Prolactin and Other Pituitary Disorders in Kidney Disease PDF

Prolactin and Other Pituitary Disorders in Kidney Disease Wenyu Huang, MD, PhD and Mark E. Molitch, MD Summary: Prolactin levels are increased in chronic kidney disease...

Prolactin and Other Pituitary Disorders in Kidney Disease Wenyu Huang, MD, PhD and Mark E. Molitch, MD Summary: Prolactin levels are increased in chronic kidney disease (CKD) as a result of reduced clearance and increased secretion. Hyperprolactinemia manifests as galactorrhea and hypogonadism. Treatment of hyperprolacti- nemia should focus on improving bothersome galactorrhea or hypogonadism by using dopamine agonists and/or replacement of sex hormone(s). Changes in the hypothalamic−pituitary−adrenal axis in CKD are characterized by increases in adrenocorticotropic hormone (ACTH) and cortisol levels, largely preserved circadian rhythms of ACTH and cortisol, and a normal response of cortisol to ACTH, metyrapone, and insulin-induced hypoglycemia. However, the hypothalamic−pituitary−adrenal axis is less inhibited by 1 mg dexamethasone but retains normal suppression by higher-dose dexamethasone. Diagnosis of adrenal insufficiency in CKD patients, as in normal subjects, usually is made by finding a subnormal cortisol response to ACTH. The mainstay of treatment of adrenal insufficiency is to replace glucocorticoid hormone. Cushing’s disease in CKD is difficult to diagnose and relies on the dexamethasone suppression test and the midnight salivary cortisol test because the 24-hour urine free cortisol test is not useful because it is increased already in CKD. Treatment of Cushing’s disease involves surgery, complemented by radia- tion and/or medical therapy if necessary. Growth hormone levels are increased and insulin-like growth factor 1 lev- els are normal in patients with CKD. In a normal patient with CKD, as in one with acromegaly, there can be a paradoxic increase in growth hormone after an oral glucose load. Therefore, diagnosis of acromegaly in renal insuf- ficiency is challenging. The treatment of choice for acromegaly is surgery, although data for medical treatment for acromegaly in CKD are rare. In patients with renal impairment, arginine vasopressin levels are increased as a result of decreased clearance, and there also is impairment of arginine vasopressin signaling in renal tubules. Diabetes insipidus can be masked in advanced kidney disease until kidney transplantation. Diagnosis of the syndrome of inappropriate antidiuretic hormone is similar in mild or moderate kidney disease as in normal subjects, but is chal- lenging in patients with advanced kidney disease owing to the impairment in urine dilution. Semin Nephrol 41:156−167 Ó 2021 Elsevier Inc. All rights reserved. Keywords: Hyperprolactinemia, adrenal insufficiency, Cushing’s disease, acromegaly, diabetes insipidus, syn- drome of inappropriate antidiuretic hormone P rolactin (PRL) is synthesized and secreted from sleep period followed by a gradual decrease to lower lev- the lactotrophs in the anterior pituitary.1 Hypotha- els during the daytime.9 lamic dopamine exerts tonic inhibition of PRL In patients with chronic kidney disease (CKD) there secretion,2 while several hypothalamic factors, including is an increase in PRL levels. The prevalence of hyper- vasoactive intestinal polypeptide and thyrotropin-releas- prolactinemia ranges from 18.3% in mild renal ing hormone, stimulate PRL secretion.3,4 In addition, the insufficiency10,11 to more than 70% in patients on hemo- lactotrophs also are stimulated directly by estrogen,5-7 dialysis (HD) and peritoneal dialysis (PD).12,13 However, which explains the increased PRL levels during preg- in a recent study of 100 men between ages 18 and nancy.8 After delivery, PRL increases with each suckling 50 years with CKD but no HD or PD, mean prolactin episode, stimulating milk production. In addition, circu- levels were increased only in patients with CKD stages 4 lating levels of PRL display a strong circadian rhythm, and 5, but not early stages of CKD.14 In addition, more in which PRL levels peak during the first half of the frequent dialysis did not seem to change prolactin levels.15 In patients with CKD who also are taking medications known to interfere with dopamine, PRL Division of Endocrinology, Metabolism and Molecular Medicine, levels up to 2,200 ng/mL have been reported, which is a Northwestern University Feinberg School of Medicine, Chicago, IL level usually associated with PRL-producing pituitary Financial disclosure: none. macroadenomas.10 Of course, patients with CKD also Conflict of interest statement: Wenyu Huang: Research support was provided by Chiasma, Strongbridge, Ionis, Crinetics, and Corcept; can have PRL-secreting pituitary adenomas or other Consulting: Chiasma, Recordati, and Corcept. hypothalamic−pituitary lesions causing decreased dopa- Mark E. Molitch: Research Support: Novartis, Chiasma, Strong- mine reaching the pituitary. bridge, Ionis, Crinetics; Consulting: Pfizer, Merck, Novartis and Chiasma. Address reprint requests to Wenyu Huang, Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University PATHOPHYSIOLOGY Feinberg School of Medicine, 645 N. Michigan Ave, Suite 530, Chi- Multiple mechanisms exist to explain the increase of cago, IL 60611. E-mail: [email protected] 0270-9295/ - see front matter PRL in CKD. One main mechanism is decreased © 2021 Elsevier Inc. All rights reserved. renal clearance of PRL molecules.12 In one study, the https://doi.org/10.1016/j.semnephrol.2021.03.010 metabolic clearance rate of PRL was reported to be 156 Seminars in Nephrology, Vol 41, No 2, March 2021, pp 156−167 Prolactin and Pituitary Disorders 157 decreased by approximately 33% in patients with imaging (MRI) is not needed in the assessment of hyper- CKD.12 In addition, the secretion of PRL also is prolactinemia in patients with CKD. However, if there is enhanced in CKD. Compared with that in normal sub- a concern that hyperprolactinemia may be caused by jects, the PRL secretion rate increases by approximately sellar or suprasellar lesions in patients with CKD, for three- to four-fold in patients with CKD.12 The mecha- example, patients present with a headache, vision nism underlying the increase in PRL release in CKD is change, or a defective visual field, suggesting compres- believed to be resistance of PRL secretion to dopaminer- sion of an optic chiasm, a pituitary MRI can be per- gic suppression.16 Interestingly, resistance of PRL secre- formed. However, given the potential severe tion to regulatory signals also exists for thyrotropin- complications associated with intravenous MRI contrast releasing hormone, vasoactive intestinal polypeptide, use in patients with CKD, the MRI should be performed and chlorpromazine,16,17 but not for metoclopramide,18 either without contrast in patients with CKD but not on suggesting that several hypothalamic mechanisms regu- dialysis, or, if medically necessary, with contrast in lating PRL secretion are differentially affected in CKD. patients on HD who then would require additional PRL molecules are not removed by HD or PD.19 Not sur- dialysis sessions to clear the contrast. prisingly, after kidney transplant, hyperprolactinemia usually corrects or significantly improves, even within CLINICAL MANIFESTATION OF days.20,21 HYPERPROLACTINEMIA Clinically, hyperprolactinemia can cause galactorrhea DIAGNOSIS OF HYPERPROLACTINEMIA and hypogonadism (manifested as amenorrhea or oligo- PRL is commonly measured by two-site immunometric menorrhea, low libido, erectile dysfunction, gynecomas- assays. It should be emphasized that breast and nipple tia, infertility, and so forth). Galactorrhea usually is manipulations can transiently increase PRL secretion, so bilateral, multiductal, and milky. The color can range PRL levels should not be checked shortly after a breast from clear to yellow, green, or brown.28,29 On the other examination. Three distinct molecular forms of PRL hand, nipple discharges that are from single-duct, have been identified, with corresponding molecular bloody, or serosanguinous, or associated with a palpable weights of 23 (monomeric), 50 to 60 (big PRL). and or radiologically evident breast mass, will need further more than 100 kDa (big big PRL or macroprolactin). evaluation for breast tumors.30 Sudan IV staining for fat The high molecular forms are thought to result from droplets in the nipple discharge can confirm the diagno- dimerization or binding of PRL to IgG. Polyethylene sis of milk.28 Hyperprolactinemia generally causes hypo- glycol is commonly used to precipitate macroprolactin gonadotropic hypogonadism. Interestingly, a recent molecules before measuring PRL monomers in the study found that despite decreasing levels of total and supernatant to calculate the percentage of PRL recovery, free testosterone and increasing levels of luteinizing hor- and has been shown to correlate well with the gold stan- mone and prolactin with progression of kidney disease, dard for measuring monomeric PRL (ie, gel filtration sexual dysfunction is similar from CKD stage 1 to stage chromatography).22 A PRL recovery of 40% or less is 5.14 Hypergonadotropic hypogonadism also is seen com- suggested as the cut-off value for diagnosis of macropro- monly in patients with CKD,31 suggesting different lactinemia, while a recovery greater than 50% makes the mechanisms leading to hypogonadism in CKD. It also is diagnosis of macroprolactinemia unlikely.22 interesting to note that after renal transplantation, there In normal individuals, the monomeric form of PRL is an improvement in sexual function in both men and accounts for 85% to 95% of PRL in circulation.23 In women, which is correlated with low levels of prolactin, CKD, an increase in PRL immunoreactivity exceeds that young age, and a short duration of dialysis.32 of PRL bioactivity.24 Although some studies found Recently, it has been suggested that PRL levels are monomeric PRL to be the predominant form of PRL associated directly with endothelial dysfunction and with contributing to the hyperprolactinemia in patients with increased risk of cardiovascular events and mortality in CKD25 on HD and PD,26 a recent study showed that CKD patients.33 However, the direct relationship of macroprolactin levels are correlated positively with the hyperprolactinemia and increased cardiovascular risk is decrease in renal function, suggesting that macroprolac- not firmly established and there are no studies showing tin also may contribute to the hyperprolactinemia in cardiovascular benefit from lowering PRL levels in such CKD patients.27 patients. During evaluation for hyperprolactinemia, it is impor- tant to carefully check the medications that a patient is taking because some medications have been shown to TREATMENT OF HYPERPROLACTINEMIA increase PRL levels28 and that stopping medications that Indications for treatment of hyperprolactinemia in increase PRL can significantly lower PRL levels, even in patients with CKD include bothersome galactorrhea and patients with CKD.10 Normally, magnetic resonance hypogonadism. Because most hyperprolactinemia in 158 W. Huang and M.E. Molitch CKD is related to decreased kidney function, dopamine Accordingly, the diagnosis and treatment of disorders agonists can be considered for lowering PRL levels in involving the HPA axis are affected by CKD. these patients. It should be noted that there are very lim- ited data available on the efficacy and safety of dopa- mine agonists in patients with CKD or on dialysis.34,35 PATHOPHYSIOLOGY Moreover, PRL secretion is resistant to dopaminergic suppression in CKD, so a higher dose of dopamine ago- Circulating Levels of Adrenocorticotropic Hormone nist may be needed.16,36 There are no CKD dose restric- and Cortisol tions listed in the package inserts for either cabergoline In patients with CKD, adrenocorticotropic hormone or bromocriptine. and cortisol (ACTH) levels usually are found to be In addition, for patients with a possible cause or increased, likely owing to the chronic inflammatory exacerbation of hyperprolactinemia by medications, the state associated with CKD,40,41 but there are conflict- offending medication(s) ideally should be considered for ing data regarding the level of cortisol. Although discontinuation. If the underlying condition warrants some studies have shown that morning and afternoon continuation of such medications, switching to another levels of plasma cortisol are similar in patients with medication in the same class that has a lower potential, CKD compared with normal subjects,40,42 other stud- or no potential, to cause hyperprolactinemia would be ies have shown that the mean morning plasma total the most appropriate management. It is very important to and free cortisol levels and the mean 24-hour plasma work closely with the provider who initially prescribed total cortisol levels were increased in patients with the medication to address the adjustment of such medica- CKD on chronic HD.43,44 In addition, it has been tion.37 Table 1 contains a list of medications that com- shown that HD alone can transiently increase cortisol monly cause hyperprolactinemia. levels for a few hours, which should be considered If the major concern is decreased reproductive hor- when evaluating for Cushing’s syndrome.41 mones, then they can be replaced judiciously. Estrogen replacement using oral contraceptives will not restore ovulation, and referral to a reproductive endocrinologist Circadian Rhythms of ACTH and Cortisol usually will be necessary if fertility is desired. Likewise, in male patients, replacement of testosterone will not In healthy individuals with normal sleep patterns, there is usually help with spermatogenesis. The use of injectable a strong circadian rhythm of ACTH and cortisol secre- follicle-stimulating hormone and luteinizing hormone to tion. After reaching their nadir at approximately mid- stimulate spermatogenesis in patients with CKD has not night, ACTH and cortisol levels start to increase and been studied. In one study, clomiphene also was found reach their peaks in the morning after waking up, which to increase testosterone levels in two thirds of patients then is followed by a decline throughout the day before with prolactinoma who had sustained low testosterone reaching their nadir again at midnight. despite adequate treatment with a dopamine agonist.38 Although circadian rhythms of plasma and salivary But whether this will work in patients with CKD has not cortisol are largely preserved in patients with CKD,45 been studied. For patients who do not meet indications patients with advanced CKD on chronic dialysis, and who choose no intervention, it is reasonable to reas- compared with normal subjects, have higher trough sure the patient and monitor.39 levels of plasma and salivary cortisol at midnight,45 likely explained by higher levels of ACTH at that time point.46 HYPOTHALAMIC−PITUITARY−ADRENAL AXIS AND KIDNEY DISEASE Altered Metabolism of Endogenous Cortisol In CKD, many aspects of the physiology of the hypotha- Cortisol has a strong affinity to and is able to activate lamic−pituitary−adrenal (HPA) axis are altered. mineralocorticoid receptors. Normally, cortisol is con- verted to biologically inactive cortisone by 11 b-hydroxysteroid dehydrogenase 2 at mineralocorti- Table 1. Medications or Substances That Cause Hyperprolactinemia coid target tissues, including the kidney, pancreas, Antipsychotics, especially phenothiazines and risperidone and its and colon.47 As a result, circulating cortisol does not derivatives normally activate mineralocorticoid receptors. In Gastrointestinal motility medications (eg, metoclopramide, domperidone) patients with CKD, it has been reported that there is Antidepressants: rare ineffective deactivation of cortisol by 11 b-hydroxys- Antihypertensive medications: verapamil, methyldopa, reserpine teroid dehydrogenase 2,48 which may lead to exagger- Antinausea agents: chlorpromazine Others: opioids, cocaine ated activation of the mineralocorticoid receptors and, eventually, hypertension.49 Prolactin and Pituitary Disorders 159 Altered Metabolism of Exogenous Glucocorticoids including nausea, diarrhea, and abdominal pain; hypo- In addition to changes in metabolism of endogenous glu- tension; hyponatremia; and so forth. However, in cocorticoid in patients with CKD, there is prolongation patients with advanced CKD, such symptoms are rela- of the half-life of hydrocortisone and prednisolone owing tively nonspecific. Hyperkalemia does not occur with to a reduced metabolic clearance rate, but a shortening of ACTH deficiency because mineralocorticoid production the half-life of dexamethasone owing to an increased by the adrenals remains little changed. However, in metabolic clearance rate, highlighting the differences in patients with CKD, hyperkalemia may occur as a result the metabolism of exogenous steroids in CKD.50 More- of CKD, thus clouding the diagnostic picture. In addi- over, it also has been shown that orally administered tion, adrenal insufficiency can manifest as hypercalcemia dexamethasone has a lower absorption rate in patients in patients on dialysis.52 Indeed, one study showed that with CKD compared with normal subjects,42 which may the prevalence of hypercalcemia in patients with adrenal explain why oral dexamethasone fails to suppress endog- insufficiency and CKD is 1.3%.52 enous cortisol in some patients (see the section “Cushing’s Disease in CKD” for more discussion). Fur- Diagnosis of Adrenal Insufficiency in CKD thermore, there also are altered responses of cortisol to exogenous stimulators or suppressors. Changes in gluco- corticoids in CKD are summarized in Table 2. Cosyntropin stimulation test Patients with secondary or tertiary adrenal insufficiency, that is, deficiency of cortisol owing to inadequate ACTH ADRENAL INSUFFICIENCY IN CKD or corticotropin-releasing hormone (CRH), respectively, are commonly diagnosed with cosyntropin (1 or 250 mg, Etiology of Adrenal Insufficiency in CKD the latter is the standard dose) stimulation tests. In the It is likely that the most common cause of adrenal insuf- cosyntropin stimulation test, patients with adrenal insuf- ficiency in patients with CKD is prior treatment with ficiency fail to mount an increase in cortisol level to exogenous steroids, as it is for patients without CKD. It 18 mg/dL (some investigators prefer 20 mg/dL) at 30 or should be remembered that the HPA axis can be sup- 60 minutes after cosyntropin administration owing to pressed for more than 1 year with steroid use and 10% to adrenal atrophy. However, if the ACTH deficiency is 15% of patients never recover their axis.51 Otherwise, sudden (eg, after pituitary surgery or apoplexy), the adre- autoimmune disease of the adrenals is the most common nals will not have atrophied and a normal response to cause in the United States, but infections with tuberculo- cosyntropin may be present. It should be remembered in sis and fungal diseases are relatively common causes in testing that an ACTH level should always be drawn with individuals coming from other countries. Anticoagula- the baseline cortisol before administering the cosyntro- tion with hemorrhage into both adrenal glands is another pin; a low ACTH level indicates ACTH deficiency and a frequently overlooked cause. As a cause of adrenal insuf- high ACTH level indicates primary adrenal disease as ficiency, ACTH deficiency usually occurs as part of pan- the cause of adrenal insufficiency. hypopituitarism and an isolated form is very rare. In one study, patients with CKD on HD or continuous ambulatory PD (CAPD) mounted increases in cortisol levels after 1 mg, 5 mg, and 250 mg cosyntropin stimula- Clinical Manifestation of Adrenal tion, similar to those seen in healthy subjects.53 In the Insufficiency in CKD same study, baseline cortisol levels were similar between Symptoms of adrenal insufficiency in CKD patients are the controls and dialysis patients, whereas baseline similar to those in patients without CKD. The common ACTH levels were higher in patients on dialysis,53 con- presentations are fatigue; gastrointestinal symptoms sistent with other studies.40,42,44 Table 2. Changes in Endogenous and Exogenous Glucocorticoid in CKD Changes in CKD Endogenous ACTH Increased Endogenous cortisol Normal to increased, especially on HD Circadian rhythm of the HPA axis Preserved in CKD; higher nadir level at night on dialysis Deactivation of cortisol to cortisone Reduced Hydrocortisone, prednisolone Levels increased owing to reduced clearance Dexamethasone Levels decreased owing to reduced absorption and enhanced clearance Abbreviations: ACTH, adrenocorticotropic hormone; CKD, chronic kidney disease; HD, hemodialysis; HPA, hypothalamic−pituitary−adrenal. 160 W. Huang and M.E. Molitch Metyrapone stimulation test in divided doses with 3/4 of the daily dose given in the Metyrapone inhibits 11b hydroxylase, a key enzyme in morning. Adjustment of glucocorticoid doses should be adrenal steroidogenesis, and results in suppression of based mainly on symptoms of the patients. Similar sick- cortisol production, which in turn stimulates secretion of day rules and use of stress-dose glucocorticoid during ACTH and immediate precursors of cortisol (ie, 11- extreme stress (eg, surgery) also should apply; thus 50 to deoxycortisol).54 Therefore, the metyrapone stimulation 75 mg of hydrocortisone usually is given parenterally test is able to assess the response of the whole HPA axis. every 8 hours.55,59 However, it is less commonly used because of the lim- ited availability of metyrapone and the possibility of CUSHING’S DISEASE IN CKD inducing an adrenal crisis in patients with adrenal insuf- ficiency. In CKD patients, there appears to be a pre- Diagnosis of Cushing’s Syndrome in CKD served response to metyrapone (30 mg/kg), as manifested by a similar decrease in cortisol and an Cushing’s syndrome may be caused by exogenous ste- increase in ACTH and 11-deoxycortisol levels after roids (the most common cause), excessive ACTH pro- overnight oral metyrapone, as in control subjects.42 duction by a pituitary tumor (Cushing’s disease) or an ectopic tumor, or autonomous production of steroids by an adrenal adenoma/carcinoma with suppression of Insulin tolerance test ACTH levels. The diagnosis of Cushing’s syndrome Similar to the metyrapone stimulation test, the insulin relies on showing cortisol levels that cannot be sup- tolerance test (ITT) also tests the integrity of the whole pressed fully with dexamethasone and findings of HPA axis. In the ITT, transient hypoglycemia induced increased 24-hour urine free cortisol (UFC) levels and by an exogenous intravenous insulin bolus (0.1 U/kg) midnight salivary cortisol levels.60 leads to activation of the HPA axis and an increase in ACTH and cortisol levels. Although considered the gold Clinical Manifestation of Cushing’s Syndrome in standard for the diagnosis of adrenal insufficiency, the CKD ITT is also not commonly recommended because of its inconvenience, complexity, and safety concerns.55 Simi- Patients with Cushing’s syndrome normally present with larly to what was observed in the metyrapone stimulation symptoms of hypercortisolism. Because cortisol affects test, patients on CAPD or chronic HD have normal corti- almost every organ system, symptoms and signs of sol responses in the ITT,42 suggestive of the validity of hypercortisolism are broad. The symptoms, in the order both tests in diagnosing adrenal insufficiency. of prevalence, include weight gain, menstrual irregular- ity, hirsutism, psychiatric dysfunction, backache, muscle weakness, fractures, and loss of scalp hair. The clinical The CRH stimulation test signs of hypercortisolism include truncal or generalized The CRH stimulation test has been used to differentiate obesity, plethora, moon facies, hypertension, bruising, secondary and tertiary adrenal insufficiency, in which red−purple striae, muscle weakness, ankle edema, and exogenous CRH generates higher ACTH levels in skin hyperpigmentation.61 patients with tertiary, but not secondary, adrenal insuffi- ciency.56 In CKD patients on chronic dialysis, after cor- rection of anemia by erythropoietin, the cortisol Diagnosis of Cushing’s Disease in CKD response to exogenous CRH was prolonged.57 Further- The biochemical diagnosis of Cushing’s syndrome is more, compared with end-stage kidney disease (ESKD) challenging in CKD, owing to the significant alterations patients not on dialysis and those on HD, patients on in glucocorticoid metabolism by reduced renal function. CAPD showed a more normal response to CRH Table 3 summarizes the dynamic tests for Cushing syn- stimulation.58 drome in patients with CKD. Treatment of Adrenal Insufficiency in CKD Dexamethasone suppression test The mainstay of the treatment of adrenal insufficiency in Although most studies have shown that 1 mg dexametha- CKD patients is similar to that in patients with normal sone overnight does not adequately suppress cortisol renal function (ie, replacement of glucocorticoid). The secretion in non-Cushing’s patients with CKD,43,62 one clinician should consider the altered metabolism of study showed normal suppression of cortisol by 1 mg exogenous glucocorticoids, especially those commonly oral dexamethasone in patients with various degrees of used in adrenal insufficiency, including hydrocortisone, CKD, including ESKD on HD.40 A recent study showed prednisone, and so forth. The usual hydrocortisone that dexamethasone levels did not differ significantly replacement doses are in the 15 to 20 mg/d range, given between control subjects and CKD patients at various Prolactin and Pituitary Disorders 161 Table 3. Dynamic Tests for Diagnosis of Hypercortisolism in Chronic Kidney Disease 1 mg Overnight Dexamethasone Suppression Test Less Suppression of Cortisol, May Cause False-Positive Results 2-day, low-dose (0.5 mg every 6 h) dexamethasone suppression test Similar response as in normal renal function High-dose (3 mg) overnight dexamethasone suppression test Similar response as in normal renal function Midnight salivary cortisol test Higher nadir level of cortisol, may cause false-positive results 24-hour urine free cortisol Not useful Inferior petrosal sinus sampling Not recommended stages after 1 mg dexamethasone overnight.62 Despite patients with CKD and that patients with Cushing’s disease seemingly inadequate suppression by the 1 mg dexa- and CKD may not have increased levels, the measurement methasone overnight test in most studies, the regular 2- of UFC in this setting may be inaccurate and not useful. day low-dose,63 2 mg overnight,62 and 3 mg overnight42 dexamethasone suppression tests appear to fully inhibit Inferior petrosal sinus sampling the cortisol levels as in normal subjects. In contrast, in patients with Cushing’s disease and Inferior petrosal sinus sampling (IPSS) is recommended CKD, low-dose dexamethasone almost never suppressed for confirming the pituitary source of ACTH-dependent cortisol levels.41 Even 8 mg dexamethasone was not able Cushing’s syndrome, which is most commonly owing to to suppress cortisol levels in patients with Cushing’s dis- a pituitary adenoma. Based on the understanding of ease and CKD in two reported cases.41 Conflicting Cushing’s disease and the effects of CKD on the HPA results exist as to the metabolism of 1 mg dexametha- axis, it is expected that there is still a pituitary-to-periph- sone administered orally. Although one study showed eral gradient of ACTH in patients with Cushing’s disease that the metabolism of dexamethasone is similar in both complicated with CKD, as shown by IPSS. CKD patients and normal subjects,63 another study sug- However, there are no reports of the use of IPSS in the gested that there is inadequate absorption of 1 mg dexa- setting of CKD, perhaps because of the known toxicity methasone after oral administration, which may account of radiocontrast media in CKD, and because of this tox- for the insufficient suppression of cortisol by 1 mg, but icity IPSS cannot be recommended in this setting. not 3 mg, dexamethasone.42 In addition, there seems to be some resistance of the HPA axis to exogenous ste- roids in CKD because 1 mg intravenous dexamethasone Treatment of Cushing’s Syndrome in CKD in CKD patients does not suppress cortisol to the level Because of the absence of strong clinical evidence, there seen in normal subjects.64 When performing dexametha- is no guideline for treating Cushing’s syndrome in CKD sone suppression tests, it is important to measure dexa- patients. As in patients with normal renal function, the methasone levels at the same time as cortisol levels to be principal treatment of Cushing’s syndrome in CKD sure an adequate amount of dexamethasone was taken. should be surgical removal of the pituitary or adrenal tumor, followed by subsequent treatment(s) with radio- therapy and/or medications if necessary. Medical treat- Midnight salivary cortisol test ment of Cushing’s syndrome includes the somatostatin An increased midnight salivary cortisol level has an excel- analog pasireotide (Signifor, Signifor LAR; Recordati, lent ability to indicate the presence of Cushing’s syndrome Milan, Italy), dopamine agonist cabergoline, adrenal in subjects without CKD.65 The validity of the midnight enzyme inhibitors such as osilodrostat (Isturisa; Record- salivary cortisol test in the diagnosis of Cushing’s syn- ati) and ketoconazole, and the glucocorticoid-receptor drome in CKD is lacking. However, progression of CKD mifepristone (Korlym; Corcept, Menlo Park, CA), and has been shown to be associated with increasing levels of their use in CKD is summarized in Table 4. These agents midnight salivary cortisol but stable levels of morning sali- can be considered in individual patients who do not attain vary cortisol,45,62 the normal levels used in the current control after surgical intervention.68,69 Although there are diagnosis criteria may result in more false-positive tests; no data on their use in patients with CKD, the package therefore, this test will warrant further investigation. inserts for these drugs show no restrictions except for a maximum dose of 600 mg/d for mifepristone. 24-hour UFC test The utility of the 24-hour UFC test in diagnosing Cushing’s ACROMEGALY AND CKD syndrome is uncertain because it has been reported that patients with Cushing’s disease complicated by CKD have Pathophysiology either lower66 or undetectable levels of UFC.67 Because Acromegaly is caused by increased growth hormone increased levels of UFC can be found in non-Cushing’s secretion, predominantly from a pituitary adenoma, but 162 W. Huang and M.E. Molitch Table 4. Medical Treatment for Cushing’s Disease in CKD Medication Target FDA Approved for Dosing in Renal Disease per Package Insert Treatment of Cushing’s Disease in United States Cabergoline Pituitary No No dose adjustment needed Pasireotide Pituitary Yes No dose adjustment needed Etomidate Adrenal gland No Lower doses may be required in patients with renal insufficiency Osilodrostat Adrenal gland Yes No dose adjustment needed Ketoconazole Adrenal gland No No dose adjustment needed Metyrapone Adrenal gland No No dose adjustment needed Mitotane Adrenal gland No No dose adjustment needed Mifepristone Glucocorticoid receptor Yes (for those with hyperglycemia) Do not exceed 600 mg/d orally in patients with renal impairment Abbreviations: CKD, chronic kidney disease; FDA, Food and Drug Administration. also can be seen very rarely with ectopic production of helpful. If a patient with CKD is suspected to have acro- growth hormone releasing hormone and growth hormone megaly, an MRI (without intravenous contrast) usually (GH). Acromegaly is characterized by typical facial and is needed to confirm the presence of a pituitary lesion acral features, carpal tunnel syndrome, hyperhidrosis, and to determine the surgical approach. joint pain and swelling, and comorbidities including Interestingly, there are case reports of coincidences of hypertension, diabetes, cardiovascular disease, malig- acromegaly and autosomal-dominant polycystic kidney nancy, sleep apnea, respiratory disease, osteoarthritis, disease. A most recent report showed a heterozygous and so forth.70 GH exerts most of its action through insu- mutation of somatostatin receptor type 5 in a patient lin-like growth factor (IGF-1), which is produced mainly with polycystic kidney disease resulting from a PKD1 in the liver. gene mutation.74 It was postulated that the close proxim- In patients with CKD, there are substantial changes ity of the somatostatin receptor type 5 gene and the of GH and IGF-1 metabolism, including increased PKD1 gene on chromosome 16 may explain the coinci- GH levels caused by decreased renal clearance, dence of these two conditions.74 decreased levels of GH binding protein, normal IGF- In addition to assessing the GH axis, other pituitary 1 levels with reduced IGF-1 bioactivity, increased axes also should be assessed for hypopituitarism. It levels of IGF-1 binding proteins, and GH resistance.71 should be borne in mind that metabolism of many hor- In patients with acromegaly, increased GH and IGF-1 mones is affected in CKD, including prolactin (discussed levels cause renal hypertrophy, increased glomerular earlier), ACTH/cortisol (discussed earlier), gonadotro- filtration rate, water and sodium retention, hyperphos- pins, and sex hormones. Careful interpretation of these phatemia, and hypercalciuria.71 hormone levels based on knowledge of the extensive changes of hormones in CKD therefore is needed. Diagnosis of Acromegaly in CKD Acromegaly usually is considered when patients show Treatment of Acromegaly in CKD typical facial (prognathism, thick lips, enlarged nose and Surgery is usually the treatment of choice for acromeg- tongue, prominent supraorbital ridges, and zygomatic aly.70 If surgery is not curative or the patient is ineligible arches) and acral features. In patients without CKD, the for surgery or refuses surgery, then medical treatment is biochemical diagnosis of acromegaly is established with recommended. Medical treatments for acromegaly can an increased IGF-1 level and nonsuppressed GH levels target pituitary tumors by using the dopamine agonist after a glucose challenge. The diagnosis of acromegaly cabergoline and/or somatostatin analogues, or GH recep- is a challenge in patients with CKD because of the pro- tors by using the GH-receptor antagonist, pegvisomant found changes in GH and IGF-1 metabolism in CKD, (Somavert; Pfizer, New York, NY). There is a paucity of namely increased GH but normal IGF-1 levels. There is literature on the medical treatment of acromegaly in a paradoxic increase in GH after a glucose challenge in patients with CKD. Cabergoline is a plausible choice in patients with CKD, but no acromegaly.72,73 Importantly, patients with only modest increases of postoperative GH a similar paradoxical increase in GH after glucose load and IGF-1 levels, but it is effective in only approxi- also can been seen in patients with acromegaly and mately one third of patients. No dose adjustment of CKD, further complicating the diagnosis of acromegaly cabergoline is needed in patients with CKD. Long-acting in CKD.72,73 Currently, there is no consensus on the bio- somatostatin analogues are the mainstay for controlling chemical diagnostic criteria for acromegaly in patients acromegaly. Currently available somatostatin analogues with CKD, but an increased IGF-1 level likely will be in the United States are octreotide LAR (Sandostatin; Prolactin and Pituitary Disorders 163 Novartis, Basel, Switzerland), lanreotide depot (Somatu- posterior pituitary. Upon stimulation by a variety of sig- line; Ipsen, Paris, France), and pasireotide LAR. nals, including an increase in serum osmolarity, a Intramuscular injection of octreotide LAR depot has decrease in intravascular volume, stress, nausea, and so been shown to be effective in patients with acromegaly forth, AVP and copeptin are secreted in equimolar and CKD to reduce GH and IGF-1 levels and improve amounts. renal hyperfiltration.75 There are no reports of the use of Upon its release into systemic circulation, AVP exerts octreotide LAR or lanreotide depot in patients with its action at multiple tissues through activation of its var- CKD, but their package inserts do not contain any dose ious receptors, primarily vasopressin receptor 1a (V1a), adjustments for renal impairment except for starting at receptor 1b (V1b), and receptor 2 (V2R). V1a receptors the lowest dose. Similarly, there are no reports on the are found mainly in smooth muscles of the arterioles. use of recently approved oral octreotide in acromegalic Activation of V1a receptors results in constriction of the patients with CKD, but the manufacturer recommends a arterioles, leading to an increase in the systemic circula- lower starting dose of this medication in acromegalic tory resistance and, eventually, an increase in blood pres- patients with CKD. sure. V1b receptors are located in the anterior pituitary Pasireotide LAR is metabolized mainly in the liver, and are responsible for the stimulatory effect of AVP on and only a small fraction is excreted via the kidney. ACTH secretion. Distinct from V1a and V1b receptors, There is one case report in which pasireotide LAR was V2Rs are mostly present in the principal cells of the dis- used in a patient with acromegaly and CKD requiring tal convoluted tubes and the collecting ducts of the hemodialysis,76 and its package insert does not recom- kidney. Binding of AVP to V2R activates the cyclic mend dose adjustments for CKD. There are no data on adenosine monophosphate signaling pathway, insertion the use of pegvisomant in patients with CKD and its of aquaporin 2 molecules (water channels) into the apical package insert simply states that fact. Table 5 summa- membrane of the principal cells, and, subsequently, rizes the medical treatment of acromegaly in CKD. absorption of water from the glomerular filtrate, resulting in urinary concentration. V2Rs also are found in extrare- nal tissues, including the vascular endothelial cells, in ARGININE VASOPRESSIN AND KIDNEY DISEASE which activation of the V2Rs causes release of coagula- tion factor VIII and von Willebrand factor, and tissue Pathophysiology plasminogen.77 Arginine vasopressin (AVP), also called antidiuretic hor- In patients on HD, AVP levels are found to be mone (ADH), is secreted by magnocellular neurons in increased owing to a variety of mechanisms, including the supraoptic and paraventricular nuclei of the hypo- decreased metabolic clearance rate78-80 and imperme- thalamus. The AVP molecule is first synthesized as a ability of AVP molecules of the dialysis membranes.78,81 pre-pro vasopressin precursor in the cytoplasm of these Because copeptin is co-secreted in equimolar amounts neurons. The precursor then undergoes proteolytic cleav- with AVP and because AVP has a short half-life in circu- age into AVP, neurophysin II, and copeptin (also known lation, copeptin has been proposed as a surrogate marker as C-terminal pro-arginine vasopressin) during axonal of AVP secretion.82 Measurement of AVP is difficult, transport from the cytosol to neuronal terminals at the requiring meticulous handling of the blood specimen, posterior pituitary gland (neurohypophysis), where these and measurement of copeptin is much less exacting. molecules are stored in secretory vesicles. The peptide Similar to AVP, copeptin levels also are increased in content in the secretory vesicles accounts for the typical patients with CKD or on chronic HD.82,83 However, the bright signal observed on the T1-weighted MRI of the increase in copeptin in CKD is much faster than that of Table 5. Medical Treatment for Acromegaly in CKD Medication Target FDA Approved Dosing in Renal Disease per Package Insert o Treat Acromegaly in United States Cabergoline Pituitary Yes No dose adjustment needed Lanreotide depot Pituitary Yes No dose adjustment except starting at 60 mg every 4 weeks for those with CrCL