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.


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