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Departments of Molecular and Clinical Endocrinology and Oncology (A.F., R.P., M.F., M.C.D.M, C.D.S., G.L., A.C.), Pediatrics (D.M.), and Internal Medicine (M.P.), "Federico II" University, Naples, Italy
Address all correspondence and requests for reprints to: Annamaria Colao, M.D., Ph.D., Department of Molecular and Clinical Endocrinology and Oncology, "Federico II" University of Naples, Via Sergio Pansini 5, 80131 Naples, Italy. E-mail: colao{at}unina.it.
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Abstract |
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In conclusion, patients with active CD have an increased prevalence of nephrolithiasis compared with general population, which decreases but not disappears in patients successfully cured from the disease. This complication is likely caused by the synergic effect of different hypercortisolism-dependent metabolic and hemodynamic abnormalities, among which systemic arterial hypertension and excessive urinary uric acid excretion seem to play a pivotal role.
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Introduction |
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The aim of this study was 3-fold: first, to evaluate the prevalence of nephrolithiasis in a large series of patients with Cushing’s disease (CD); second, to investigate the role of different lithogenic factors characterizing glucocorticoid excess; third, to verify whether nephrolithiasis and/or its correlated lithogenic factors reverse or persist, such as metabolic syndrome, cardiovascular and bone damage (11, 12, 13), after stable remission of CD.
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Subjects and Methods |
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Forty-six CD patients, 24 active consecutive patients admitted to our Department for Cushing clinical appearance (15 women and 9 men, 33.4 ± 1.85, mean ± SEM, 20–48 yr) and 22 patients cured from CD followed-up for the persistence of metabolic and/or endocrine alterations (16 women and 6 men, 41.2 ± 1.80 mean ± SEM, 25–54 yr) were enrolled in this study after their informed consent had been obtained. All the patients potentially eligible agreed to participate in this study. Forty-six healthy subjects, sex- and age-matched to the patients, among the medical and paramedical personnel of the Department of Molecular and Clinical Endocrinology and Oncology of the University "Federico II" of Naples, agreed to participate in this study and were used as controls.
The diagnosis of CD was based on: 1) increase of daily urinary cortisol excretion with inappropriately high plasma ACTH concentrations; 2) increase of basal serum cortisol concentrations with lack of the physiological circadian rhythm; 3) failure of urinary and serum cortisol suppression after low dose but greater than 50% decrease after high dose dexamethasone test. The group of active patients included 15 patients with relapse of CD after trans-sphenoidal surgery (followed by pituitary irradiation in 3) and 9 newly diagnosed CD patients. Inclusion criteria for cured patients were a stable remission from CD for at least 5 yr (range: 5–10 yr; mean: 6.7 ± 1.1 yr; median: 6.6 yr) defined by: 1) urinary daily cortisol excretion and plasma ACTH concentrations below or within the normal range; 2) serum cortisol concentrations below or within the normal range with restoration of physiological circadian rhythm; 3) suppression of urinary and serum cortisol concentrations after low-dose dexamethasone test (12). Recovery from CD was obtained by trans-sphenoidal selective adenomectomy in 14 patients. In six of them, stable normalization of cortisol levels was achieved after surgery, whereas it was preceded by transient hypocortisolism in three. Persistent hypocortisolism was obtained in five patients, who were treated with cortisone acetate at the dose of 12.5–37.5 mg/d. The remaining eight patients became eucortisolemic after second surgery in five and radiotherapy in three. These latter had been treated with ketoconazole at doses ranged 400–800 mg/d, which induced suppression of serum and urinary cortisol levels, while awaiting the effects of radiotherapy.
At study entry, 10 of 22 cured patients had secondary hormonal deficiencies: central hypothyroidism in 4; hypogonadism in 5; GH deficiency in 5; and diabetes insipidus in 3 patients. All patients with secondary pituitary deficiencies were treated with appropriate hormonal replacement (levothyroxine, testosterone, or oestroprogestinic, recombinant GH or desmopressin at the appropriate dose). Levothyroxine replacement at the dose 75–125 µg/d was given to five cured patients, because of a postthyroiditic hypothyroidism occurring 3–6 months after remission of the disease. The adequacy of replacement therapy was periodically monitored during the follow-up by measuring free urinary cortisol, thyroid and sex steroid hormones and IGF-I levels, daily water balance, systemic arterial blood pressure, serum electrolyte levels, and regularity of menses in females. All patients had been followed at least twice yearly to verify the possible onset of other pituitary insufficiencies, in the cured patients the persistent control of cortisol secretion was also carefully monitored at least twice yearly. At study entry, all patients were taking a normocaloric diet regimen, providing approximately 50%, 35%, and 15% of total energy intake from carbohydrates, fat and mixed proteins, respectively. Neither the patients nor the controls referred inheritance for nephrolithiasis, gout, hyperuricemia, hypercystinuria: none of them was a smoker. Two controls referred a single episode of renal colic, spontaneously remitted after medical therapy with spasmolytic and analgesic drugs.
Seven cured patients have had renal colic during active phase of CD. Radiographic and ultrasonographic scans revealed multiple kidney stones in all patients, with bilateral involvement in four. They were submitted to medical therapy with spasmolytic and analgesic drugs, achieving restoration from disease. Such symptoms did not occur after CD remission anymore. Seven active patients had nephrolithiasis with renal colic before the diagnosis of CD, remitted by medical therapy with spasmolytic and analgesic drugs. No other episodes of renal colic occurred afterwards. In three of the seven cured and in three of the seven active patients who had suffered from renal colic, the ejected kidney stones were analyzed by infrared spectrophotometry. In all cases, stones were formed by mixed calcium-phosphates and calcium-oxalates crystals. At entry study, patients and controls did not refer symptoms suggestive of renal colic, presented signs of nephrolithiasis or urinary infection at physical examination, or received drugs influencing renal function.
Study protocol
A three-step study (clinical, biochemical, and morphological) was performed in all patients and controls.
1. Clinical study. Height, weight, body mass index (BMI), and measurements of heart rate, systolic blood pressure (SBP), and diastolic blood pressure (DBP) were evaluated by standard methods. BMI was measured as the ratio between the weight and the square of the height. A BMI between 25 and 30 was considered as index of overweight, and greater than 30 was index of obesity (14). Blood pressure was measured in the right arm, with the subjects in relaxed sitting position. The average of six measurements (three taken by each of two examiners) with a mercury sphygmomanometer was used. Hypertension was diagnosed when DBP values were more than 90 mm Hg (15). In patients treated with antihypertensive drugs, pretreatment blood pressure values were considered for the diagnosis and evaluation of the severity of hypertension.
2. Biochemical study. Fasting glucose and insulin, serum and urinary electrolytes, uric acid, urea and creatinine levels, and urinary oxalate and citrate were measured by standard procedures. Serum and urinary cystine levels were analyzed in all patients and controls by means of cationic exchange HPLC "System Gold" (Beckman, Coulter, Milan, Italy). Mean value of 2 d consecutive serum sample and 2 d consecutive 24-h urine collection was considered for all biochemical parameters. Glucose tolerance was evaluated on the basis of fasting blood glucose levels or the response of blood glucose levels to a standard oral glucose tolerance test (75 g of glucose diluted in 250 ml of saline solution, measuring blood glucose every 30 min for 2 h). Diabetes mellitus was diagnosed when fasting blood glucose levels were more than 7 mmol/liter in two consecutive determinations or 11.1 mmol/liter or more 2 h after oral glucose, whereas an impairment of glucose tolerance was diagnosed when blood glucose levels were between 7–11.1 mmol/liter 2 h after oral glucose with an additional measurement of 11.1 mmol/liter or more between 0 and 2 h after glucose load (16). Hypercalciuria was diagnosed when 24-h urinary calcium levels were at least 250 mg/d for females and at least 300 mg/d for males, hyperuricosuria when 24-h urinary uric acid levels were at least 750 mg/d for females and at least 800 mg/d for males, hyperoxaluria when 24-h urinary oxalate levels were at least 32 mg/d for females and at least 43 mg/d for males, and hypocitraturia when 24-h urinary citrate levels were 320 mg/d or less in according with standard accepted definitions. Creatinine clearance was calculated according to literature, using the following formula: [urinary creatinine (µmol/liter) x 24 h urinary volume (ml/min)/serum creatinine (µmol/liter)] (17). Plasma ACTH and serum and urinary cortisol, assayed by RIA using commercially available kits, were measured to assess the hypothalamus-pituitary-adrenal axis. In the present study, only the results of urinary cortisol assay are shown. Serum intact PTH levels were measured in all subjects by IRMA (Radim, Pomezia, Italy).
3. Ultrasonographic study. Renal US was carried out by a commercially available real-time instrument. Scanning variables such as transducer frequency, time gain compensation curve and power output were adjusted individually to optimize image quality. Multiple anatomic approaches, including supine and decubitus views obtained in transverse and longitudinal planes, were used in imaging the kidneys. The pictures were stored on magnetic media and analyzed later. US studies were performed by a single operator (M.P.) blind in respect to patient or control study. Based on high sensitivity demonstrated by US in diagnosis of kidney stones, the diagnosis of nephrolithiasis was considered in presence of hyperechoic areas more than 2.5 mm in size, detected at level of renal pelvis or calyces (18).
Statistical analysis
The statistical analysis was performed by SPSS for Windows, version 9.0 (SPSS, Inc., Chicago, IL). The comparison between the categorical data were performed by 
2 test with Yates correction and Fisher exact test where appropriate. The comparison between the numerical data were performed by ANOVA, followed by Bonferroni test for the adjustment for multiple comparison. Data were reported as mean ± SEM. The significance was set at 5%. The odds ratio and 95% confidence interval were used to approximately estimate the relative risk of stone formation after adjusting simultaneously for multiple factors. The variables included simultaneously in the multivariate model were age, gender, BMI, blood pressure levels, and 24-h urinary excretion of electrolytes, urea, uric acid, cystine, oxalate, citrate, creatinine, and cortisol, and urinary total volume and pH as well as disease duration. Data are expressed as mean ± SE. Significance was set at 5%.
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Results |
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Nephrolithiasis was diagnosed by US in 12 patients (50%) and three controls (6.5%; P < 0.001; Fig. 1). Stones size was 2.5–5 mm in seven patients and in all controls and 5–7.5 mm in the remaining five patients. Six patients and one control had bilateral renal involvement. Among the patients with positive US, seven had suffered from renal colic before CD diagnosis.
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). BMI, SBP, DBP, fasting glucose, and insulin levels were significantly higher in the patients than in the controls (Table 1
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). Urinary pH and total volume were similar in both groups. Compared with controls, CD patients had significantly increased urinary creatinine, potassium, calcium, phosphorus, and oxalate levels, decreased urinary citrate levels, and significantly increased serum and urinary uric acid and cystine levels (Table 1). Patients cured from CD
In patients with previous CD, nephrolithiasis was diagnosed by US in six patients (27.3%; P < 0.05 vs. controls; Fig. 1). They were between 2.5 and 5 mm in size in five, with bilateral involvement in three and of 6 mm in one. These six patients had been already affected by nephrolithiasis associated to renal colic symptoms, before remission from CD, as well as another one who did not have kidney stones.
Obesity was observed in three patients and overweight in eight (P < 0.01 vs. controls). Arterial hypertension was found in 16 patients (P < 0.001 vs. controls). Diabetes mellitus was found in two patients, and impaired glucose tolerance was observed in nine patients (P < 0.001 vs. controls; Table 2). BMI, SBP, DBP, fasting glucose, and insulin levels were significantly higher in the patients than in controls. BMI, SBP, DBP, and fasting glucose and insulin levels were similar in cured and active patients (Table 1).
Hypercalciuria was found in 1 patient (P < 0.001 vs. active patients), hyperuricosuria in 2, hyperoxaluria in 3, and hypocitraturia in 11 (P < 0.001 vs. controls; Table 2). Patients and controls had similar levels of serum and urinary sodium, potassium, calcium, phosphorus, uric acid, cystine, and urinary pH and total volume. Compared with controls, the patients had a significant decrease of urinary citrate levels. Compared with active patients, the patients cured from CD had significantly decreased urinary potassium, calcium, phosphorus, uric acid, oxalate, and cystine levels and serum cystine levels and significantly increased serum citrate levels (Table 1). There was no difference between the patients cured from the disease taking or not glucocorticoid replacement therapy. No significant correlation was found between duration of disease free interval and any of the biochemical or radiological features related to the kidney stone formation.
The multivariate analysis
An increased risk to develop kidney stones was independently associated with urinary excretion of uric acid (odds ratio=1.6, confidence interval=1.0–2.5) and systemic arterial blood pressure (odds ratio=2.6, confidence interval=1.1–6.6). No other clinical, metabolic, and urinary parameter was independently associated with the risk of stone formation.
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Discussion |
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Nephrolithiasis is a common clinical disorder occurring in 1–5% of the general population of industrialized countries (3, 4, 5). This prevalence was reported to be increased in conditions of chronic hypercortisolism. Indeed, in early studies of Cushing’s syndrome, kidney stones were reported in about 15% of patients (2). However, in the current series the prevalence of nephrolithiasis in active CD patients was up to 3-fold greater than previous estimates. One possible explanation for this discrepancy is that a systematic research of nephrolithiasis, including well defined stones and microlithiasis, in a large population of patients with Cushing’s syndrome has never been performed to date and, therefore, only the cases with clinically overt nephrolithiasis had been taken into account in the previous studies. The high prevalence of patients in active CD presenting early signs of nephrolithiasis indicates that these patients are highly predisposed to form well defined kidney stones. Moreover, in the current study, the subjects long-term cured from CD still maintained an elevated risk to develop kidney stones compared with controls, in association with the persistence of the metabolic syndrome, and specifically of systemic arterial hypertension, despite the stable normalization of cortisol levels. This demonstrated that the stable cure of CD is not sufficient to completely normalize the risk of developing nephrolithiasis in CD patients.
Several metabolic and electrolytic abnormalities are associated to nephrolithiasis. In active CD patients, we found an increased urinary excretion of calcium, phosphorus, potassium, uric acid, cystine, and oxalate and decreased urinary excretion of citrate. Chronically elevated urinary excretion of these elements represents a direct and/or indirect risk factors for kidney stones formation, with the exception of citrate and potassium, which are protective factors by inhibiting urinary crystals formations.
Interestingly, hypercalciuria and hypocitraturia appear to be a common feature of active CD patients, accounting for 85.7% and 78.6%, respectively, and displaying a higher prevalence than nephrolithiasis. This finding suggests that hypercalciuria and hypocitraturia, although important risk factors, are not sufficient in inducing kidney stone formation. Indeed, hypercalciuria is a common abnormality of CD patients, due to enhanced bone mobilization and decreased net renal tubular reabsorption of calcium, resulting in a negative calcium balance and chronic hypercalciuria (6, 7, 19). Similarly, hypocitraturia is a common abnormality of CD patients: low urinary citrate levels favor stone formation as they cannot inhibit the formation of calcium crystals, which complex with calcium ions when in excess in the urine (20). The reason that urinary citrate levels are low in CD patients is still unknown. However, citrate and calcium excretion were inversely correlated in subjects undergoing increased dietary protein intake, because of an increased renal net acid excretion which influences urinary excretion of both substrates (19). In addition, hypocitraturia has been reported in 16% of patients with idiopathic calcium salts nephrolithiasis (8). Because both hypocitraturia and hypercalciuria are present in the majority of CD patients, a common pathogenic mechanism is likely. This mechanism may be identified in the increased acid production following the hypercatabolic CD state. However, in CD patients, hypocitraturia and hypercalciuria would represent conditions predisposing to stone formation, but they seem to be unable in inducing crystals precipitation in the absence of other lithogenic events.
Urinary excretion of phosphorus and oxalate seems to play a minor role in kidney stone formation in CD patients. These two elements are required for calcium salts stones formation (3, 8, 9) but neither they were a constant characteristic nor they were specifically associated with the presence of kidney stones in CD patients. Anyway, their increased urinary excretion may contribute in inducing a network of lithogenic events, which facilitates the formation of calcium salts kidney stones. In particular, increased phosphaturia increases urinary saturation and may favor calcium excretion (21). Increased oxaluria seems to be one of the most important risk factors of kidney stones formation in overweight hypertensive subjects (22). Therefore, the absence of a higher prevalence of hyperoxaluria in active or cured CD patients than in controls can be due to an inadequacy of the traditional definition of normal daily urinary values, and the definition of abnormal values for men and women, which is still inappropriate (23). The presence of high urinary levels of potassium in a percentage of patients with active and/or cured CD is probably a not sufficient protective factor for kidney stone formation in these patients.
In contrast to hypercalciuria and hypocitraturia, hyperuricosuria represents a less common feature of CD patients but results specifically correlated with nephrolithiasis. Hyperuricosuria is likely to have an inducing effect in glucocorticoid-dependent nephrolithiasis. In fact, whether calcium crystals are the predominant mineral components in kidney stones both in the general and in the CD population (2, 3, 4, 5), uric acid/urate crystals seem to promote urinary calcium-oxalate/phosphate salts precipitation, so creating initial heterogeneous nuclei (8, 9, 24). Hyperuricosuria of CD patients is considered consequence of the hypercatabolic CD state (25, 26). BMI seems to be the most important factor independently correlated with uricosuria (25); both BMI and hyperuricosuria are significantly higher in CD patients than in controls. However, an increased renal secretion and a decreased renal reabsorption might also favor the urinary uric acid excretion.
Although a direct lithogen action of cystinuria does not appear to be relevant from our results, higher serum and urinary cystine levels were found in active patients than in controls, in agreement with the results of a previous study (10). Cystine, a cysteine dipeptide, is a poorly soluble and highly lithogenic substrate, which reaches highest urinary concentration in the hereditary cystinuria, a condition representing 1.5% of nephrolithiasis in the general population (8). The urinary cystine excretion in CD patients, however, does not compare with the levels measured in hereditary cystinuria. On the other hand, it may contribute to hypercalciuria and hypocitraturia, because of the great amount of protons released during the oxidation of sulfur to sulfate (27), which was reported to stimulate calcium and decrease citrate urinary excretion (19).
A pivotal role in the hypercortisolism-related nephrolithiasis seems to be played by systemic arterial hypertension. This is a common complication of active CD and persists also after cure from hypercortisolism (12). In the general population, hypertension was increased in subjects developing kidney stones (5). Furthermore, urinary excretion of calcium, oxalate, and uric acid was significantly higher in hypertensive than in normotensive control subjects (22). The strict association between nephrolithiasis and hypertension is also underlined by a similar pattern of related metabolic abnormalities. In fact, hypercalciuria, hyperoxaluria, hyperuricosuria, and increased body weight have been described for both kidney stone forming and hypertensive subjects (22). This evidence confirms the possible pathogenetic role of hypertension in favoring nephrolithiasis also in CD. The predominant role of hypertension is evident also in subjects cured from CD, where its frequency remains higher than control subjects, in accordance with the persistence of kidney stones in a high proportion of these patients.
A last point emerged from the current study is that age and gender did not influence the risk of forming kidney stones. Our patients was a relatively young cohort, so possibly explaining the absence of age-related differences in kidney stones formation.
In conclusion, patients with CD have a remarkably high prevalence of nephrolithiasis. The increased lithogenic risk origins from the coexistence of multiple factors, which are synergic in creating and maintaining the substrates necessary for stone formation. In particular, systemic arterial hypertension and excess urinary excretion of uric acid seem to play a pivotal role in inducing kidney stone formation in CD patients. Furthermore, although most metabolic and electrolytic balance normalize after the cure from CD, an increased risk of developing kidney stones persists compared with the general population. On this basis, both patients with active CD and those already cured from the disease might benefit from a careful evaluation of lithogenic factors and kidney US.
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Footnotes |
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Received September 24, 2002.
Accepted February 10, 2003.
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