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Acquired cystic kidney disease: The hormonal hypothesis
ACQUIRED CYSTIC KIDNEY DISEASE: THE HORMONAL HYPOTHESIS G. CONCOLINO, M.D. C. LUBRANO, M.D. M. OMBRES, M.D.
A. SANTONATI, G. P. FLAMMIA, F. DI SILVERIO,
From the Clinica Medica V, Patologia Urologica, “La Sapienza,” Rome, Italy
M.D. M.D. M.D.
Universita di Roma
ABSTRACT-Based on the reported sex difference in the incidence of acquired cystic kidney disease (ACKD) in patients with chronic renal failure, it is hypothesized that the hormonal derangement, well documented in male and female uremic patients on long-term dialysis, could be responsible for the pathogenesis of ACKD. The decreased androgen/estrogen ratio, and the increased estrogen value could be responsible for an estrogen receptor mediated effect on the tubular epithelial cell proliferation, an event further potentiated by the action of regulatory peptides like epidermal growth factor (EGF). The epithelial stimulation is more pronounced in men because male tissues are less adapted than female tissues to high estrogen values. Furthermore the androgen reduction, more remarkable in male than female patients, is responsible for an up-regulation of EGF-R. Therefore hormones and growth factors, by means of their own receptor in renal tissue (homologous to the two oncogenes c-erb A and c-erb B), may be responsible for the development of ACKD, and may play an important role in the pathogenesis of multiple adenomas and renal carcinomas reported with high incidence among uremic patients with ACKD. In the last decade a new acquired disease characterized by the formation of bilateral renal cysts in uremic patients on long-term dialysis has been reported: the acquired cystic kidney disease. The well-known endocrine derangement in uremic patients and the sex-related differences in the occurrence of ACKD prompt us to speculate whether a hormonal etiology could be hypothesized. The acquired cystic kidney disease described since 1977l in patients with chronic renal failure (CRF) on long-term dialysis is characterized by the presence of multiple cysts in both kidneys, usually in the cortex, occasionally in the medulla or at corticomedullary junction, with increased renal volume, frequently associated with multiple renal adenomas or renal cell carcinomas (RCC). The main differences between the acquired cystic kidney disease and the autosomal dominant inherited2 polycystic Presented at the “First Review Course on Nephrology and Urology” held in Fiuggi, Italy, May 9, 1988.
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kidney disease (PCKD) are: the absence of associated cystic disease, 3 the increased renal volume with long-term hemodialysis (HD),3 and the absence of cysts with aboral proliferation in the acquired form.4 ACKD could be considered a specific complication of dialysis since cysts are present even in patients with incipient renal failure. However, the incidence of multiple cysts in patients with CRF increases with the increase of the time on dialysis (both HD and continuous ambulatory peritoneal dialysis): from 22 percent in patients with initial CRF to 35 percent in patients on dialysis for less than two years, and 95 percent in those on dialysis for more than eight years.4 The cysts that develop during dialysis in some patients with ACKD occasionally regress after successful renal transplantation, i.e., early renal transplantation tends to prevent or impede ACKD.5 On pathologic basis the cysts are predominant in the outer cortex (although any part of the nephron can be subject to cystic dilatation),
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have a size of l-25 mm, contain clear fluid and oxalate crystals, have cuboidal or columnar and papillary hyperplasia surepithelium, rounded by thickened basement membranes; on electron microscopic scanning there are cysts lined with epithelium derived from proximal tubule epithelia studded with microvilli in cluster, or cysts lined with smoother surface (epithelial cells derived from distal nephron) with short microvilli in clusters4 ACKD develops more frequently in tubulointerstitial renal diseases, less likely in membranoproliferative glomerulonephritis, and rarely in diabetic kidneys.4 The histologic pattern of membranoproliferative glomerulonephritis is characterized by hyalinized glomerular tuft with maintained lobularity, atrophic tubules with lack of distinction between proximal and distal tubules, interstitial fibrosis, a common arterio- and arteriolosclerosis.’ Therefore the most likely pathogenetic mechanism underlying the ACKD is represented by continued glomerular filtration in the presence of luminal obstruction4 Many etiologic theories, however, have been proposed for this recently identified pathologic process of the kidney. 1. The occlusive theory takes into account the obstruction of renal tubules by surrounding interstitial fibrosis, along with the focal proliferation of tubular epithelial cells, and the possible presence of intratubular oxalate crystals.5 2. The ischemic theory has been proposed by Helper6 and others who produced cysts in rabbit kidney with a combination of ischemia and obstruction obtained by means of ligation of segmental arteries and papillary cauterization, respectively: it is well documented, in fact, that both ischemia and obstruction are alterations seen in patients with end-stage renal failure. 3. The chemical theory is based on the observation that certain diphenyl compounds induced cysts in rats. 7-QAccumulation of similar substances in patients undergoing dialysis might cause ACKD; furthermore, it has been supposed that substances leached out of the plastic dialysis circuit (such as plasticizer di-ethylexylphtalate) or, alternatively, a metabolite which accumulates in uremia, inadequately removed by dialysis, might be responsible for ACKD. l”.ll 4. The immunologic theory takes into account that uremia acts as an immunosuppressive factor responsible for the decrease of the Thelper lymphocytes and the increase of the T-suppressor lymphocytes. I2
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5. The growth factors theory has been proposed on the demonstration that polypeptides with renotrophic action could act with autocrine and paracrine action on renal tissues.13 To the aforementioned theories we propose to add the hormona2 theory. This theory is based on some clinicopathologic and biochemical observations and on the experimentally hormoneinduced renal cystic disease. It has been reported that in 120 predialysis patients there was no correlation between ACKD and sex, i.e., the disease has been found with equal incidence in male and female patients with CRF regardless of the duration of the renal disease14; while in 108 long-term hemodialysis patients, the ACKD occurred mainly in male rather than female patients Some authors have re(50% vs 20%). 3.4~14~15 ported an even higher incidence of ACKD in male than in female patients at baseline examination: 84 percent vs 50 percent in the two sexes, respectively; furthermore, after three years of HD the incidence of the cysts is 100 percent in male and 66 percent in female patients. Similarly after long-term dialysis the grade of cystic transformation is significantly increased in males and unchanged in females, and a remarkable increase in renal volume (more than twofold) is reported in male rather than in female patients. l5 This is well documented both with the frequency distribution for the increase of kidney volume, and with follow-up study of visible cysts, that demonstrated an increased amount of cysts after three to six years of HD mainly in male patients. l5 Furthermore the rate of increase in kidney volume showed a tendency toward an inverse correlation with age in males and a direct correlation in females.15 All these observations led to the conclusion that a sex-related endogenous substance might play a role in the pathogenesis of ACKD.15 It has been proposed that a hemodialysis-related substance,le or uremic metabolites such as polyamines or nephrotrophic growth factors (GFs)13 could be the sex-related compounds involved in the onset of ACKD. We rather suggest that steroid or polypeptide hormones could be responsible for the aforementioned male to female prevalence of ACKD. It is well known that the kidney is a target organ for many hormones, such as antidiuretic hormone (ADH) l7 and calcitonin (CT),ls and that both the normal human kidney and renal cell carcinoma (RCC) are able to synthesize erythropoietin,‘s plasma renin precursor, lQ and
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TABLE I. Hypothalamic-pituitary-endocrine Hypothalamic-pituitary-thyroid Hypothalamic-pituitary-adrenal Hypothalamic-pituitary a) GH:
down setting of the feedback set-point to thyroid hormones ( - T3 - T4 - TSH) axis: increase in the feedback set-point to glucocorticoids ( + F + ACTH).
axis: increase in the feedback set-point to short closed loop ( + GH + IGFII + IGFI) lactotrope insensitivity to dopamine ( +PRL mainly in females) males + females N males N females + males + females +
(Y subunits:
KEY: N: normal value;
+ : increased value:
-
chorionic gonadotropin.20 Steroid hormones are of particular interest, since in a large number of experimental animals they are able to induce morphologic and biochemical changeqz1s2
More recently described has been the role played by regulatory polypeptides like epiderma1 growth factor (EGF) and its embryonic form transforming growth factor Q! (TFGa) found in high concentrations in normal human kidney and in human RCC, respectively.23,24 Furthermore receptors for steroid hormones have been demonstrated in the kidney of experimental animals25-28 and in normal human kidney. 2g-31 With monoclonal antibody raised against EGF receptors it has been proven that among various tumorous cell lines tested, astrocytoma and RCC cell lines are those with the highest expression of this receptor.32 Recently we have been able to demonstrate that the EGF-R is present also in the normal human kidney surrounding human RCC, with a concentration lower than that found in the tumorous counterpart.33,34 As far as the relationships between steroid hormones and renal cystic disease are concerned, it is worthwhile to remind that estrogens are able to induce degenerative cystic changes in experimental animal renal tissue,35 and, in combination with prolactin, to induce RCC in golden Syrian hamsters.3e Androgens induce proliferative changes in mouse kid37 while compounds like cortisone and 9neys, fluoroprednisolone induce marked, diffuse, and progressive renal cystic disease (mainly in the medulla but also in cortical collecting distal tubules and loops of Henle) in rabbit and newborn hamster kidneys. 38-40In this respect it is interesting that mice with PCKD (that presented macroscopic renal lesions similar to those induced by glucocorticoids) treated with the antiglucocorticoid compound RU-486 have a prolonged survival. 41 Therefore the hormonal
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in CRF patients
axis:
b) PRL: c) FSH: d) LH: e) Glycoprotein
glands dysfunction
: decreased value.
theory for the ACKD can be regarded as the expression of the action of compounds that, through specific receptors, are able to induce a tubular hyperplasia or proliferating tubules with secondary tubules obstruction, Are there some signs and symptoms that led us to believe that patients with CRF have a hormonal imbalance that could support the hypothesis of hormonal theory of ACKD? The answer is affirmative: the clinical features of hormonal imbalance in patients with CRF have been described extensively in the literature. Male uremic patients can present mono- or bilateral gynecomastia42 and decreased libido and potency (which reflect the hypoandrogenemia of the patients) 43; there is a decreased fertility by 50 percent44 and a hypospermatogenesis, with relative preservation of spermatogonia, and severe depletion of spermatids that stand in favor of a hormonal imbalance (rather than a toxic effect), i.e., a hypothalamic-pituitary-testicular dysfunction. 45 Female CRF patients may or may not present galactorrhea45 and have decreased libido or orgasmeO; as in men, a decreased fertility before or during HD (usually restored after successful renal transplantation) has been reported46; the menstrual disorders with anovulation are characterized by oligomenorrhea or amenorrhea (after long-term dialysis) with prevalence of ovarian cyst formation, which are in favor of a hormonal imbalance, i.e., a hypothalamic-pituitary-ovarian dysfunction similar to that described in the polycystic ovary syndrome (PCOS) .47 Therefore it can be concluded that patients with CRF are affected by a hypothalamic-pituitary-endocrine glands dysfunction, with alterations in the setpoint of endocrine closed loops, reset upward or downward (Table I). Pituitary thyroid stimulating hormone (TSH) response to thyroid releasing hormone (TRH) is decreased, but the negative feedback of thyroid
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hormones is maintained, although there is a downsetting of feedback set-point to thyroid hormones with decreased values of T3 and T4 and normal or decreased values of TSH. This condition characterizes the sick euthyroid state or the hypothalamic-pituitary hypothyroidism of the CRF patients4g that is maintained during long-term dialysis and restored to normal by renal transplantation. On the contrary the hypothalamic-pituitary-adrenal axis is characterized by a relative refractariness of negative feedback suppression with dexamethasone for an increase in the set-point to glucocorticoids, with high values of plasma glucocorticoids and normal or high values of plasma ACTH, both at baseline examination and after long-term dialysis.4g Similar alterations in the set-point of endocrine closed loops have been reported for the hypothalamic-pituitary axis: the regulation of GH secretion is characterized by an increase in feedback set-point to short closed loop with high values of GH and IGF-II, while IGF-I is decreased50; there is a lactotrope insensitivity to dopamine with increase in prolactin (PRL) mainly in female CRF patientssl; FSH is increased or normal in male patients, and significantly increased in long-term dialysis male patientqs2 while normal in female patients.52 LH is normal in male uremic patientqs2 and stands in favor of a hypothalamic-pituitary-Leydig cells dysfunction because of the low values of plasma testosterone (T),53 while elevated in female uremic patients as expression of loss of positive estrogen feedback and LH pulsatility54; an excessive release of glycoprotein CYsubunits is also demonstrated by their high plasma values and their increased metabolic clearance rate (MCR) both in male and female CRF patients. 52An increase of GnRH output mainly after long-term dialysis has been reported: immunoreactive GnRH-like material derived from the gonads55 could account for this increase, and could lead to pituitary desensitization and decreased gonadotropin output. 56 Non-endocrine hypothalamic dysfunction of sleep, thirst, and thermoregulation have also been reported in uremic patients.45 The flattening of FSH response to GnRH and the exaggerated LH response with a delayed peak and delayed rate of decline back to baseline are early features of male uremic hypogonadism, expression of the hypothalamic-pituitary-testis dysfunction.57 In female uremic patients FSH response to GnRH is appropriate for an apparent menopausal status, and LH re-
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Steroid pattern in male and female TABLE II. patients with chronic renal failure (CRF) and after hemodialysis (HD)
Steroids Testosterone Dihydrotestosterone Androstenedione Estradiol Estrone Progesterone
-MalesCRF HD _ N N _ N + + . .
. .
KEY: N: normal value; + : increased value;
-FemalesCRF HD -or+ N r;
N + -
i
I
: decreased value.
sponse is delayed, prolonged, and excessive as in the male uremic patients: i.e., in female uremic patients the hypothalamic-pituitary-ovarian dysfunction is revealed by the premature menopause without consistent elevation of FSH and LH.54 The endocrine derangement in uremic patients is also documented by the abnormality of plasma steroids of adrenal and gonadal origin. T, in fact, and dihydrotestosterone (DHT) have been found decreased in male patients with incipient CRF or after long-term dialysis53 (Table II) for the normal value of MCP of T but decreased production rate (PR) of T due to the intrinsic defect in Leydig cells steroidogenesis; in female uremic patients T is either decreased or increased, but always decreased after long-term dialysiqss while DHT remains within the normal range. Androstenedione (A) has been found in the normal range or slightly increased in uremic male patients, although the MCR of A was increased leading to the high value of PR of A,5g but significantly increased both at baseline examination and after dialysis in females.5g 170 estradiol (E2) has been found in the normal range or decreased for lack of effective stimulation by endogenous LH in male patients45; the pattern of this steroid in female patients shows also normal or low plasma values mainly in hyperprolactinemic patients.e0 The behavior of estrone (El) at baseline examination or after dialysis is different in the opposite sexes: male patients presenting high values and female patients low valuesG1 Plasma progesterone is normal or decreased in uremic female patients.54.5s The increased PR of A, the high plasma values of El, of cortisol and of androstenediol-sulfate, along with the decreased plasma values of dehydroepiandrosterone (DHEA) and DHEA-sulfate, stand in favor of an abnormal steroidogenesis in uremic patients.45 Some authors reported that male hypogonadism of uremic patients on dialysis is mainly
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characterized by the high plasma values of A and El and the low plasma values of T and E2 compared with normal controls. The A/T and El/E2 ratio higher than controls could presumably be due to the uremic damage at the testis level, impairing the activity of the enzyme 17fl-hydroxysteroid-dehydrogenase.62 Other authors reported an impairment of 5cr-reductase activity with altered metabolism of T into DHT induced by hyperprolactinemia in uremic male patients.e3 From the aforementioned observations it can be concluded that the reduced T and increased El values, along with the presence of steroid and polypeptide receptors in human renal tissue, may represent the biochemical support to the hormonal theory of ACKD and could account for the male prevalence of ACKD. The hormonal imbalance in uremic male patients, in fact, is characterized by decreased values of androgens (particularly of T) with increased values of estrogens (mainly of El) and decreased androgens/estrogens ratio. The increased value of estrogens is likely to account for the morphologic changes found in the human renal tissue of male uremic patients: female tissues, in fact, are more adapted to the high values of estrogens, and the estrogen action is partially balanced by the antiestrogen effect of progesterone, at least during the childbearing period of a woman’s life. This is in keeping with the observation that the rate of increase in kidney volume shows a tendency toward a direct correlation with age in uremic female patients. l5 Estrogen action, mediated by ER, could affect renal tissue mainly by inducing tubular epithelial cell proliferation, and this effect could be further potentiated by the action of regulatory polypeptides like PRL (increased for the lactotrope insensitivity to dopamine), and EGF (a growth factor highly expressed in normal human kidney). Furthermore the reduced value of T, more pronounced in males than females, is responsible for an up-regulation of EGF-R.64 Therefore, taking into consideration that the analysis of viscoelastic properties of tubule basement membrane in acquired, hereditary, and spontaneous renal cystic diseases does not allow to consider an abnormality of tubule basement membrane as the central process in the formation of renal cysts, while tubular epithelial cell proliferation is responsible for the formation of all renal cysts,e5 it is reasonable to suppose that hormones and growth factors play
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an important role in stimulating this cell proliferation. This etiopathogenetic mechanism could also explain the onset of renal adenomas, and of bilateral carcinomas that develop in ACKD. In the carcinogenesis process of the kidney, in fact, a constitutive expression of EGF-R, homologous to the c-erb B oncogeneGe in the tubular epithelial cells could act in combination with that of steroid hormone receptors, which presents some analogies with the c-erb A oncogene.67xe8These biochemical events could be responsible not only for the tubular cellular hyperplasia and the consequent ACKD, but also for the onset of multiple renal adenomas or bilateral carcinomas found in combination with multiple cysts in uremic patients treated with long-term dialysis. 00161 Rome, Italy (DR. CONCOLINO) References 1. Dunnil MS, Millard PR, and Oliver D: Acquired cystic disease of the kidneys a hazard of long-term intermittent maintenance haemodialysis, J Clin Path01 30: 868 (1977). 2. Grabow PA, Ikle DW, and Holms JH: Polycystic kidney disease prospective analysis of nonazotemic patients and the family members, Ann Intern Med 101: 238 (1984). 3. Mirahmadi MK, and Vaziri ND: Cystic transformation and stage of kidneys in patients undergoing hemodialysis, Int J Artif Org 3: 257 (1980). 4. Mickisck 0; et ol: Multicystic transformation of kidneys in chronic renal failure, Nephron 38: 93 (1984). 5. Levine E, et al: CT of acquired cystic kidney disease and renal tumors in long-term dialysis patients, AJR 142: 125 (1984). 6. Hepler AB: Solitary cysts of the kidney. A renort of 7 cases and observation on the pathogen&s of these cysts,&Surg Gynecol Obstet 50: 668 (1936). 7. Carone FA, Rowland RG, Perlam SG, and Ganote CE: The pathogenesis of drug-induced renal cystic disease, Kidney Int 5: 411 (1974). 8. Gardner KD, Solomon S, Fitzgerrez WW. and Evan AP: Function and structure in the diphenylamine-exposed kidney, J Clin Invest 57: 796 (1976). 9. Evan AP, and Gardner KD: Nephron obstruction in nordihydroguaiaretic acid-induced renal cystic disease, Kidney Int 15: 7 (1979). 10. Minar E, Tscholakff D, and Zazgornik J: Acquired cystic disease of the kidneys in chronic hemodialyzed and renal transplant patients, Eur Urol 10: 245 (1984). 11. Beardsworth SF, Goldsmith HJ, Ahmad R, and Lamb G: Acquisition of renal cysts during peritoneal dialvsis. Lancet 2: 148-2 (1985). 12. QPPT Tan KH 1 Donner R, and Scholtmeyer RJ: Development 01: renal carcinoma in a patient with polycystic kidneys unrlarnnin chronic haemodialysis, Eur Urol 6: 316 (1980). Uu.6Y.a.g 13. Torrence RJ, Elbers JD, and Clayman RV: The presence of a growth factor in cystic fluid from patients with acquired renal cvstic disease (ARCD), 1 Urol 137: 251 (1987). ’ 14. Elliott HL, M&dougall AI, and Buchanan WL: Acquired cystic disease of the kidney, Lancet 2: 1359 (1977). 15. Ishikawa I, et al: Sex differences in acquired cystic disease of the kidney in long-term dialysis, Nephron 39: 336 (1985). 16. Ishikawa I, Yuri T, Kitada H, and Shinoda A: Regression of acquired cystic disease of the kidney after successful renal transplantation, Am J Nephro13: 310 (1983). 17. Dousa TP, and Valtin H: Cellular action of vasopressin on mammalian kidney, Kidney Int 10: 45 (1976). I
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tion in renal failure, dialysis and renal transplantation, Endocrine Rev 6: 151 (1985). 46. Milner JF, Golden JS, and Fibus L: Sexual dysfunction in renal failure: a survey of chronic hemodialysis on the reproductive cycle, Am J Obstet Gynecol 166: 528 (1967). 47. Yen SSC: The polycystic ovary syndrome, Clin Endocrinol (Oxf) 12: 177 (1980). 48. Wartofsky L, and Burman KD: Alterations in thyroid function in patients with systemic illness: the euthyroid sick syndrome, Endocrine Rev 3: 164 (1982). 49. Wallace EZ, et al: Pituitary adrenocortical function in chronic renal failure: studies on episodic secretion and dexametasone suppressibility, Clin Endocrinol Metab 50: 46 (1980). 50. Goldberg AC. et al: Uremia reduces serum insulin-like growth factor [ increase insulin-like growth factor II and modifies their serum protein binding, J Clin Endocrinol Metab 55: 1040 (1982). 51. Lim WS, Kathpalia SC, and Frohman LA: Hyperprolactinemia and impaired pituitary response to suppression and stimulation in chronic renal failure: reversal after transplantation, J Clin Endocrinol Metab 48: 101 (1979). 52. Blackman MR, et al: Discordant elevation of the common alpha subunity of the glycoprotein hormones compared to beta subunits in serum of uremic patients, J Clin Endocrinol Metab 53: 139 (1981). 53. Guervara A, et al: Serum gonadotropin testosterone levels in uremic males undergoing intermittent dialysis, Metabolism 18: 1062 (1969). 54. Lim VS, Henriquez C, Sievertsen G, and Frohman LA: Ovarian function in chronic renal failure: evidence suggesting hypothalamic anovulation, Ann Intern Med 93: 21 (1980). 55. Sharpe RM, Fraser HM, and Cooper D: The secretion measurement and function of testicular LHRH-like factor, Ann NY Acad Sci 383: 272 (1982). 56. Clayton RC, and Catt KY: Gonadotropin releasing hormone receptors: characterization physiological regulation and relationship to reproductive function, Endocrine Rev, p 186 (1981). 57. Winter SJ, and Troen P: Episodic luteinizing hormone (LH) secretion and the response of LH and follicle-stimulating hormone to LH releasing hormone in aged man: evidence for coexistent primary testicular insufficiency and impairment in gonadotropin secretion, J Clin Endocrinol Metab 55: 560 (1982). 58. Morley JE, et al: Menstrual disturbances in chronic renal failure, Horm Metab Res 11: 68 (1979). 59. Van Kammen E, Thijssen JHH, and Schwarz F: Sex hormones in male patients with chronic renal failure. I. The production of testosterone and of androstenedione. Clin Endocrinol (Oxf) 8: 7 (1978). 60. Gomez F, De La Cueva R, Wauterz J, and Lemarchand Beraud T: Endocrine abnormalities in patients undergoing longterm hemodialysis, Am J Med 68: 522 (1980). 61. Mastrogiacomo I, et al: Prolactin gonadotropins, testosterone and estrogens in uremic men undergoing periodic hemodialysis, Arch Androl9: 279 (1982). 62. Mastrogiacomo I, et ali Maie hypogonadism in uremic patients on hemodialvsis. Arch Androl 20: 171 (1988). 63. Magrini G, Ebtner JR Burkhardt P, and Feiber JP: Study on the relationship between plasma prolactin levels and androgen metabolism in man, J Clin Endocrinol Metab 43: 944 (1976). 64. Traish AM, and Wotiz HH: Prostatic epidermal growth factor receptors and their regulation by androgen, Endocrmology 121: 1461 (1987). 65. Grantham JJ, et al: Viscoelastic properties of tubule basement membranes in experimental renal cystic disease, Kidney lnt 32: 187 (1987). 66. Downward J, et al: Close similarity of epidermal growth factor receptor and v-erb-B oncogene protein sequences, Nature 307: 521 (1984). 67. Green S, et al: Human oestrogen receptor c-DNA: sequence, expression and homology to verb-A, Nature 326: 134 (1986). 68. Krust A, et al: The chicken oestrogen receptor sequence: homology with v-erb-A and the human oestrogen and glucocorticoid receptors, Eur Molecular Biol Organ 5: 891 (1986).
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A. SANTONATI, G. P. FLAMMIA, F. DI SILVERIO,
From the Clinica Medica V, Patologia Urologica, “La Sapienza,” Rome, Italy
M.D. M.D. M.D.
Universita di Roma
ABSTRACT-Based on the reported sex difference in the incidence of acquired cystic kidney disease (ACKD) in patients with chronic renal failure, it is hypothesized that the hormonal derangement, well documented in male and female uremic patients on long-term dialysis, could be responsible for the pathogenesis of ACKD. The decreased androgen/estrogen ratio, and the increased estrogen value could be responsible for an estrogen receptor mediated effect on the tubular epithelial cell proliferation, an event further potentiated by the action of regulatory peptides like epidermal growth factor (EGF). The epithelial stimulation is more pronounced in men because male tissues are less adapted than female tissues to high estrogen values. Furthermore the androgen reduction, more remarkable in male than female patients, is responsible for an up-regulation of EGF-R. Therefore hormones and growth factors, by means of their own receptor in renal tissue (homologous to the two oncogenes c-erb A and c-erb B), may be responsible for the development of ACKD, and may play an important role in the pathogenesis of multiple adenomas and renal carcinomas reported with high incidence among uremic patients with ACKD. In the last decade a new acquired disease characterized by the formation of bilateral renal cysts in uremic patients on long-term dialysis has been reported: the acquired cystic kidney disease. The well-known endocrine derangement in uremic patients and the sex-related differences in the occurrence of ACKD prompt us to speculate whether a hormonal etiology could be hypothesized. The acquired cystic kidney disease described since 1977l in patients with chronic renal failure (CRF) on long-term dialysis is characterized by the presence of multiple cysts in both kidneys, usually in the cortex, occasionally in the medulla or at corticomedullary junction, with increased renal volume, frequently associated with multiple renal adenomas or renal cell carcinomas (RCC). The main differences between the acquired cystic kidney disease and the autosomal dominant inherited2 polycystic Presented at the “First Review Course on Nephrology and Urology” held in Fiuggi, Italy, May 9, 1988.
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kidney disease (PCKD) are: the absence of associated cystic disease, 3 the increased renal volume with long-term hemodialysis (HD),3 and the absence of cysts with aboral proliferation in the acquired form.4 ACKD could be considered a specific complication of dialysis since cysts are present even in patients with incipient renal failure. However, the incidence of multiple cysts in patients with CRF increases with the increase of the time on dialysis (both HD and continuous ambulatory peritoneal dialysis): from 22 percent in patients with initial CRF to 35 percent in patients on dialysis for less than two years, and 95 percent in those on dialysis for more than eight years.4 The cysts that develop during dialysis in some patients with ACKD occasionally regress after successful renal transplantation, i.e., early renal transplantation tends to prevent or impede ACKD.5 On pathologic basis the cysts are predominant in the outer cortex (although any part of the nephron can be subject to cystic dilatation),
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have a size of l-25 mm, contain clear fluid and oxalate crystals, have cuboidal or columnar and papillary hyperplasia surepithelium, rounded by thickened basement membranes; on electron microscopic scanning there are cysts lined with epithelium derived from proximal tubule epithelia studded with microvilli in cluster, or cysts lined with smoother surface (epithelial cells derived from distal nephron) with short microvilli in clusters4 ACKD develops more frequently in tubulointerstitial renal diseases, less likely in membranoproliferative glomerulonephritis, and rarely in diabetic kidneys.4 The histologic pattern of membranoproliferative glomerulonephritis is characterized by hyalinized glomerular tuft with maintained lobularity, atrophic tubules with lack of distinction between proximal and distal tubules, interstitial fibrosis, a common arterio- and arteriolosclerosis.’ Therefore the most likely pathogenetic mechanism underlying the ACKD is represented by continued glomerular filtration in the presence of luminal obstruction4 Many etiologic theories, however, have been proposed for this recently identified pathologic process of the kidney. 1. The occlusive theory takes into account the obstruction of renal tubules by surrounding interstitial fibrosis, along with the focal proliferation of tubular epithelial cells, and the possible presence of intratubular oxalate crystals.5 2. The ischemic theory has been proposed by Helper6 and others who produced cysts in rabbit kidney with a combination of ischemia and obstruction obtained by means of ligation of segmental arteries and papillary cauterization, respectively: it is well documented, in fact, that both ischemia and obstruction are alterations seen in patients with end-stage renal failure. 3. The chemical theory is based on the observation that certain diphenyl compounds induced cysts in rats. 7-QAccumulation of similar substances in patients undergoing dialysis might cause ACKD; furthermore, it has been supposed that substances leached out of the plastic dialysis circuit (such as plasticizer di-ethylexylphtalate) or, alternatively, a metabolite which accumulates in uremia, inadequately removed by dialysis, might be responsible for ACKD. l”.ll 4. The immunologic theory takes into account that uremia acts as an immunosuppressive factor responsible for the decrease of the Thelper lymphocytes and the increase of the T-suppressor lymphocytes. I2
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5. The growth factors theory has been proposed on the demonstration that polypeptides with renotrophic action could act with autocrine and paracrine action on renal tissues.13 To the aforementioned theories we propose to add the hormona2 theory. This theory is based on some clinicopathologic and biochemical observations and on the experimentally hormoneinduced renal cystic disease. It has been reported that in 120 predialysis patients there was no correlation between ACKD and sex, i.e., the disease has been found with equal incidence in male and female patients with CRF regardless of the duration of the renal disease14; while in 108 long-term hemodialysis patients, the ACKD occurred mainly in male rather than female patients Some authors have re(50% vs 20%). 3.4~14~15 ported an even higher incidence of ACKD in male than in female patients at baseline examination: 84 percent vs 50 percent in the two sexes, respectively; furthermore, after three years of HD the incidence of the cysts is 100 percent in male and 66 percent in female patients. Similarly after long-term dialysis the grade of cystic transformation is significantly increased in males and unchanged in females, and a remarkable increase in renal volume (more than twofold) is reported in male rather than in female patients. l5 This is well documented both with the frequency distribution for the increase of kidney volume, and with follow-up study of visible cysts, that demonstrated an increased amount of cysts after three to six years of HD mainly in male patients. l5 Furthermore the rate of increase in kidney volume showed a tendency toward an inverse correlation with age in males and a direct correlation in females.15 All these observations led to the conclusion that a sex-related endogenous substance might play a role in the pathogenesis of ACKD.15 It has been proposed that a hemodialysis-related substance,le or uremic metabolites such as polyamines or nephrotrophic growth factors (GFs)13 could be the sex-related compounds involved in the onset of ACKD. We rather suggest that steroid or polypeptide hormones could be responsible for the aforementioned male to female prevalence of ACKD. It is well known that the kidney is a target organ for many hormones, such as antidiuretic hormone (ADH) l7 and calcitonin (CT),ls and that both the normal human kidney and renal cell carcinoma (RCC) are able to synthesize erythropoietin,‘s plasma renin precursor, lQ and
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TABLE I. Hypothalamic-pituitary-endocrine Hypothalamic-pituitary-thyroid Hypothalamic-pituitary-adrenal Hypothalamic-pituitary a) GH:
down setting of the feedback set-point to thyroid hormones ( - T3 - T4 - TSH) axis: increase in the feedback set-point to glucocorticoids ( + F + ACTH).
axis: increase in the feedback set-point to short closed loop ( + GH + IGFII + IGFI) lactotrope insensitivity to dopamine ( +PRL mainly in females) males + females N males N females + males + females +
(Y subunits:
KEY: N: normal value;
+ : increased value:
-
chorionic gonadotropin.20 Steroid hormones are of particular interest, since in a large number of experimental animals they are able to induce morphologic and biochemical changeqz1s2
More recently described has been the role played by regulatory polypeptides like epiderma1 growth factor (EGF) and its embryonic form transforming growth factor Q! (TFGa) found in high concentrations in normal human kidney and in human RCC, respectively.23,24 Furthermore receptors for steroid hormones have been demonstrated in the kidney of experimental animals25-28 and in normal human kidney. 2g-31 With monoclonal antibody raised against EGF receptors it has been proven that among various tumorous cell lines tested, astrocytoma and RCC cell lines are those with the highest expression of this receptor.32 Recently we have been able to demonstrate that the EGF-R is present also in the normal human kidney surrounding human RCC, with a concentration lower than that found in the tumorous counterpart.33,34 As far as the relationships between steroid hormones and renal cystic disease are concerned, it is worthwhile to remind that estrogens are able to induce degenerative cystic changes in experimental animal renal tissue,35 and, in combination with prolactin, to induce RCC in golden Syrian hamsters.3e Androgens induce proliferative changes in mouse kid37 while compounds like cortisone and 9neys, fluoroprednisolone induce marked, diffuse, and progressive renal cystic disease (mainly in the medulla but also in cortical collecting distal tubules and loops of Henle) in rabbit and newborn hamster kidneys. 38-40In this respect it is interesting that mice with PCKD (that presented macroscopic renal lesions similar to those induced by glucocorticoids) treated with the antiglucocorticoid compound RU-486 have a prolonged survival. 41 Therefore the hormonal
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in CRF patients
axis:
b) PRL: c) FSH: d) LH: e) Glycoprotein
glands dysfunction
: decreased value.
theory for the ACKD can be regarded as the expression of the action of compounds that, through specific receptors, are able to induce a tubular hyperplasia or proliferating tubules with secondary tubules obstruction, Are there some signs and symptoms that led us to believe that patients with CRF have a hormonal imbalance that could support the hypothesis of hormonal theory of ACKD? The answer is affirmative: the clinical features of hormonal imbalance in patients with CRF have been described extensively in the literature. Male uremic patients can present mono- or bilateral gynecomastia42 and decreased libido and potency (which reflect the hypoandrogenemia of the patients) 43; there is a decreased fertility by 50 percent44 and a hypospermatogenesis, with relative preservation of spermatogonia, and severe depletion of spermatids that stand in favor of a hormonal imbalance (rather than a toxic effect), i.e., a hypothalamic-pituitary-testicular dysfunction. 45 Female CRF patients may or may not present galactorrhea45 and have decreased libido or orgasmeO; as in men, a decreased fertility before or during HD (usually restored after successful renal transplantation) has been reported46; the menstrual disorders with anovulation are characterized by oligomenorrhea or amenorrhea (after long-term dialysis) with prevalence of ovarian cyst formation, which are in favor of a hormonal imbalance, i.e., a hypothalamic-pituitary-ovarian dysfunction similar to that described in the polycystic ovary syndrome (PCOS) .47 Therefore it can be concluded that patients with CRF are affected by a hypothalamic-pituitary-endocrine glands dysfunction, with alterations in the setpoint of endocrine closed loops, reset upward or downward (Table I). Pituitary thyroid stimulating hormone (TSH) response to thyroid releasing hormone (TRH) is decreased, but the negative feedback of thyroid
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hormones is maintained, although there is a downsetting of feedback set-point to thyroid hormones with decreased values of T3 and T4 and normal or decreased values of TSH. This condition characterizes the sick euthyroid state or the hypothalamic-pituitary hypothyroidism of the CRF patients4g that is maintained during long-term dialysis and restored to normal by renal transplantation. On the contrary the hypothalamic-pituitary-adrenal axis is characterized by a relative refractariness of negative feedback suppression with dexamethasone for an increase in the set-point to glucocorticoids, with high values of plasma glucocorticoids and normal or high values of plasma ACTH, both at baseline examination and after long-term dialysis.4g Similar alterations in the set-point of endocrine closed loops have been reported for the hypothalamic-pituitary axis: the regulation of GH secretion is characterized by an increase in feedback set-point to short closed loop with high values of GH and IGF-II, while IGF-I is decreased50; there is a lactotrope insensitivity to dopamine with increase in prolactin (PRL) mainly in female CRF patientssl; FSH is increased or normal in male patients, and significantly increased in long-term dialysis male patientqs2 while normal in female patients.52 LH is normal in male uremic patientqs2 and stands in favor of a hypothalamic-pituitary-Leydig cells dysfunction because of the low values of plasma testosterone (T),53 while elevated in female uremic patients as expression of loss of positive estrogen feedback and LH pulsatility54; an excessive release of glycoprotein CYsubunits is also demonstrated by their high plasma values and their increased metabolic clearance rate (MCR) both in male and female CRF patients. 52An increase of GnRH output mainly after long-term dialysis has been reported: immunoreactive GnRH-like material derived from the gonads55 could account for this increase, and could lead to pituitary desensitization and decreased gonadotropin output. 56 Non-endocrine hypothalamic dysfunction of sleep, thirst, and thermoregulation have also been reported in uremic patients.45 The flattening of FSH response to GnRH and the exaggerated LH response with a delayed peak and delayed rate of decline back to baseline are early features of male uremic hypogonadism, expression of the hypothalamic-pituitary-testis dysfunction.57 In female uremic patients FSH response to GnRH is appropriate for an apparent menopausal status, and LH re-
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Steroid pattern in male and female TABLE II. patients with chronic renal failure (CRF) and after hemodialysis (HD)
Steroids Testosterone Dihydrotestosterone Androstenedione Estradiol Estrone Progesterone
-MalesCRF HD _ N N _ N + + . .
. .
KEY: N: normal value; + : increased value;
-FemalesCRF HD -or+ N r;
N + -
i
I
: decreased value.
sponse is delayed, prolonged, and excessive as in the male uremic patients: i.e., in female uremic patients the hypothalamic-pituitary-ovarian dysfunction is revealed by the premature menopause without consistent elevation of FSH and LH.54 The endocrine derangement in uremic patients is also documented by the abnormality of plasma steroids of adrenal and gonadal origin. T, in fact, and dihydrotestosterone (DHT) have been found decreased in male patients with incipient CRF or after long-term dialysis53 (Table II) for the normal value of MCP of T but decreased production rate (PR) of T due to the intrinsic defect in Leydig cells steroidogenesis; in female uremic patients T is either decreased or increased, but always decreased after long-term dialysiqss while DHT remains within the normal range. Androstenedione (A) has been found in the normal range or slightly increased in uremic male patients, although the MCR of A was increased leading to the high value of PR of A,5g but significantly increased both at baseline examination and after dialysis in females.5g 170 estradiol (E2) has been found in the normal range or decreased for lack of effective stimulation by endogenous LH in male patients45; the pattern of this steroid in female patients shows also normal or low plasma values mainly in hyperprolactinemic patients.e0 The behavior of estrone (El) at baseline examination or after dialysis is different in the opposite sexes: male patients presenting high values and female patients low valuesG1 Plasma progesterone is normal or decreased in uremic female patients.54.5s The increased PR of A, the high plasma values of El, of cortisol and of androstenediol-sulfate, along with the decreased plasma values of dehydroepiandrosterone (DHEA) and DHEA-sulfate, stand in favor of an abnormal steroidogenesis in uremic patients.45 Some authors reported that male hypogonadism of uremic patients on dialysis is mainly
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characterized by the high plasma values of A and El and the low plasma values of T and E2 compared with normal controls. The A/T and El/E2 ratio higher than controls could presumably be due to the uremic damage at the testis level, impairing the activity of the enzyme 17fl-hydroxysteroid-dehydrogenase.62 Other authors reported an impairment of 5cr-reductase activity with altered metabolism of T into DHT induced by hyperprolactinemia in uremic male patients.e3 From the aforementioned observations it can be concluded that the reduced T and increased El values, along with the presence of steroid and polypeptide receptors in human renal tissue, may represent the biochemical support to the hormonal theory of ACKD and could account for the male prevalence of ACKD. The hormonal imbalance in uremic male patients, in fact, is characterized by decreased values of androgens (particularly of T) with increased values of estrogens (mainly of El) and decreased androgens/estrogens ratio. The increased value of estrogens is likely to account for the morphologic changes found in the human renal tissue of male uremic patients: female tissues, in fact, are more adapted to the high values of estrogens, and the estrogen action is partially balanced by the antiestrogen effect of progesterone, at least during the childbearing period of a woman’s life. This is in keeping with the observation that the rate of increase in kidney volume shows a tendency toward a direct correlation with age in uremic female patients. l5 Estrogen action, mediated by ER, could affect renal tissue mainly by inducing tubular epithelial cell proliferation, and this effect could be further potentiated by the action of regulatory polypeptides like PRL (increased for the lactotrope insensitivity to dopamine), and EGF (a growth factor highly expressed in normal human kidney). Furthermore the reduced value of T, more pronounced in males than females, is responsible for an up-regulation of EGF-R.64 Therefore, taking into consideration that the analysis of viscoelastic properties of tubule basement membrane in acquired, hereditary, and spontaneous renal cystic diseases does not allow to consider an abnormality of tubule basement membrane as the central process in the formation of renal cysts, while tubular epithelial cell proliferation is responsible for the formation of all renal cysts,e5 it is reasonable to suppose that hormones and growth factors play
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an important role in stimulating this cell proliferation. This etiopathogenetic mechanism could also explain the onset of renal adenomas, and of bilateral carcinomas that develop in ACKD. In the carcinogenesis process of the kidney, in fact, a constitutive expression of EGF-R, homologous to the c-erb B oncogeneGe in the tubular epithelial cells could act in combination with that of steroid hormone receptors, which presents some analogies with the c-erb A oncogene.67xe8These biochemical events could be responsible not only for the tubular cellular hyperplasia and the consequent ACKD, but also for the onset of multiple renal adenomas or bilateral carcinomas found in combination with multiple cysts in uremic patients treated with long-term dialysis. 00161 Rome, Italy (DR. CONCOLINO) References 1. Dunnil MS, Millard PR, and Oliver D: Acquired cystic disease of the kidneys a hazard of long-term intermittent maintenance haemodialysis, J Clin Path01 30: 868 (1977). 2. Grabow PA, Ikle DW, and Holms JH: Polycystic kidney disease prospective analysis of nonazotemic patients and the family members, Ann Intern Med 101: 238 (1984). 3. Mirahmadi MK, and Vaziri ND: Cystic transformation and stage of kidneys in patients undergoing hemodialysis, Int J Artif Org 3: 257 (1980). 4. Mickisck 0; et ol: Multicystic transformation of kidneys in chronic renal failure, Nephron 38: 93 (1984). 5. Levine E, et al: CT of acquired cystic kidney disease and renal tumors in long-term dialysis patients, AJR 142: 125 (1984). 6. Hepler AB: Solitary cysts of the kidney. A renort of 7 cases and observation on the pathogen&s of these cysts,&Surg Gynecol Obstet 50: 668 (1936). 7. Carone FA, Rowland RG, Perlam SG, and Ganote CE: The pathogenesis of drug-induced renal cystic disease, Kidney Int 5: 411 (1974). 8. Gardner KD, Solomon S, Fitzgerrez WW. and Evan AP: Function and structure in the diphenylamine-exposed kidney, J Clin Invest 57: 796 (1976). 9. Evan AP, and Gardner KD: Nephron obstruction in nordihydroguaiaretic acid-induced renal cystic disease, Kidney Int 15: 7 (1979). 10. Minar E, Tscholakff D, and Zazgornik J: Acquired cystic disease of the kidneys in chronic hemodialyzed and renal transplant patients, Eur Urol 10: 245 (1984). 11. Beardsworth SF, Goldsmith HJ, Ahmad R, and Lamb G: Acquisition of renal cysts during peritoneal dialvsis. Lancet 2: 148-2 (1985). 12. QPPT Tan KH 1 Donner R, and Scholtmeyer RJ: Development 01: renal carcinoma in a patient with polycystic kidneys unrlarnnin chronic haemodialysis, Eur Urol 6: 316 (1980). Uu.6Y.a.g 13. Torrence RJ, Elbers JD, and Clayman RV: The presence of a growth factor in cystic fluid from patients with acquired renal cvstic disease (ARCD), 1 Urol 137: 251 (1987). ’ 14. Elliott HL, M&dougall AI, and Buchanan WL: Acquired cystic disease of the kidney, Lancet 2: 1359 (1977). 15. Ishikawa I, et al: Sex differences in acquired cystic disease of the kidney in long-term dialysis, Nephron 39: 336 (1985). 16. Ishikawa I, Yuri T, Kitada H, and Shinoda A: Regression of acquired cystic disease of the kidney after successful renal transplantation, Am J Nephro13: 310 (1983). 17. Dousa TP, and Valtin H: Cellular action of vasopressin on mammalian kidney, Kidney Int 10: 45 (1976). I
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