World J. Surg. 25, 708 –712, 2001 DOI: 10.1007/s00268-001-0019-2
WORLD Journal of
SURGERY © 2001 by the Socie´te´ Internationale de Chirurgie
Subtotal Parathyroidectomy in Renal Failure: Still Needed after All These Years P. Anthony Decker, M.D.,1 Eric P. Cohen, M.D.,2 Kara M. Doffek, B.S.,1 Blake A. Ashley, M.D.,1 Mary E. Bienemann, M.D.,1 Yong Ran Zhu, M.D.,1 Mark E. Adams, M.D.,1 Stuart D. Wilson, M.D.,1 Michael J. Demeure, M.D.1 1
Department of Surgery, Medical College of Wisconsin, 9200 West Wisconsin Avenue, Milwaukee, Wisconsin 53226, USA Department of Internal Medicine, Medical College of Wisconsin, 9200 West Wisconsin Avenue, Milwaukee, Wisconsin 53226, USA
2
Abstract. There are scant data on the frequency of parathyroidectomy (PTX) for end-stage renal disease (ESRD). Medical therapy for ESRD and secondary hyperparathyroidism has evolved to include better dialytic urea removal and the use of calcitriol. The aim of this study was to determine whether medical therapy has changed the frequency or indications for PTX in the management of renal failure. Hospital and clinic records were analyzed to gather information on all patients undergoing PTX for secondary hyperparathyroidism (2HPT) (n ⴝ 48) and tertiary hyperparathyroidism (3HPT) (n ⴝ 26) from 1986 through 1998 at our institution. Prospective computer databases were queried for information concerning both chronic dialysis and renal transplant patients at our center. The patients were divided based on date of operation before or after 1991, a divider that separated the patients into groups before or after the widespread adoption of intravenous calcitriol treatment during hemodialysis at our institution. Over the 12 year period, the proportion of our chronic dialysis patients undergoing PTX did not change significantly, ranging from 0% to 2.5% per year. Comparing all patients undergoing PTX for 2HPT during 1986 –1991 versus 1992–1998, there was no significant difference in time on dialysis [7.0 ⴞ 4.2 (n ⴝ 11) vs. 7.5 ⴞ 4.6 (n ⴝ 36) years, mean ⴞ SD]. The later group had higher intact parathyroid hormone (iPTH) levels [765 ⴞ 415 (n ⴝ 6) vs. 1377 ⴞ 636 (n ⴝ 28) pg/ml; p ⴝ 0.03], lower serum calcium [11.2 ⴞ 1.0 (n ⴝ 12) vs. 9.9 ⴞ 1.5 (n ⴝ 34) mg/dl; p ⴝ 0.006], and higher serum phosphate [5.7 ⴞ 1.6 (n ⴝ 12) vs. 7.2 ⴞ 2.3 (n ⴝ 31) mg/dl; p ⴝ 0.042]. Among the population of patients with transplants undergoing PTX for 3HPT, the average percent per year undergoing PTX ranged from 0% to 4.2% and did not change during the study period. Comparing the 1986 –1991 group to the 1992– 1998 group, the time from transplantation to PTX did not change during the study period (3.3 ⴞ 2.3 vs. 2.9 ⴞ 3.0 years; p ⴝ 0.391), and there were no significant differences between preoperative calcium levels or iPTH levels. Despite advances in dialysis technique and pharmacologic therapy, there has been no change in the proportion of dialysis patients requiring PTX for 2HPT or 3HPT. There was also no change in the time on dialysis for patients with 2HPT or the time from transplant to PTX for patients with 3HPT. Analysis of preoperative biochemical markers as evidence of disease severity suggests there was no change in indications for PTX during our study. From this information we conclude that parathyroid pathophysiology is incompletely understood and medical therapy is not optimal, resulting in a continuing need for PTX in some patients.
This International Association of Endocrine Surgeons (IAES) article was presented at the 38th World Congress of Surgery International Surgical Week (ISW99), Vienna, Austria, August 15–20, 1999. Correspondence to: M.J. Demeure, M.D., e-mail:
[email protected].
In some end-stage renal failure patients, secondary hyperparathyroidism causes pruritus, bone pain, malaise, or pathologic fractures. Despite medical therapy, up to 5% of these patients eventually require parathyroidectomy (PTX) to gain control of the manifestations of their hyperparathyroidism [1]. Disease progression despite aggressive medical therapy, soft tissue calcifications, and persistent symptoms that are likely to resolve with surgery are typical indications for surgical intervention [2, 3]. Many advances in medical treatment and renal transplantation have improved the overall care of end-stage renal disease (ESRD) patients. Modern dialysis regimens are more efficient at urea removal and produce less hemodynamic instability than older regimens. Tight control of phosphate and calcium levels by dialysis and medications has been shown to decrease parathyroid hormone (PTH) levels. A major change has been the routine administration of calcitriol (1,25-dihydroxyvitamin D), which inhibits parathyroid cell hyperplasia, suppresses parathyroid hormone secretion, and increases calcium absorption [4, 5]. Our clinical impression is that a smaller proportion of ESRD patients has been requiring PTX since the advent of vitamin D therapy associated with management of the renal failure. To test this hypothesis, we analyzed our data to determine whether the need for PTX for secondary and tertiary hyperparathyroidism has lessened. In so doing, we examined the biochemical indicators of disease severity and rate of PTX in the management of renal failure before and after the widespread adoption of calcitriol administration in 1991 at our institution. Materials and Methods The study population was identified by examining records for all patients undergoing PTX at The Medical College of Wisconsin (MCW) from January 1, 1986 to December 31, 1998 for secondary (n ⫽ 48) or tertiary (n ⫽ 26) hyperparathyroidism. To find the yearly parathyroidectomy rate, we compared the MCW dialysis population undergoing PTX to the group as a whole. A linear regression model was used to assess the stability of the annual PTX rate. Biochemical markers, time on dialysis, and time from renal transplant to PTX were assessed. This population includes the
Decker et al.: Subtotal Parathyroidectomy in Renal Failure
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Table 1. Characteristics of three populations of patients.
Parameter Average age (years) % Female % Caucasian % African-American ESRD cause Diabetes mellitus Hypertension Glomerulonephritis Other/unknown
PTX group
MCW dialysis population
National dialysis population
43.1 40.5 58 34
52.5 48.0 44 55
60.2 48.0 56 36
7 19 25 49
36 17 24 23
38 28 13 21
PTX: parathyroidectomy; MCW: Medical College of Wisconsin; ESRD: end-stage renal disease.
patients served by our dialysis unit as well as a large number referred from regional dialysis centers for surgery. In some cases, biochemical markers, such as markedly elevated intact parathyroid hormone (iPTH) or hypercalcemia, were used as justification for PTX. To answer whether the biochemical indications for PTX had changed over the years in our area, we examined all of the patients who underwent PTX for secondary or tertiary (which we defined as patients with a functional renal allograft at the time of PTX) hyperparathyroidism at our institution, including those referred from regional dialysis centers. For comparison of biochemical markers, this patient group was divided into two subgroups based on the date of surgery before or after January 1, 1991 to coincide with the initiation of widespread use of intravenous calcitriol. Preoperative PTH represents the most recent iPTH level recorded prior to parathyroidectomy. Our laboratory uses a radioimmunoassay (Nichols Institute Diagnostics, San Juan Capistrano, CA, USA) to determine the iPTH levels, which became available in 1989. Prior to this time, N-terminal and midregion PTH radioimmunoassays were used. Specimens for preoperative calcium levels were primarily obtained the morning of surgery. Preoperative phosphate levels represent the last predialysis phosphate level obtained before surgery. SigmaStat, a computerized statistics program (SPSS, Chicago, IL, USA) was used to compare the groups using the MannWhitney test for nonparametric data. Differences between the groups were significant at p ⬍ 0.05. Results The MCW dialysis population included 135 to 211 patients per year on January 1 during the study years. The PTX group, the MCW dialysis population as of 1997, and national dialysis patient characteristics for 1997 are shown for comparison in Table 1. The data charted in Figure 1 compare the total number of chronic hemodialysis patients at our institution on January 1 of each year from 1986 to 1998 to the number of these patients undergoing PTX for secondary hyperparathyroidism during the same year. There was no significant change in the yearly fraction of chronic dialysis patients undergoing PTX during the study period. This fraction ranged between 1% and 3%. The average time from initiation of dialysis to PTX among the groups before and after 1991 was found to be the same [7.0 ⫾ 4.2 (n ⫽ 11) vs. 7.5 ⫾ 4.6 (n ⫽ 36) years], suggesting consistent progression of the disease. Furthermore, preoperative iPTH lev-
els were higher in the late group than the early group [765 ⫾ 415 (n ⫽ 6) vs. 1377 ⫾ 636 (n ⫽ 28) pg/ml; p ⫽ 0.03]. The low sample number in the pre-1991 group is due to the use of the C-terminal PTH assay in many of the patients; it does not correlate with the iPTH assay, which is independent of renal function [6]. Preoperative calcium and phosphorus levels were also compared between the two groups. The late group (after 1991) of patients was found to have significantly lower calcium levels [9.9 ⫾ 1.5 (n ⫽ 34) vs. 11.2 ⫾ 1.0 (n ⫽ 12) mg/dl; p ⫽ 0.006] and significantly higher phosphorus levels [7.2 ⫾ 2.3 (n ⫽ 31) vs. 5.7 ⫾ 1.6 (n ⫽ 12) mg/dl; p ⫽ 0.042] than the early group of patients. For tertiary HPT patients the mean time from transplant to PTX was not found to be significantly different between the early group (n ⫽ 14) and the late group (n ⫽ 7). Also, there were no significant differences in the preoperative calcium level between the early and late groups [11.3 ⫾ 1.1 (n ⫽ 15) vs. 11.1 ⫾ 1.3 (n ⫽ 8); p ⫽ 0.52) or iPTH (p ⫽ 0.149). These data are summarized in Table 2. Discussion End-stage renal disease causes many metabolic derangements, some of which are ameliorated by dialysis. Some of these mineral derangements are seen in patients who do not require dialysis but have a decreased glomerular filtration rate of 40 to 50 ml/min [7]. Decreased renal cell mass leads to decreased production of 1,25dihydroxyvitamin D, presumably due to loss of renal 1␣-hydroxylase activity, which results in hypocalcemia. Decreased renal cell function also causes phosphate retention. Hyperphosphatemia and hypocalcemia are potent stimulators of PTH secretion. Chronic parathyroid gland stimulation results in parathyroid hyperplasia, leading to clinical hyperparathyroidism [8]. Multiple studies have influenced the care dialysis patients receive. The efficacy of calcitriol in regulating calcium and suppressing PTH secretion has been shown [9]. Calcium-based phosphate binders have been substituted for aluminum-based binders because they have been found to be safer, and they provide calcium supplementation. Use of high calcium dialysate has been shown to reduce serum iPTH levels [10, 11]. Correction of acidosis in dialysis patients by substituting acetate in the dialysate with bicarbonate has also been shown to increase the sensitivity of the parathyroid glands to serum calcium levels [12]. These individual measures have all been reported to provide benefit in the medical treatment of secondary hyperparathyroidism (2HPT), so treatment at our institution has evolved to include these advances. Our study is an effort to assess whether these collective changes have reduced the need for parathyroid surgery in our patient population. In our series over the 12 year period from 1986 to 1998, there has been no significant change in the proportion of chronic dialysis or renal transplant patients undergoing PTX for 2HPT or tertiary hyperparathyroidism (3HPT). Similarly, the time from onset of dialysis to PTX for 2HPT patients and from renal transplant to PTX for 3HPT patients has remained constant during the study interval. These findings suggest that there is a persistent fraction of ESRD patients who ultimately require parathyroidectomy, and that recent advances in dialysis care have not been shown to decrease this fraction. One limitation of the present study is that it is retrospective. All blood tests were not performed within the same time frame relative to surgery or dialysis. The lack of documented symptoms of hyperparathyroidism or indications for surgery forced us to
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World J. Surg. Vol. 25, No. 6, June 2001
Fig. 1. Prevalence of chronic dialysis in patients at FMLH/ZVAMC versus number of surgeries for secondary hyperparathyroidism. This graph depicts the constant low incidence of parathyroidectomy. The bars indicate the number of patients undergoing chronic dialysis at our center. The diamonds indicate the number of patients undergoing parathyroidectomy from this population. FMLH: Froedtert Memorial Lutheran Hospital, Milwaukee, WI; ZVAMC: Zablocki VA Medical Center, Milwaukee, WI.
Table 2. Characteristics of early and late treatment groups with secondary or tertiary HPT. Parameter Secondary HPT Time on dialysis (years) Preop PTH (pg/ml) Preop calcium (mg/dl) Preop phosphorus (mg/dl) Tertiary HPT Time from transplant to parathyroidectomy (years) Preop iPTH (pg/ml) Preop calcium (mg/dl)
1986 –1991
1992–1998
p
7.0 ⫾ 4.2 765 ⫾ 415 11.2 ⫾ 1.0 5.7 ⫾ 1.6
7.5 ⫾ 4.6 1377 ⫾ 636 9.9 ⫾ 1.5 7.2 ⫾ 2.3
NS 0.03 0.006 0.042
2.9 ⫾ 3.0
2.9 ⫾ 1.9
NS
387 ⫾ 252 11.3 ⫾ 1.1
625 ⫾ 379 11.1 ⫾ 1.3
NS NS
HPT: hyperparathyroidism.
draw conclusions based on indirect indicators of disease severity, such as iPTH, calcium, and phosphate levels, which may not always coincide with clinical symptoms. Another indicator of absolute parathyroid hyperplasia is the excised gland weight [13], which was not routinely recorded by our pathology department. Although operations for 2HPT and 3HPT are not highly prevalent, assessment of results would benefit from prospective data collection and standard patient evaluation. Despite the limitations of our study, we have found useful information relative to the management of ESRD patients. Our data show that the proportion of our ESRD and transplant patients undergoing PTX for control of 2HPT and 3HPT has not changed during the last 12 years. Similarly, the average time on dialysis or time from transplant to PTX has not changed, indicating that changes in medical management designed to control parathyroid hyperplasia and hypersecretion have not had a favor-
able impact on these problems. Although the biochemical markers suggest improved mineral balance, iPTH levels are higher in patients referred for PTX after 1991. This may mean that patients are not being referred for surgery as early in the disease process. Hence we conclude that the indications for PTX have not become more liberal. Conclusions The medical management of secondary hyperparathyroidism has yet to decrease the need for PTX at our institution, suggesting that although medical such advances as calcitriol administration may improve serum levels of minerals, they have not altered disease progression. Advances in pharmacotherapy and dialysis continue, but medical management remains suboptimal. Parathyroid surgery remains an important, often necessary therapeutic option for patients with hyperparathyroidism associated with renal failure. Re´sume´ Introduction: Il existe peu de donne´es sur la fre´quence de la parathyroidectomie (PTX) pour insuffisance re´nale terminale (IRT). La the´rapeutique me´dicale pour IRT et pour l’hyperparathyroı¨die secondaire (HPT2) a ´evolue´ dans la dernie`re de´cennie avec notamment une meilleure ´epuration ure´ique par dialyse et par l’utilisation de calcitriol. Le but de cette ´etude a ´ete´ de de´terminer si le traitement me´dical a pu changer la fre´quence ou les indications de la PTX dans la prise en charge de l’IRT. Patients et me´thodes: Les dossiers hospitaliers et cliniques provenant de tous les patients dans notre institution ayant eu une PTX pour HPT2 (n ⫽ 48) ou tertiaire (HPT3) (n ⫽ 26) entre 1986
Decker et al.: Subtotal Parathyroidectomy in Renal Failure
et 1999 ont ´ete´ analyse´s. Une banque de donne´es prospectives, informatise´e, a ´ete´ consulte´e pour cueillir l’information concernant tous les patients sous dialyse chronique et/ou ayant eu une transplantation re´nale dans notre centre. Les patients ont ´ete´ divise´s en deux groupes selon qu’ils ont ´ete´ traite´s avant ou apre`s 1991, ce qui permettait de se´parer les patients traite´s par calcitriol par voie intraveineuse avant ou apre`s l’utilisation re´pandue du calcitriol pour cette indication pendant l’he´modialyse dans notre institution. Re´sultats: Pendant la pe´riode de 12 ans, la proportion de nos patients en dialyse chronique ayant eu une PTX, situe´e entre 0 –2.5% par an, n’a pas change´ de fac¸on significative. En comparant tous les patients ayant eu une PTX pour HPT2 entre 1986 –91 par rapport `a la pe´riode 1992–98, on n’a note´ aucune diffe´rence significative en ce qui concernait le temps passe´ en dialyse (7.0 ⫾ 4.2 [n ⫽ 11] vs. 7.5 ⫾ 4.6 [n ⫽ 36] ans, (moyenne ⫾ ET)). Le dernier groupe avait un taux de parathormone intact (PTHi) plus ´eleve´ (765 ⫾ 415[n ⫽ 6] vs. 1377 ⫾ 636 [n ⫽ 28] pg/ml, p ⫽ 0.03), un taux de calcium se´rique plus bas (11.2 ⫾ 1.0 [n ⫽ 12] vs. 9.9 ⫾ 1.5 [n ⫽ 34] mg/dl, p ⫽ 0.006) et un taux de phosphore´mie plus ´eleve´ (5.7 ⫾ 1.6 [n ⫽ 12] vs. 7.2 ⫾ 2.3 [n ⫽ 31] mg/dl, p ⫽ 0.042). Parmi les patients de la population ayant eu une PTX et une transplantation pour HPT3, le pourcentage moyen de patients ayant eu une PTX par an allait de 0 – 4.2% et n’a pas varie´ pendant la pe´riode d’e´tude. En comparant le groupe 1986 –91 au groupe 1992–98, le temps entre la transplantation `a la PTX n’a pas varie´ pendant la pe´riode d’e´tude (3.3 ⫾ 2.3 vs. 2.9 ⫾ 3.0 ans, p ⫽ 0.391) et il n’y avait aucune diffe´rence significative entre les taux de calcium pre´ope´ratoire ou les taux de PTHi. Conclusions: En de´pit des progre`s de la technique de dialyse et de la pharmacothe´rapie, on n’a pas constate´ de changement dans la proportion de dialyse´s ne´cessitant une PTX pour HPT2 ou pour HPT3. De meˆme, on n’a constate´ aucun changement en ce qui concerne le temps passe´ en dialyse pour les patients HPT2 ou le temps entre la transplantation et la PTX pour les patients ayant une HPT3. L’analyse des marqueurs biochimiques pre´ope´ratoires en faveur de la maladie sugge`re qu’il n’y avait aucun changement dans les indications pendant la dure´e de l’e´tude. Nous concluons que la physiopathologie de la parathyroı¨de est mal comprise et que la the´rapie me´dicale n’est pas optimale, avec comme re´sultat un besoin continu pour la PTX chez quelques patients. Resumen Introduccio ´n: Se dispone de escasa informacio ´n sobre la frecuencia de la paratiroidectomı´a (PTX) en la enfermedad renal terminal (ERT). El tratamiento me´dico de la ERT con hiperparatiroidismo secundario ha evolucionado en el u ´ltimo decenio incluyendo mejores me´todos de dia´lisis y el uso de calcitriol. El propo ´sito del presente estudio fue determinar si el tratamiento me´dico ha modificado la frecuencia y las indicaciones para PTX en el manejo de la falla renal. Pacientes y me´todos: Se analizaron las historias clı´nicas para recoger la informacio ´n sobre todos los pacientes sometidos a PTX por hiperparatiroidismo secundario (HPT2) (n ⫽ 48) e hiperparatiroidismo terciario (HPT3) (n ⫽ 26) entre 1986 y 1998 en nuestra institucio ´n. Tambie´n fueron consultadas nuestras bases de datos en cuanto a dia´lisis cro ´nica y trasplante renal. Los pacientes fueron divididos con base en la fecha de la operacio ´n, antes o despue´s de 1991, an ˜o en que se generalizo ´ el uso del calcitriol intravenoso durante la hemodia´lisis en nuestra institucio ´n. Resultados: No se observo ´
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cambio significativo en la proporcio ´n de los pacientes en dia´lisis cro ´nica sometidos a PTX en el periodo de 12 an ˜os, que exhibio ´ un rango de 0 –2.5% por an ˜o. Al comparar los pacientes con PTX por HPT2 en el periodo 1986 –91 vs. 1992–98, no se hallo ´ diferencia en cuanto al tiempo de dia´lisis (7.0 ⫾ 4.2 {n ⫽ 11} vs. 7.5 ⫾ 4.6 {n ⫽ 36} an ˜os). El u ´ltimo grupo exhibio ´ mayores niveles de parathormona intacta (765 ⫾ 415 {n ⫽ 6} vs. 1377 ⫾ 636 {n ⫽ 28} pg/ml, p ⫽ 0.03), menores niveles de calcio se´rico (G11.2 ⫾ 1.0 {n ⫽ 12} vs. 9.9 ⫾ 1.5 {n ⫽ 34} mg/dl, p ⫽ 0.006), y mayores niveles de fosfato se´rico (5.7 ⫾ 1.6 {n ⫽ 12} vs. 7.2 ⫾ 2.3 {n ⫽ 31} mg/dl, p ⫽ 0.042). En el grupo de la poblacio ´n sometida a PTX por HPT3, el promedio de PTX por an ˜o oscilo ´ entre 0 y 4.2% y no mostro ´ variacio ´n a lo largo del periodo de estudio. Al comparar el grupo 1986 –91 con el grupo 1992–98, no se hallo ´ cambio en cuanto al intervalo entre el trasplante y la PTX (3.3 ⫾ 2.3 vs. 2.9 ⫾ 3.0 an ˜os, p ⫽ 0.391). y tampoco se encontraron diferencias significativas entre los niveles preoperatorios de calcio o de PTHi. Conclusiones: A pesar de los avances en las te´cnicas de dia´lisis y en farmacoterpia, no se observa cambio en la proporcio ´n de los pacientes en dia´lisis que requieren PTX por HPT2 o HPT3. Tampoco se observo ´ cambio en el tiempo de dia´lisis en los pacientes con HPT2 o el intervalo entre el trasplante y la PTX en los casos de HPT3, ni en el tiempo de dia´lisis en los casos de HPT2 o en el intervalo entre el trasplante y la PTX en los de HPtT3. El ana´lisis de los marcadores bioquı´micos como para´metro de severidad de la enfermedad sugiere que no hubo cambios en la indicacio ´n para PTX en el curso de nuestro estudio. Podemos concluir que el conocimiento de la fisiopatologı´a paratiroidea es todavı´a incompleto y que el tratamiento me´dico no es o ´ptimo, lo cual se traduce en una continua necesidad de practicar PTX en estos pacientes. References 1. Demeure, M.J., McGee, D.C., Wilkes, W., Duh, Q., Clark, O.: Results of surgical treatment for hyperparathyroidism associated with renal disease. Am. J. Surg. 160:337, 1990 2. Packman, K.S., Demeure, M.J.: Indication for parathyroidectomy and extent of treatment for patients with secondary hyperparathyroidism. Endocr. Surg. 75:465, 1995 3. Tominaga, V., Johansson, H., Takagi, H.: Secondary hyperparathyroidism: pathophysiology, histopathology, and medical and surgical management. Surg. Today 27:787, 1997 4. Felsenfeld, A.J.: Considerations for the treatment of secondary hyperparathyroidism in renal failure. J. Am. Soc. Nephrol. 8:993, 1997 5. Daisley-Kydd, R.E., Mason, N.A.: Calcitriol in the management of secondary hyperparathyroidism of renal failure. Pharmacotherapy 16: 619, 1996 6. Synder, W.H., editor: Parathyroid. Selected Readings Gen. Surg. 23:1, 1996 7. Massry, S.G., Smogorzewski, M.J., Klahr, S.: Metabolic and endocrine dysfunction in uremia. In Diseases of the Kidney, 6th edition, Schrier, R.W., Gottschalk, C.W., editors, Boston, Little, Brown, 1997, pp. 2661–2698 8. DeFrancisco, A.L.M., Cobo, M.A., Setien, M.A., Rodrigo, E., Fresnedo, G.F., Unzueta, M.T., Amado, J.A., Ruiz, J.C., Arias, M., Rodriguez, M.: Effect of serum phosphate on parathyroid hormone secretion during hemodialysis. Kidney Int. 54:2140, 1998 9. Rapoport, J., Mostoslavski, M., Ben-David, A., Knecht, A., Blau, A., Arad, J., Zlotnik, M., Chaimovitz, C.: Successful treatment of secondary hyperparathyroidism in hemodialysis patients with oral pulse 1-alpha-hydroxy-cholecalciferol therapy. Nephron 72:150, 1996 10. Fernandez, E., Borras, M., Pais, B., Montoliu, J.: Low-calcium dialysate stimulates parathormone secretion and its long-term use worsens secondary hyperparathyroidism. J. Am. Soc. Nephrol. 6:132, 1995
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