectile dysfunction in uremic dialysis patients: Diagnostic evaluation in the sildenafil era.  Am J Kidney Dis  2001; 38(4Suppl 1):S115-S117.

24. Lawrence IG, Price DE, Howlett TA, et al: Correcting impotence in the male dialysis patient: Experience with testosterone replacement and vacuum tumescence therapy.  Am J Kid Dis  1998; 31:313-319.

25. Mahajan SK, Abbasi AA, Prasad AS, et al: Effect of oral zinc therapy on gonadal function in hemodialysis patients.  Ann Intern Med  1982; 97:357-361.

26. Holley JL, Schmidt RJ, Bender FH, et al: Gynecologic and reproductive issues in women on dialysis.  Am J Kid Dis  1997; 29:685-690.

27. Ginsburg ES, Owen Jr WF: Reproductive endocrinology and pregnancy in women on hemodialysis.  Semin Dial  1993; 6:105-116.

28. Peng Y, Chiang C, Kao T, Hung K, et al: Sexual dysfunction in female hemodialysis patients: A multicenter study.  Kidney Int  2005; 68:760-765.

29. Hou S: Pregnancy in chronic kidney insufficiency and end-stage kidney disease.  Am J Kidney Ds  1999; 33:235-252.

30. Lim VS, Henriquez C, Sievertsen G, Frohman LA: Ovarian function in chronic kidney failure: evidence suggesting hypothalamic anovulation.  Ann Intern Med  1980; 93:21-27.

31. Simon J, Braunstein G, Nachtigall L, et al: Testosterone patch increases sexual activity and desire in surgically menopausal women with hypoactive sexual desire disorder.  J Clin Endocrinol Metab  2005; 90:5226-5233.

32. Weisinger JR, Gonzalez L, Alvarez H, et al: Role of persistent amenorrhea in bone mineral metabolism of young hemodialyzed women.  Kidney Int  2000; 58:331-335.

33. Cochrane R, Regan L: Undetected gynaecological disorders in women with kidney disease.  Hum Reprod  1997; 12:667-670.

34. Holley JL, Schmidt RJ, Bender FH, et al: Gynecologic and reproductive issues in women on dialysis.  Am J Kidney Dis  1997; 29:685-690.

35. Holley JL, Schmidt RJ: Hormone replacement therapy in postmenopausal women with end-stage kidney disease: A review of the issues.  Semin Dial  2001; 14:146-149.

36. Ramirez G, Jubiz W, Gutch CF, et al: Thyroid abnormalities in renal failure. A study of 53 patients on chronic hemodialysis.  Ann Intern Med  1973; 79:500.

37. Kutlay S, Atli T, Koseogullari O, et al: Thyroid disorders in hemodialysis patients in an iodine-deficient community.  Artificial Organs  2005; 29:329-332.

38. Lo JC, Chertow GM, Go AS, Hsu CY: Increased prevalence of subclinical and clinical hypothyroidism in persons with chronic kidney disease.  Kidney Int  2005; 67:1047.

39. Kaptein EM: Thyroid hormone metabolism and thyroid diseases in chronic renal failure.  Endocr Rev  1996; 17:45.

40. Kaptein EM, Quion-Verde H, Chooljian CJ, et al: The thyroid in end-stage renal disease.  Medicine (Baltimore)  1998; 67:187.

41. Medri G, Carella C, et al: Pituitary glycoprotein hormones in chronic renal failure: Evidence for an uncontrolled alpha-subunit release.  J Endocrinol Invest  1993; 16:169.

42. Wartofsky L, Burman KD: Alterations in thyroid function in patients with systemic illness: The “euthyroid sick syndrome”.  Endocr Rev  1982; 3:164.

43. Hochstetler L, Flanigan M, Lim V: Abnormal endocrine testing in a hemodialysis patient.  J Am Soc Nephrol  1994; 4:1754.

44. Zoccali C, Tripepi G, Cutrupi S, et al: Low triiodothyronine: A new facet of inflammation in end-stage renal disease.  J Am Soc Nephrol  2005; 16:2789.

45. Wiederkehr MR, Kalogiros J, Krapf R: Correction of metabolic acidosis improves thyroid and growth hormone axes in haemodialysis patients.  Nephrol Dial Transplant  2004; 19:1190.

46. Duntas L, Wolf CF, Keck FS, et al: Thyrotropin-releasing hormone: Pharmacokinetic and pharmacodynamic properties in chronic renal failure.  Clin Nephrol  1992; 38:214.

47. Pasqualini T, Zantleifer D, Balzaretti M, et al: Evidence of hypothalamic-pituitary thyroid abnormalities in children with end-stage renal disease.  J Pediatr  1991; 118:873.

48. Wheatley T, Clark PM, Clark JD, et al: Abnormalities of thyrotropin (TSH) evening rise and pulsatile release in hemodialysis patients: Evidence of hypothalamic-pituitary changes in chronic renal failure.  Clin Endocrinol (Oxf)  1989; 31:39.

49. Ramirez G: Abnormalities in the hypothalamic-hypophyseal axes in patients with chronic renal failure.  Semin Dial  1994; 7:138.

50. Malyszko J, Malyszko J, Wolczynski S, Mysliwiec M: Adiponectin, leptin, and thyroid hormones in patients with chronic renal failure and on renal replacement therapy: Are they related.  Nephrol Dial Transplant  2006; 21:145-152.

51. Castellano M, Turconi A, Chaler E, et al: Thyroid function and serum thyroid binding proteins in prepubertal and pubertal children with chronic renal insufficiency receiving conservative treatment, undergoing hemodialysis, or receiving care after renal transplantation.  J Pediatr  1996; 128:784.

52. Lin CC, Chen TW, Ng YY, et al: Thyroid dysfunction and nodular goiter in hemodialysis and peritoneal dialysis patients.  Perit Dial Int  1998; 18:516.

53. Santos G, Pantoja C, Silva A, Rodrigues M, et al: Thyroid hormone receptor binding to DNA and T3-dependent transcriptional activation are inhibited by uremic toxins.  Nuclear Receptor  2005; 3:1-11.

54. Alvestrand A: Carbohydrate and insulin metabolism in renal failure.  Kidney Int Suppl  1997; 62:S48-S52.

55. Rigalleau V, Gin H: Carbohydrate metabolism in uraemia.  Curr Opin Clin Nutr Metab Care  2005; 8:463-469.

56. Haviv YS, Sharkia M, Safadi R: Hypoglycemia in patients with renal failure.  Renal Fail  2000; 22:219-223.

57. Cramp DG, Wills MR: Disorders of carbohydrate and lipid metabolism in renal disease: A short review.  Ann Clin Biochem  1975; 12(5):179-181.

58. Stefikova K, Spustova V, Krivosikova Z, Dzurik R: Insulin resistance in kidney disease patients with mild to moderate kidney disease.  Bratisl Lek Listy  2004; 105(12):397-399.

59. Dzurik R, Spustova V, Janekova K: The prevalence of insulin resistance in kidney disease patients before the development of renal failure.  Nephron  1995; 69(3):281-285.

60. Sit D, Kadiroglu AK, Yilmaz ME, et al: The prevalence of insulin resistance and its relationship between anemia, secondary hyperparathyroidism, inflammation, and cardiac parameters in chronic hemodialysis patients.  Ren Fail  2005; 27(4):403-407.

61. Kobayashi S, Maesato K, Moriya H, et al: Insulin resistance in patients with chronic kidney disease.  Am J Kidney Dis  2005; 45(2):275-280.

62. Corry DB, Tuck ML: Selective aspects of the insulin resistance syndrome.  Curr Opin Nephrol Hypertens  2001; 10(4):507-514.

63. Defronzo RA, Tobin JD, Rowe JW, Andres R: Glucose intolerance in uremia: Quantification of pancreatic beta cell sensitivity to glucose and tissue sensitivity to insulin.  J Clin Invest  1978; 62(2):425-435.

64. Horton ES, Johnson C, Lebovitz HE: Carbohydrate metabolism in uremia.  Ann Intern Med  1968; 68(1):63-74.

65. Spitz IM, Rubenstein AH, Bersohn I, et al: Carbohydrate metabolism in renal disease.  Q J Med  1970; 39(154):201-226.

66. Chamberlain MJ, Stimmler L: The renal handling of insulin.  J Clin Invest  1967; 46(6):911-919.

67. Hampers CL, Soeldner JS, Doak PB, Merrill JP: Effect of chronic renal failure and hemodialysis on carbohydrate metabolism.  J Clin Invest  1966; 45(11):1719-1731.

68. Perkoff GT, Thomas CL, Newton JD, et al: Mechanism of impaired glucose tolerance in uremia and experimental hyperazotemia.  Diabetes  1958; 7(5):375-383.

69. Westervelt Jr FB, Schreiner GE: The carbohydrate intolerance of uremic patients.  Ann Intern Med  1962; 57:266-276.

70. Teuscher A, Fankhauser S, Kuffer FR: (Studies on carbohydrate metabolism in renal insufficiency.).  Klin Wochenschr  1963; 41:706-715.

71. Teuscher A: beurteilung der blutzuckerwerte und der glukosetoleranz bei uraemie.  Schweiz Med Wochenschr  1964; 94:69-74.

72. Cerletty JM, Engbring NH: Azotemia and glucose intolerance.  Ann Intern Med  1967; 66(6):1097-1108.

73. Cohen BD, Horowitz HI: Carbohydrate metabolism in uremia: Inhibition of phosphate release.  Am J Clin Nutr  1968; 21(5):407-413.

74. Eidemak I, Feldt-Rasmussen B, Kanstrup IL, et al: Insulin resistance and hyperinsulinemia in mild to moderate progressive renal failure and its association with aerobic work capacity.  Diabetologia  1995; 38:565-572.

75. Sechi LA, Catena C, Zingaro L, et al: Abnormalities of glucose metabolism in patients with early renal failure.  Diabetes  2002; 51:1226-1232.

76. Stenvinkel P, Ottosson-Seeberger A, Alvestrand A, et al: Renal hemodynamics and sodium handling in moderate renal insufficiency: The role of insulin resistance and dyslipidemia.  J Am Soc Nephrol  1994; 5:1751-1760.

77. Bodlaj G, Berg J, Pichler R, Biesenbach G: Prevalence, severity and predictors of HOMA-estimated insulin resistance in diabetic and nondiabetic patients with end-stage renal disease.  J Nephrol  2006; 19:607-612.

78. Vareesangthip K, Tong P, Wilkinson R, et al: Insulin resistance in adult polycystic kidney disease.  Kidney Int  1997; 52:503-508.chronic renal failure: Effect of insulin and amino acids. Am J Physiol 262:F168-F176, 1992.

79. Tuzcu A, Bahceci M, Yilmaz ME, et al: The determination of insulin sensitivity in hemodialysis and continuous ambulatory peritoneal dialysis in nondiabetic patients with end-stage renal disease.  Saudi Med J  2005; 26(5):786-791.

80. Schmitz O: Insulin-mediated glucose uptake in non dialyzed and dialyzed uremic insulin-dependent diabetic subjects.  Diabetes  1985; 34:1152-1159.

81. Wong TY, Szeto CC, Chow KM, et al: Rosiglitazone reduces insulin requirement and C-reactive protein levels in type 2 diabetic patients receiving peritoneal dialysis.  Am J Kidney Dis  2005; 46(4):713-719.

82. Sit D, Kadiroglu AK, Yilmaz ME, et al: The prevalence of insulin resistance and its relationship between anemia, secondary hyperparathyroidism, inflammation, and cardiacparameters in chronic hemodialysis patients.  Ren Fail  2005; 27(4):403-407.

83. Zoccali C, Tripepi G, Cambareri F, et al: Adipose tissue cytokines, insulin sensitivity, inflammation, and cardiovascular outcomes in end-stage renal disease patients.  J Ren Nutr  2005; 15(1):125-130.

84.   Lee SW, Park GH, Lee SW, et al: Insulin resistance and muscle wasting in non-diabetic end-stage renal disease patients. Nephrol Dial Transplant 2007 (in press).

85. Allegra V, Mengozzi G, Martimbianco L, Vasile A: Glucose-induced insulin secretion in uremia: Effects of aminophylline infusion and glucose loads.  Kidney Int  1990; 38(6):1146-1150.

86. Foss MC, Gouveia LM, Moyses Neto M, et al: Effect of hemodialysis on peripheral glucose metabolism of patients with chronic renal failure.  Nephron  1996; 73(1):48-53.

87. Schmitz O, Hjollund E, Alberti KG, et al: Assessment of tissue sensitivity to insulin in uraemic patients on long-term haemodialysis therapy.  Diabetes Res  1985; 2(2):57-63.

88. Kobayashi S, Maejima S, Ikeda T, Nagase M: Impact of dialysis therapy on insulin resistance in end-stage renal disease: Comparison of haemodialysis and continuous ambulatory peritoneal dialysis.  Nephrol Dial Transplant  2000; 15(1):65-70.

89. Mak RH: Insulin secretion and growth failure in uremia.  Pediatr Res  1995; 38(3):379-383.

90. Tuzcu A, Bahceci M, Yilmaz ME, et al: The determination of insulin sensitivity in hemodialysis and continuous ambulatory peritoneal dialysis in nondiabetic patients with end-stage renal disease.  Saudi Med J  2005; 26(5):786-791.

91. Graf H, Prager R, Kovarik J, et al: Glucose metabolism and insulin sensitivity in patients on chronic hemodialysis.  Metabolism  1985; 34(10):974-977.

92. Axelsson J, Heimburger O, Lindholm B, Stenvinkel P: Adipose tissue and its relation to inflammation: The role of adipokines.  J Ren Nutr  2005; 15(1):131-136.

93. Axelsson J, Bergsten A, Qureshi AR, et al: Elevated resistin levels in chronic kidney disease are associated with decreased glomerular filtration rate and inflammation, but not with insulin resistance.  Kidney Int  2006; 69(3):596-604.

94. Nusken KD, Kratzsch J, Wienholz V, et al: Circulating resistin concentrations in children depend on renal function.  Nephrol Dial Transplant  2006; 21(1):107-112.

95. Kraus LM, Traxinger R, Kraus AP: Uremia and insulin resistance: N-carbamoyl-asparagine decreases insulin-sensitive glucose uptake in rat adipocytes.  Kidney Int  2004; 65(3):881-887.

96. Cheng SC, Chu TS, Huang KY, et al: Association of hypertriglyceridemia and insulin resistance in uremic patients undergoing CAPD.  Perit Dial Int  2001; 21(3):282-289.

97. Allegra V, Mengozzi G, Martimbianco L, Vasile A: Glucose-induced insulin secretion in uremia: Effects of aminophylline infusion and glucose loads.  Kidney Int  1990; 38(6):1146-1150.

98. Delarue J, Maingourd C: Acute metabolic effects of dialysis fluids during CAPD.  Am J Kidney Dis  2001; 37(1 Suppl 2):S103-S107.

99. Amici G, Orrasch M, Da Rin G, Bocci C: Hyperinsulinism reduction associated with icodextrin treatment in continuous ambulatory peritoneal dialysis patients.  Adv Perit Dial  2001; 17:80-83.

100. Furuya R, Odamaki M, Kumagai H, Hishida A: Beneficial effects of icodextrin on plasma level of adipocytokines in peritoneal dialysis patients.  Nephrol Dial Transplant  2006; 21(2):494-498.Epub 2005 Oct 12.

101. Wong TY, Szeto CC, Chow KM, et al: Rosiglitazone reduces insulin requirement and C-reactive protein levels in type 2 diabetic patients receiving peritoneal dialysis.  Am J Kidney Dis  2005; 46(4):713-719.

102. Lin SH, Lin YF, Kuo SW, et al: Rosiglitazone improves glucose metabolism in nondiabetic uremic patients on CAPD.  Am J Kidney Dis  2003; 42(4):774-780.

103. Stefanovic V, Nesic V, Stojimirovic B: Treatment of insulin resistance in uremia.  Int J Artif Organs  2003; 26(2):100-104.

104. Procopio M, Borretta G: Derangement of glucose metabolism in hyperparathyroidism.  J Endocrinol Invest  2003; 26(11):1136-1142.

105. Haap M, Heller E, Thamer C, et al: Association of serum phosphate levels with glucose tolerance, insulin sensitivity and insulin secretion in non-diabetic subjects.  Eur J Clin Nutr  2006; 60(6):734-739.

106. Bolland MJ, Grey AB, Gamble GD, Reid IR: Association between primary hyperparathyroidism and increased body weight: A meta-analysis.  J Clin Endocrinol Metab  2005; 90(3):1525-1530.

107. Tuzcu A, Bahceci M, Yilmaz E, et al: The comparison of insulin sensitivity in non-diabetic hemodialysis patients treated with and without recombinant human erythropoietin.  Horm Metab Res  2004; 36(10):716-720.

108. Spaia S, Pangalos M, Askepidis N, et al: Effect of short-term rHuEPO treatment on insulin resistance in haemodialysis patients.  Nephron  2000; 84(4):320-325.

109. Igaki N, Takashima M, Ohyama M, et al: The beneficial effect of effective control of anemia on hyperinsulinemia and hypoxemia in a hemodialysis patient with corrected transposition of the great arteries.  Clin Exp Nephrol  2004; 8(2):163-167.

110. Fishman S, Rapoport MJ, Weissgarten J, et al: The effect of Losartan on insulin resistance and beta cell function in chronic hemodialysis patients.  Ren Fail  2001; 23(5):685-692.

111. DREAM Investigators : Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: A randomised controlled trial.  Lancet  2006; 368:1096-1105.

112. Leiter LA: Can thiazolidinediones delay disease progression in type 2 diabetes?.  Curr Med Res Opin  2006; 22(6):1193-1201.

113. Scheen AJ: Prevention of type 2 diabetes mellitus through inhibition of the renin-angiotensin system.  Drugs  2004; 64(22):2537-2565.

114. Hjelmesaeth J, Hagen M, Hartmann A, et al: The impact of impaired insulin release and insulin resistance on glucose intolerance after renal transplantation.  Clin Transplant  2002; 16(6):389-396.

115. Hjelmesaeth J, Jenssen T, Hagen M, et al: Determinants of insulin secretion after renal transplantation.  Metabolism  2003; 52(5):573-578.

116. Ekstrand A, Ahonen J, Gronhagen-Riska C, Groop L: Mechanisms of insulin resistance after kidney transplantation.  Transplantation  1989; 48(4):563-568.

117. Midtvedt K, Hartmann A, Hjelmesaeth J, et al: Insulin resistance is a common denominator of post-transplant diabetes mellitus and impaired glucose tolerance in renal transplant recipients.  Nephrol Dial Transplant  1998; 13(2):427-431.

118. de Vries AP, Bakker SJ: Insulin resistance after renal transplantation.  Diabetes Care  2002; 25(7) reply 1260-1261

119. Giordano M, Colella V, Dammacco A, et al: A study on glucose metabolism in a small cohort of children and adolescents with kidney transplant.  J Endocrinol Invest  2006; 29(4):330-336.

120. Siirtola A, Antikainen M, Ala-Houhala M, et al: Insulin resistance, LDL particle size, and LDL susceptibility to oxidation in pediatric kidney and liver recipients.  Kidney Int  2005; 67(5):2046-2055.

121. Chudek J, Adamczak M, Karkoszka H, et al: Plasma adiponectin concentration before and after successful kidney transplantation.  Transplant Proc  2003; 35(6):2186-2189.

122. Midtvedt K, Hjelmesaeth J, Hartmann A, et al: Insulin resistance after renal transplantation: The effect of steroid dose reduction and withdrawal.  J Am Soc Nephrol  2004; 15(12):3233-3239.

123. Boots JM, van Duijnhoven EM, Christiaans MH, et al: Glucose metabolism in renal transplant recipients on tacrolimus: The effect of steroid withdrawal and tacrolimus trough level reduction.  J Am Soc Nephrol  2002; 13(1):221-227.

124. Hjelmesaeth J, Midtvedt K, Jenssen T, Hartmann A: Insulin resistance after renal transplantation: impact of immunosuppressive and antihypertensive therapy.  Diabetes Care  2001; 24(12):2121-2126.

125. Dmitrewski J, Krentz AJ, Mayer AD, et al: Metabolic and hormonal effects of tacrolimus (FK506) or cyclosporin immunosuppression following renal transplantation.  Diabetes Obes Metab  2001; 3(4):287-292.

126. Nam JH, Mun JI, Kim SI, et al: beta-Cell dysfunction rather than insulin resistance is the main contributing factor for the development of postrenal transplantation diabetes mellitus.  Transplantation  2001; 71(10):1417-1423.

127. Teutonico A, Schena PF, Di Paolo S: Glucose metabolism in renal transplant recipients: Effect of calcineurin inhibitor withdrawal and conversion to sirolimus.  J Am Soc Nephrol  2005; 16(10):3128-3135.

128. van Duijnhoven EM, Christiaans MH, Boots JM, et al: Glucose metabolism in the first 3 years after renal transplantation in patients receiving tacrolimus versus cyclosporine-based immunosuppression.  J Am Soc Nephrol  2002; 13(1):213-220.

129. Boden G, Chen X, Ruiz J, et al: Insulin receptor down-regulation and impaired antilipolytic action of insulin in diabetic patients after pancreas/kidney transplantation.  J Clin Endocrinol Metab  1994; 78(3):657-663.

130. Pietruck F, Kribben A, Van TN, et al: Rosiglitazone is a safe and effective treatment option of new-onset diabetes mellitus after renal transplantation.  Transpl Int  2005; 18(4):483-486.

131. Ergun I, Keven K: Short-term rosiglitazone treatment in renal transplant recipients.  Nephrol Dial Transplant  2005; 20(7) reply 1512.

132. Voytovich MH, Simonsen C, Jenssen T, et al: Short-term treatment with rosiglitazone improves glucose tolerance, insulin sensitivity and endothelial function in renal transplant recipients.  Nephrol Dial Transplant  2005; 20(2):413-418.

133. de Vries AP, Bakker SJ, van Son WJ, et al: Insulin resistance as putative cause of chronic renal transplant dysfunction.  Am J Kidney Dis  2003; 41(4):859-867.(review)

134. Fliser D, Kielstein JT, Menne J: Insulin resistance and renal disease.  Contrib Nephrol  2006; 151:203-211.

135. Sarafidis PA, Ruilope LM: Insulin resistance, hyperinsulinemia, and renal injury: Mechanisms and implications.  Am J Nephrol  2006; 26(3):232-244.

136. Ahmed MH: Insulin resistance and nitric oxide and associated renal injury: Innocent bystanders or accessories to the crime?.  N Z Med J  2006; 119(1239):U2112.

137. Emoto M, Nishizawa Y, Maekawa K, et al: Insulin resistance in non-obese, non-insulin-dependent diabetic patients with diabetic nephropathy.  Metabolism  1997; 46:1013-1018.

138. Parvanova AI, Trevisan R, Iliev IP, et al: Insulin resistance and microalbuminuria: A cross-sectional, case-control study of 158 patients with type 2 diabetes and different degrees of urinary albumin excretion.  Diabetes  2006; 55(5):1456-1462.

139. Yu Y, Suo L, Yu H, et al: Insulin resistance and endothelial dysfunction in type 2 diabetes patients with or without microalbuminuria.  Diabetes Res Clin Pract  2004; 65:95-104.

140. Takahashi N, Anan F, Nakagawa M, et al: Microalbuminuria, cardiovascular autonomic dysfunction, and insulin resistance in patients with type 2 diabetes mellitus.  Metabolism  2004; 53:1359-1364.

141. Yip J, Mattock MB, Morocutti A, et al: Insulin resistance in insulin-dependent diabetic patients with microalbuminuria.  Lancet  1993; 342:883-887.

142. May RC, Clark AS, Goheer MA, et al: Specific defects in insulin-mediated muscle metabolism in acute uremia.  Kidney Int  1985; 28:490-497.

143. Rosen ED, Spiegelman BM: PPARgamma: A nuclear regulator of metabolism, differentiation, and cell growth.  J Biol Chem  2001; 276:37731-37734.

144. Willson TM, Lambert MH, Kliewer SA: Peroxisome proliferator-activated receptor gamma and metabolic disease.  Annu Rev Biochem  2001; 70:341-367.

145. Guan Y: Peroxisome proliferator-activated receptor family and its relationship to renal complications of the metabolic syndrome.  J Am Soc Nephrol  2004; 15(11):2801-2815.(review).

146. Iglesias P, Diez JJ: Peroxisome proliferator-activated receptor gamma agonists in renal disease.  Eur J Endocrinol  2006; 154(5):613-621.

147. Guan Y, Zhang Y, Davis L, Breyer MD: Expression of peroxisome proliferator-activated receptors in urinary tract of rabbits and humans.  Am J Physiol  1997; 273(6 Pt 2):F1013-F1022.

148. Guan Y: Targeting peroxisome proliferator-activated receptors (PPARs) in kidney and urologic disease.  Minerva Urol Nefrol  2002; 54(2):65-79.

149. Guan Y, Zhang Y, Schneider A, et al: Peroxisome proliferator-activated receptor-gamma activity is associated with renal microvasculature.  Am J Physiol Renal Physiol  2001; 281(6):F1036-F1046.

150. Guan Y, Breyer MD: Peroxisome proliferator-activated receptors (PPARs): Novel therapeutic targets in renal disease.  Kidney Int  2001; 60(1):14-30.

151. Sarafidis PA, Bakris GL: Protection of the kidney by thiazolidinediones: An assessment from bench to bedside.  Kidney Int  2006; 70(7):1223-1233.

152. Park CW, Kim HW, Ko SH, et al: Accelerated diabetic nephropathy in mice lacking the peroxisome proliferator-activated receptor alpha.  Diabetes  2006; 55(4):885-893.

153. Nicholas SB, Aguiniga E, Ren Y, et al: Plasminogen activator inhibitor-1 deficiency retards diabetic nephropathy.  Kidney Int  2005; 67(4):1297-1307.

154. Sartori C, Scherrer U: Insulin, nitric oxide and the sympathetic nervous system: At the crossroads of metabolic and cardiovascular regulation.  J Hypertens  1999; 17:1517-1525.

155. Steinberg HO, Baron AD: Vascular function, insulin resistance and fatty acids.  Diabetologia  2002; 45:623-634.

156. Komers R, Anderson S: Paradoxes of nitric oxide in the diabetic kidney.  Am J Physiol Renal Physiol  2003; 284:F1121-F1137.

157. Prabhakar SS: Role of nitric oxide in diabetic nephropathy.  Semin Nephrol  2004; 24:333-344.

158. Chana RS, Lewington AJ, Brunskill NJ: Differential effects of peroxisome proliferator activated receptor-gamma (PPAR gamma) ligands in proximal tubular cells: Thiazolidinediones are partial PPAR gamma agonists.  Kidney Int  2004; 65:2081-2090.

159. Panchapakesan U, Pollock CA, Chen XM: The effect of high glucose and PPAR-gamma agonists on PPAR-gamma expression and function in HK-2 cells.  Am J Physiol Renal Physiol  2004; 287:F528-F534.

160. Isshiki K, Haneda M, Koya D, et al: Thiazolidinedione compounds ameliorate glomerular dysfunction independent of their insulin-sensitizing action in diabetic rats.  Diabetes  2000; 49:1022-1032.

161. Ma LJ, Marcantoni C, Linton MF, et al: Peroxisome proliferator-activated receptor-gamma agonist troglitazone protects against nondiabetic glomerulosclerosis in rats.  Kidney Int  2001; 59:1899-1910.

162. Dong FQ, Li H, Cai WM, et al: Effects of pioglitazone on expressions of matrix metalloproteinases 2 and 9 in kidneys of diabetic rats.  Chin Med J (England)  2004; 117:1040-1044.

163. Rerolle JP, Hertig A, Nguyen G, et al: Plasminogen activator inhibitor type 1 is a potential target in renal fibrogenesis.  Kidney Int  2000; 58:1841-1850.

164. Hagiwara H, Kaizu K, Uriu K, et al: Expression of type-1 plasminogen activator inhibitor in the kidney of diabetic rat models.  Thromb Res  2003; 111:301-309.

165. Vasavada N, Agarwal R: Role of oxidative stress in diabetic nephropathy.  Adv Chronic Kidney Dis  2005; 12:146-154.

166. Ruan XZ, Moorhead JF, Fernando R, et al: PPAR agonists protect mesangial cells from interleukin 1beta-induced intracellular lipid accumulation by activating the ABCA1 cholesterol efflux pathway.  J Am Soc Nephrol  2003; 14:593-600.

167. Wu J, Zhang Y, Wang N, et al: Liver X receptor-alpha mediates cholesterol efflux in glomerular mesangial cells.  Am J Physiol Renal Physiol  2004; 287:F886-F895.

168.   Ruan XZ, Varghese Z, Powis SH, Moorhead JF: Dysregulation of LDL receptor under the influence of inflammatory cytokines: A new pathway for foam cell formation. Kidney Int 60:1716-1725.

169. Mehls O, Blum WF, Schaefer F, et al: Growth failure in renal disease.  Baillieres Clin Endocrinol Metab  1992; 6(3):665-685.

170. Rabkin R, Sun DF, Chen Y, et al: Growth hormone resistance in uremia, a role for impaired JAK/STAT signaling.  Pediatr Nephrol  2005; 20(3):313-318.

171. Sun DF, Zheng Z, Tummala P, et al: Chronic uremia attenuates growth hormone-induced signal transduction in skeletal muscle.  J Am Soc Nephrol  2004; 15(10):2630-2636.

172. Zheng Z, Sun DF, Tummala P, Rabkin R: Cardiac resistance to growth hormone in uremia.  Kidney Int  2005; 67(3):858-866.

173. Ji S, Guan R, Frank SJ, Messina JL: Insulin inhibits growth hormone signaling via the growth hormone receptor/JAK2/STAT5B pathway.  J Biol Chem  1999; 274(19):13434-13442.

174. Tonshoff B, Kiepe D, Ciarmatori S: Hormone/insulin-like growth factor system in children with chronic renal failure.  Pediatr Nephrol  2005; 20(3):279-289.

175. Gorman G, Fivush B, Frankenfield D, et al: Short stature and growth hormone use in pediatric hemodialysis patients.  Pediatr Nephrol  2005; 20(12):1794-1800.

176. Kari JA, Rees L: Growth hormone for children with chronic renal failure and on dialysis.  Pediatr Nephrol  2005; 20(5):618-621.

177. Furth SL: Growth and nutrition in children with chronic kidney disease.  Adv Chronic Kidney Dis  2005; 12(4):366-371.

178. Furth SL, Hwang W, Yang C, et al: Growth failure, risk of hospitalization and death for children with end-stage renal disease.  Pediatr Nephrol  2002; 17(6):450-455.

179. Johannsson G, Ahlmen J: End-stage renal disease: Endocrine aspects of treatment.  Growth Horm IGF Res  2003; 13(Suppl A):S94-S101.

180. Blake PG: Growth hormone and malnutrition in dialysis patients.  Perit Dial Int  1995; 15(6):210-216.

181. Flyvbjerg A: The role of growth hormone in the pathogenesis of diabetic kidney disease.  Pediatr Endocrinol Rev  2004; 1(Suppl 3):525-529.

182. French CB, Genel M: Pathophysiology of growth failure in chronic renal insufficiency.  Kidney Int Suppl  1986; 19:S59-S64.

182. Warady B, Watkins SL: Current advances in the therapy of chronic renal failure and end stage renal disease.  Semin Nephrol  1998; 18(3):341-354.

183. Kohaut EC: Chronic renal disease and growth in childhood.  Curr Opin Pediatr  1995; 7(2):171-175.

184. Lewy JE: Treatment of children in the U.S. with end-stage renal disease (ESRD).  Med Arh  2001; 55(4):201-202.

185. Sandberg DE, Voss LD: The psychosocial consequences of short stature: A review of the evidence.  Best Pract Res Clin Endocrinol Metab  2002; 16(3):449-463.

186. Zlotkin D, Varma SK: Psychosocial effects of short stature.  Indian J Pediatr  2006; 73(1):79-80.

187. van Balen H, Sinnema G, Geenen R: Growing up with idiopathic short stature: Psychosocial development and hormone treatment; a critical review.  Arch Dis Child  2006; 91(5):433-439.

188. Ross JL: Effects of growth hormone on cognitive function.  Horm Res  2005; 64(Suppl 3):89-94.

189. Norrby U, Nordholm L, Andersson-Gare B, Fasth A: Health-related quality of life in children diagnosed with asthma, diabetes, juvenile chronic arthritis or short stature.  Acta Paediatr  2006; 95(4):450-456.

190. Sandberg DE, Colsman M: Growth hormone treatment of short stature: status of the quality of life rationale.  Horm Res  2005; 63(6):275-283.

191. Norman LJ, Macdonald IA, Watson AR: Optimising nutrition in chronic renal insufficiency—growth.  Pediatr Nephrol  2004; 19(11):1245-1252.

192. Quintos JB, Salas M: Use of growth hormone and gonadotropin releasing hormone agonist in addition to L-thyroxine to attain normal adult height in two patients with severe Hashimoto's thyroiditis.  J Pediatr Endocrinol Metab  2005; 18(5):515-521.

193. Cetinkaya E, Aslan A, Vidinlisan S, Ocal G: Height improvement by L-thyroxine treatment in subclinical hypothyroidism.  Pediatr Int  2003; 45(5):534-537.

194. Bryant J, Baxter L, Cave C, Milne R: Recombinant growth hormone for idiopathic short stature in children and adolescents.  Cochrane Database Syst Rev  2007; 18(3):CD004440

195. Iglesias P, Diez JJ: Recombinant human growth hormone therapy in adult dialysis patients.  Int J Artif Organs  2000; 23(12):802-804.

196. Haffner D, Schaefer F, Nissel R, et al: Effect of growth hormone treatment on the adult height of children with chronic renal failure. German Study Group for Growth Hormone Treatment in Chronic Renal Failure.  N Engl J Med  2000; 343(13):923-930.

197. Vimalachandra D, Craig JC, Cowell C, Knight JF: Growth hormone for children with chronic renal failure.  Cochrane Database Syst Rev  2001;CD003264

198. Van Dyck M, Proesmans W: Growth hormone therapy in chronic renal failure induces catch-up of head circumference.  Pediatr Nephrol  2001; 16(8):631-636.

199. Andre JL, Bourquard R, Guillemin F, et al: Final height in children with chronic renal failure who have not received growth hormone.  Pediatr Nephrol  2003; 18(7):685-691.

200. Haffner D, Wuhl E, Schaefer F, et al: Factors predictive of the short- and long-term efficacy of growth hormone treatment in prepubertal children with chronic renal failure. The German Study Group for Growth Hormone Treatment in Chronic Renal Failure.  J Am Soc Nephrol  1998; 9(10):1899-1907.

201. Crompton CH: Australian and New Zealand Paediatric Nephrology Association. Long-term recombinant human growth hormone use in Australian children with renal disease.  Nephrology (Carlton)  2004; 9(5):325-330.

202. Vance ML, Mauras N: Growth hormone therapy in adults and children.  N Engl J Med  1999; 341:1206-1216.

203. Fine RN: Stimulating growth in uremic children.  Kidney Int  1992; 42:188-197.

204. Hokken-Koelega AC, Stijnen T, de Muinck K, et al: Placebo-controlled, double-blind, cross-over trial of growth hormone treatment in prepubertal children with chronic renal failure.  Lancet  1991; 338:585-590.

205. Fine RN, Kohaut EC, Brown D, Perlman AJ: Growth after recombinant human growth hormone treatment in children with chronic renal failure: Report of a multicenter randomized double-blind placebo-controlled study. Genentech Cooperative Study Group.  J Pediatr  1994; 124:374-382.

206. Fine RN, Ho M, Tejani A, Blethen S: Adverse events with rhGH treatment of patients with chronic renal insufficiency and end-stage renal disease.  J Pediatr  2003; 142(5):539-545.

207. Hokken-Koelega A, Mulder P, De Jong R, et al: Long-term effects of growth hormone treatment on growth and puberty in patients with chronic renal insufficiency.  Pediatr Nephrol  2000; 14(7):701-706.

208. Hammerman MR: The growth hormone? Insulin-like growth factor axis in kidney re-revisited.  Nephrol Dial Transplant  1999; 14(8):1853-1860.

209. Vijayan A, Franklin SC, Behrend T, et al: Insulin-like growth factor I improves renal function in patients with end-stage chronic renal failure.  Am J Physiol  1999; 276:R929-R934.

210. Wuhl E, Schaefer F: Effects of growth hormone in patients with chronic renal failure: Experience in children and adults.  Horm Res  2002; 58(Suppl 3):35-38.(review).

211. Roelfsema V, Clark RG: The growth hormone and insulin-like growth factor axis: Its manipulation for the benefit of growth disorders in renal failure.  J Am Soc Nephrol  2001; 12(6):1297-1306.

212. Jenkins RC, Ross RJ: Growth hormone therapy for protein catabolism.  QJM  1996; 89:813-819.

213. Kopple JD, Brunori G, Leiserowitz M, Fouque D: Growth hormone induces anabolism in malnourished maintenance haemodialysis patients.  Nephrol Dial Transplant  2005; 20(5):952-958.

214. Ziegler TR, Lazarus JM, Young LS, et al: Effects of recombinant human growth hormone in adults receiving maintenance hemodialysis.  J Am Soc Nephrol  1991; 2:1130-1135.

215. Takala J, Ruokonen E, Webster NR, et al: Increased mortality associated with growth hormone treatment in critically ill adults.  N Engl J Med  1999; 341:785-792.

216. Garibotto G, Barreca A, Russo R, et al: Effects of recombinant human growth hormone on muscle protein turnover in malnourished hemodialysis patients.  J Clin Invest  1997; 99:97-105.

217. Bengtsson BA: Rethink about growth-hormone therapy for critically ill patients.  Lancet  1999; 354:1403-1404.

218. Malozowski S, Tanner LA, Wysowski D, Fleming GA: Growth hormone, insulin-like growth factor I, and benign intracranial hypertension.  N Engl J Med  1993; 329:665-666.

219. Cutfield WS, Wilton P, Bennmarker H, et al: Incidence of diabetes mellitus and impaired glucose tolerance in children and adolescents receiving growth-hormone treatment.  Lancet  2000; 355:610-613.

220. O'Shea MH, Miller SB, Hammerman MR: Effects of IGF-I on renal function in patients with chronic renal failure.  Am J Physiol  1993; 264:F917-F922.(abstract/free full text).

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