Home About us Current issue Back issues Submission Instructions Advertise Contact Login   

Search Article 
  
Advanced search 
 
Saudi Journal of Kidney Diseases and Transplantation
Users online: 2024 Home Bookmark this page Print this page Email this page Small font sizeDefault font size Increase font size 
 

ARTICLES Table of Contents   
Year : 2002  |  Volume : 13  |  Issue : 3  |  Page : 273-280
Metabolic Disturbances in Chronic Renal Failure


Division of Nephrology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA

Click here for correspondence address and email
 

How to cite this article:
Palmer BF. Metabolic Disturbances in Chronic Renal Failure. Saudi J Kidney Dis Transpl 2002;13:273-80

How to cite this URL:
Palmer BF. Metabolic Disturbances in Chronic Renal Failure. Saudi J Kidney Dis Transpl [serial online] 2002 [cited 2020 Feb 19];13:273-80. Available from: http://www.sjkdt.org/text.asp?2002/13/3/273/33797

   Introduction Top


Disturbances in endocrine function are a feature commonly seen in patients with chronic renal failure. Changes in the secretion and metabolism of hormones as well as alterations in target organ sensitivity account for these alterations, [Table - 1]. This paper will briefly review the clinically relevant changes in endocrine function that characterize the chronic renal failure state.

Thyroid Disturbances

Most patients with end-stage renal disease have decreased plasma levels of free triio­dothyronine (T3), which reflect diminished conversion of thyroxine T4 to T3 in the periphery. [1][2] This abnormality is not associated with increased conversion of T4 to the metabolically inactive reverse T3 (rT3), since plasma rT3 levels are typically normal. This finding differentiates the uremic patient from patients with chronic illness in which the conversion of T4 to T3 is similarly reduced, but the generation of rT3 from T4 is enhanced. In addition to decreased production, low levels of total T3 also may reflect reduced protein binding. 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. This inhibition may explain why some patients with chronic renal failure have low serum T4 levels.

The plasma concentration of thyroid stimulating hormone (TSH) is usually normal in chronic renal failure. However, the TSH response to exogenous thyrotrophic-releasing hormone (TRH) is often blunted and delayed, with a prolonged time required to return to baseline levels. [3],[4] Reduced renal clearance may contribute to delayed recovery, since TSH and TRH are normally cleared by the kidney. 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. [5] The latter response is important clinically, since TSH levels should rise when a uremic patient develops hypothyroidism. [1]

There is substantial clinical overlap between chronic renal failure and hypothyroidism. In addition to low total and plasma free T3 levels, there are a number of symptoms that are common to both conditions including cold intolerance, puffy appearance, dry skin, lethargy, fatiguability, and constipation. Despite these findings, most uremic patients are considered to be euthyroid as evidenced by normal plasma concentrations of TSH and free T4, and normal basal metabolic rate and tendon relaxation time.

The kidney normally contributes to the clearance of iodide from the body. With advancing renal failure iodide excretion is diminished 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. Increases in total body inorganic iodide can potentially block thyroid hormone production (the Wolff­Chaikoff effect). These changes in iodide metabolism may account for reports of a slightly higher frequency of goiter and hypothyroidism in patients with chronic renal failure. [6],[7]

The clinical findings used to diagnose hypo­thyroidism in subjects with normal renal function can also be applied to patients with renal failure. The diagnosis of hypothyroidism in patients with renal disease can be established by the demonstration of an elevated serum TSH concentration, usually associated with a reduced serum free T4 concentration and normal TBG levels. Delayed deep tendon relaxation may be a confirmatory clinical finding.

In summary, chronic renal failure is associated with multiple disturbances in thyroid metabolism characterized by low serum free and total T3 levels and normal rT3 and free T4 concentrations. The serum TSH concentration is normal and most patients are euthyroid.

Adrenal Disturbances

The diagnosis of abnormal glucocorticoid metabolism can be challenging in the chronic renal failure patient. The kidney normally contributes to the excretion of cortisol and its water soluble metabolites. As a result, the serum half-life of cortisol becomes prolonged in advanced renal failure. [8] Both normal and elevated levels of serum cortisol have been reported in this setting. [9],[10] Methodological problems may account for some of the conflicting results since compounds such as metabolites of cortisol accumulate in renal disease and can interfere with the accurate measurement of cortisol by several commercially available assays.

Tests designed to assess the secretory capacity of the adrenal gland are typically normal. The diurnal variation in cortisol release is well preserved and circulating cortisol levels increase appropriately after an infusion of adrenocorticotrophic hormone ACTH. [11] Cortisol levels also increase after the administration of corticotropin releasing hormone (CRH). Stimulation of ACTH and cortisol secretion following insulin-induced hypoglycemia or the infusion of CRH is impaired. ACTH and 11-deoxy-cortisol responses are also blunted following the standard metyrapone test dose (30 mg/kg). [7] This defect may be due to adrenal resistance to the blocking action of metyrapone in renal failure, since the response can be normalized by the administration of higher doses.

Chronic renal failure patients' often demon­strate resistance to the suppressive effect of dexamethasone. However, this resistance may be related to decreased absorption or accelerated metabolism of dexamethasone. Low serum levels of dexamethasone have been noted in those patients who fail to suppress morning serum cortisol levels after administration of 1 mg of the drug suggesting rapid inactivation of the administered dexamthasone. [12]

Overall, there does not appear to be an overt abnormality in the function of the hypophyseal-pituitary-adrenal axis intrinsic to patients with chronic renal failure. Nevertheless, findings such as spurious overestimation of plasma cortisol, altered cortisol binding to protein, decreased gastrointestinal absorption of dexamethasone, and abnormal adrenal responses to dexa­methasone make the diagnosis of Cushing's disease exceedingly difficult in this setting. One major difference between chronic renal failure and Cushing's disease is that the circadian rhythm of cortisol secretion is preserved in the former and lost in the latter.

It is not known if subtle abnormalities in glucocorticoid metabolism contribute to some of the findings of the uremic syndrome, such as insulin resistance and negative nitrogen balance.

Growth Hormone Disturbances

Progression to end-stage renal disease is associated with a variety of abnormalities in growth hormone regulation, including changes in its plasma concentration, in the regulation of its release, and in end-organ responsiveness. The plasma growth hormone concentration is commonly elevated in chronic renal failure due to the interplay of several factors. [13] Decreased renal clearance plays a major role in the genesis of this problem, since filtered growth hormone is normally reabsorbed in and metabolized by the proximal tubule. [14] Increased growth hormone secretion also contributes to the increased levels although this mechanism is of lesser importance.

The hypothalamic-pituitary regulation of growth hormone is also perturbed in chronic renal failure. [7] As an example, normal individuals suppress growth hormone release in response to induced hyperglycemia. By contrast, glucose induces a paradoxical rise in growth hormone levels in advanced renal failure. In addition, insulin-induced hypo­glycemia, which is a potent stimulus to growth hormone release in normal subjects, elicits a blunted response in chronic renal failure patients. Thyrotropin-releasing hormone stimulates growth hormone release in uremic patients, but has little or no effect in normal subjects. The factors responsible for the abnormal growth hormone regulation in chronic renal failure are incompletely understood but impaired hypothalamic control appears to be of primary importance.

The physiologic significance of elevated growth hormone levels in chronic renal failure is not clear. Although early studies suggested an etiologic link to the glucose intolerance that is commonly present in this setting, abnormal carbohydrate metabolism appears to be independent of growth hormone secretion. The relationship between altered growth hormone metabolism and growth retardation in children with chronic renal failure has also received a great deal of interest. Patients with chronic renal failure show evidence of end-organ resistance. In animal models of chronic renal failure the number of growth hormone receptors, hepatic growth hormone receptor mRNA, and chondrocyte responsiveness to growth hormone and insulin-like growth factor-1 (IGF-1) are reduced. [15],[16] Increased levels of growth hormone binding protein found in the uremic state may also contribute to growth hormone resistance.

Somatomedins are thought to mediate the actions of growth hormone on skeletal tissue. The steady state levels of IGF-1 mRNA are diminished in the uremic state and fail to rise significantly after the administration of exogenous growth hormone due to a defect at the transcriptional level. Decreased caloric intake and the metabolic acidosis associated with chronic renal failure also may contribute to the peripheral growth hormone resistance. [17] There is also direct end-organ resistance to the effects of IGF-1. [18]

An increasing number of studies in children with renal insufficiency suggest that administration of supraphysiologic doses of recombinant human growth hormone can lead to increased growth that may allow attainment of normal adult height. [19] In addition, treatment of children with recom­binant growth hormone appears to be safe. [21] Studies to date have shown no evidence of increased risk of malignancy, accelerated loss of residual renal function, or worsening of metabolic bone disease.

Sexual Disturbances in Men

Disturbances in sexual function are a common feature of chronic renal failure. Over 50 percent of uremic men complain of symptoms that include erectile dysfunction, decreased libido, and marked declines in the frequency of intercourse. [20],[21],[22]

While sexual dysfunction is multifactorial in origin, endocrine abnormalities that accompany chronic renal failure clearly play a major role in the genesis of this problem [Table - 2].

The endocrine abnormalities that contribute to sexual dysfunction are largely centered around end-organ dysfunction. Chronic renal failure is associated with impaired spermatogenesis and testicular damage, often leading to infertility. [23] Semen analysis typically shows a decreased volume of ejaculate, oligo- or complete azoospermia, and a low percentage of motile sperms. These testicular changes lead to impaired gonadal steroidogenesis. The serum total and free testosterone concentrations are typically reduced, although the binding capacity and concentration of sex hormone­binding globulin are normal. By comparison, although the total plasma estrogen concen­tration is frequently elevated, the serum estradiol concentration is typically normal. [24]

The serum concentration of luteinizing hormone (LH) is elevated in uremic men due to diminished testosterone feedback. Follicle stimulating hormone (FSH) secretion is also elevated, although to a more variable degree. [23],[24] Elevated FSH levels are probably the result of decreased testosterone and inhibin, a Sertoli cell product. 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 after renal transplantation. The hypothalamic and pituitary axis is intact in chronic renal failure patients.

Elevated plasma prolactin concentrations are found in the majority of dialyzed men, due to increased production and to a lesser extent decreased metabolic clearance. [25]

The clinical significance of enhanced prolactin release in uremic men is incompletely understood. The administration of bromocriptine lowers prolactin levels to near normal levels but has only inconsistent effects on improving libido and potency.

Gynecomastia occurs in approximately 30 percent 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. A suggested approach to the treatment of sexual dysfunction in men with chronic renal failure is provided for in [Figure - 1].

Sexual Disturbances in Women

Disturbances in menstruation and fertility are commonly encountered in women with chronic renal failure, usually leading to amenorrhea by the time the patient reaches end-stage renal disease. [22],[26] The major menstrual cycle abnormality in uremic women is anovulation, resulting in infertility. Women receiving chronic dialysis also tend to experience decreased libido and reduced ability to reach orgasm.

In contrast to men who primarily exhibit end-organ dysfunction, sexual dysfunction in women in mostly due to abnormalities in central function. [27] During a normal menstrual cycle estradiol levels progressively increase and ultimately, through a positive feedback effect, stimulate a midcycle surge in LH release. The increase in LH secretion is a key step in inducing ovulation. Anovulatory cycles in women with chronic renal failure can be traced to the absence of the preovulatory peak in LH and estradiol concentrations. The failure of LH to rise in part reflects a disturbance in the positive estradiol feedback pathway, since the administration of exogenous estrogen to mimic the preovulatory surge in estradiol fails to stimulate LH release. 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.

Women with chronic renal failure commonly have elevated circulating prolactin concen­trations and galactorrhea due to increased secretion and decreased metabolic clearance. [28] The hypersecretion of prolactin in this setting appears to be relatively autonomous, as it is resistant to maneuvers designed to stimulate or inhibit its release.

[Figure - 2] provides an approach to the treatment of sexual dysfunction in women with chronic renal failure.

 
   References Top

1.Kaptein EM, Quion-Verde H, Chooljian CJ, et al. The thyroid in end-stage renal disease. Medicine (Baltimore) 1988;67:187-97.  Back to cited text no. 1    
2.Wartofsky L, Burman KD. Alterations in thyroid function in patients with systemic illness: The "euthyroid sick syndrome". Endocr Rev 1982;3:164-217.  Back to cited text no. 2    
3.Czernichow P, Dauzet MC, Broyer M, Rappaport R. Abnormal TSH, PRL, and GH response to TSH releasing factor in chronic renal failure. J Clin Endocrinol Metab 1976; 43:630-7.  Back to cited text no. 3    
4.Duntas L, Wolf CF, Keck FS, Rosenthal J. Thyrotropin-releasing hormone: pharma­cokinetic and pharmacodynamic properties in chronic renal failure. Clin Nephrol 1992;38:214-8.  Back to cited text no. 4    
5.Spector DA, David PJ, Helderman JH, Bell B, Utiger RD. Thyroid function and metabolic state in chronic renal failure. Ann Intern Med 1976;85:724-30.  Back to cited text no. 5    
6.Lin CC, Chen TW, Ng YY, Chou YH, Yang WC. Thyroid dysfunction and nodular goiter in hemodialysis and peritoneal dialysis patients. Perit Dial Int 1998;18:516-21.  Back to cited text no. 6    
7.Ramirez G. Abnormalities in the hypotha­lamic-hypophyseal axes in patients with chronic renal failure. Semin Dial 1994; 7:138-42.  Back to cited text no. 7    
8.Bacon GE, Kenny FM, Murdaugh HV, Richards C. Prolonged serum half-life of cortisol in renal failure. Johns Hopkins Med J 1973;132:127-31.  Back to cited text no. 8    
9.Nolan GE, Smith JB, Chavre VJ, Jubiz W. Spurious overestimation of plasma cortisol in patients with chronic renal failure. J Clin Endocrinol Metab 1981;52:1242-5.  Back to cited text no. 9    
10.Rosman PM, Benn R, Kay M, Wallace EZ. Cortisol binding in uremic plasma I. Absence of abnormal cortisol binding to corticosteroid-binding globulin. Nephron 1984;37:160-5.  Back to cited text no. 10    
11.McDonald WJ, Golper TA, Mass RD, et al. Adrenocorticotropin-cortisol axis abnor­malities in hemodialysis patients. J Clin Endocrinol Metab 1979;48:92-5.  Back to cited text no. 11    
12.Ramirez G, Gomez-Sanchez C, Meikle WA, Jubiz W. Evaluation of the hypo­thalamic hypophyseal adrenal axis in patients receiving long-term hemodialysis. Arch Intern Med 1982; 142:1448-52.  Back to cited text no. 12    
13.Veldhuis JD, Johnson ML, Wilkowski MJ, et al. Neuroendocrine alterations in the somatotropic axis in chronic renal failure. Acta Pediatr Scand Suppl 1991;379:12-22.  Back to cited text no. 13    
14.Johnson V, Maack T. Renal extraction, filtration, absorption, and catabolism of growth hormone. Am J Physiol 1977;233: F185-F96.  Back to cited text no. 14    
15.Mak RH, Pak YK. End-organ resistance to growth hormone and IGF-I in epiphyseal chondrocytes of rats with chronic renal failure. Kidney Int 1996;50:400-6.  Back to cited text no. 15    
16.Tonshoff B, Eden S, Weiser E, et al. Reduced hepatic growth hormone (GH) receptor gene expression and increased plasma GH binding protein in experimental uremia. Kidney Int 1994;45:1085-92.  Back to cited text no. 16    
17.Boirie Y, Broyer M, Gagnadoux MF, Niadudet P, Bresson JL. Alterations of protein metabolism by metabolic acidosis in children with chronic renal failure. Kidney Int 2000;58:236-41.  Back to cited text no. 17    
18.Fouque D. Insulin-like growth factor-1 resistance in chronic renal failure. Miner Electrolyte Metab 1996;22:133-7.  Back to cited text no. 18    
19.Fine RN. Recombinant human growth hormone in children with chronic renal insufficiency-clinical update: 1995. Kidney Int 1996;53:S115-8.  Back to cited text no. 19    
20.Holdsworth SR, de Kretser DM, Atkins RC. A comparison of hemodialysis and transplantation in reversing the uremic disturbance of male reproductive function. Clin Nephrol 1978;10:146-50.  Back to cited text no. 20    
21.Diemont WL, Vruggink PA, Meuleman EJ, et al. Sexual dysfunction after renal replacement therapy. Am J Kidney Dis 2000;35:845-51.  Back to cited text no. 21    
22.Palmer BF. Sexual dysfunction in uremia. J Am Soc Nephrol 1999;10:1381-8.  Back to cited text no. 22    
23.Holdsworth S, Atkins RC, de Kretser DM. The pituitary-testicular axis in men with chronic renal failure. N Engl J Med 1977;296:1245-9.  Back to cited text no. 23    
24.Lim VS, Fang VS. Restoration of plasma testosterone levels in uremic men with clomiphene citrate. J Clin Endocrinol Metab 1976;43:1370-7.  Back to cited text no. 24    
25.Foulks CJ, Cushner HM. Sexual dysfunction in the male dialysis patient: Pathogenesis, evaluation, and therapy. Am J Kidney Dis 1986;8:211-22.  Back to cited text no. 25    
26.Holley JL, Schmidt RJ, Bender FH, et al. Gynecologic and reproductive issues in women on dialysis. Am J Kidney Dis 1997;29:685-90.  Back to cited text no. 26    
27.Lim VS, Henriquez C, Sievertsen G, Frohman LA. Ovarian function in chronic renal failure: evidence suggesting hypo­thalamic anovulation. Ann Intern Med 1980;93:21-7.  Back to cited text no. 27    
28.Ginsburg ES, Owen WF. Reproductive endocrinology and pregnancy in women on hemodialysis. Semin Dial 1993;6:105-14.  Back to cited text no. 28    

Top
Correspondence Address:
Biff F Palmer
Division of Nephrology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
USA
Login to access the Email id


PMID: 18209424

Rights and Permissions


    Figures

  [Figure - 1], [Figure - 2]
 
 
    Tables

  [Table - 1], [Table - 2]



 

Top
 
 
    Similar in PUBMED
    Search Pubmed for
    Search in Google Scholar for
    Email Alert *
    Add to My List *
* Registration required (free)  
 


 
    Introduction
    References
    Article Figures
    Article Tables
 

 Article Access Statistics
    Viewed7521    
    Printed92    
    Emailed0    
    PDF Downloaded720    
    Comments [Add]    

Recommend this journal