1

Transitory decrease of renal function after parathyroidectomy: a clinical observation indicating the renal hemodynamic effect of parathyroid hormone?

Montenegro FLM, Ferreira GF, Loureno jr DM, Martin RM, Arap SS, Correa PH, Cordeiro AC, Ianhez LE. Decrscimo transitrio da funo renal no ps-operatrio imediato de paratireoidectomia: uma observao clnica indicativa da ao hemodinmica renal do hormnio da paratireide? Rev Bras Cir Cabea e Pescoo 2007; 36(4): 196-201.

Abstract Introduction: hypocalcemia is the major concern after parathyroid operations. Notwithstanding, there are some reports of decreased renal function after parathyroidectomy after renal transplantation. Little attention was given to creatinine levels after primary hyperparathyroidism operation. Objective: to evaluate the creatinine levels after the surgical treatment of different head and neck patients groups. Patients and methods: retrospective analysis of creatinine levels of patients operated on from 1997 to 2007 for primary hyperparathyroidism, hyperparathyroidism after successful renal transplantation, head and neck neoplasms in both renal transplant and non transplant patients and thyroid disorders. Creatinine values before and close after surgical treatment were evaluated. Percent creatinine variation was calculated by subtracting preoperative from postoperative value and dividing this result by the preoperative level. Results: More than 10% creatinine elevation occurred in 77 of 105 patients with primary hyperparathyroidism, in 32 of 38 cases of parathyroidectomy after renal transplantation, in 1 of 7 renal transplant patients with other head and tumors, in 11 of 22 individuals after thyroidectomy and in 3 of 18 submitted to major head and neck surgery for cancer. Mean percent variations of creatinine were +30.8%, +39.5%, -2.7%, +18.7% and 6.4%, respectively for those groups. No significant differences were observed between hyperparathyroidism transplant renal cases, thyroid patients and primary hyperparathyroidism individuals. Significant difference occurred between transplant patients with and without hyperparathyroidism (p<0.05, Kruskal-Wallis), and among those with primary hyperparathyroidism and head and neck neoplasms (p<0.001, Kruskal-Wallis). When thyroidectomy patients were stratified according to the postoperative hypocalcemia and presumed hypoparathyroidism, a significant difference was observed. Mean creatinine increase was of 28.5% for those with hypocalcemia and only 1.2% on the other group (p=0.02, non paired t test). Conclusion: Acute elevation of creatinine was observed in operations with acute reduction of parathyroid hormone. This clinical observation is in accordance with previous animals studies showing renal function reduction after parathyroidectomy.

Key words: parathyroidectomy; hyperparathyroidism; creatinine; thyroidectomy; renal insufficiency, acute; parathyroid hormone.

PDF Creator - PDF4Free v2.0

http://www.pdf4free.com

2 INTRODUCTION Hyperparathyroidism (HPT) is a rather frequent disease, but not fully understood. Although most part of the cases is presented in clearly defined clinical pictures, some patients present atypical features. Surgical treatment is of great value for primary, secondary and tertiary HPT. Postoperative course is also variable and it is not completely predictable. Right after the operation, most attention is directed to hypocalcemia, avoiding severe calcium level drop. Hypocalcemia may be caused by postoperative hypoparathyroidism, but it may be also related to bone remineralization. Even experienced authors did not mention renal function modification in this period and they refer that many patients are discharged on a same day or on a next day basis1. Some years ago, one of the authors (LEI) observed a slight increase of creatinine levels in some renal transplant patients submitted to parathyroidectomy. In one publication, preoperative creatinine ranged from 0.9 to 1.7 mg/dL (mean 1.15 mg/dL), while postoperative levels ranged from 1.0 to 3.1mg/dL (mean 1.27 mg/dL).2 Besides this observation, other authors reported the loss of residual diuresis in dialytic patients after parathyroidetomy3. Dr. Maria Odete Ribeiro Leite, an endocrinologist, made comments on a slight edema after parathyroidectomy for primary HPT, usually resolving in few days (personal communication). Although uncommon, a clinically significant decrease of renal function after parathyroidectomy has been observed in some patients with primary HPT. In those cases, blood pressure fluctuations during anesthesia were suspected as the cause, but not conclusively, because no report of these fluctuations could be detected in anesthesia records. Recently, Schwarz et. al. showed a decreased renal function in kidney transplant patients after parathyroidectomy4. Creatinine levels increase after parathyroidectomy in transplanted patients was previously mentioned by others5,6. In primary HPT, decreased renal function was a collateral observation in a study 20 years ago7. In another study, a non significant elevation of creatinine, a significant increase of urea, a significant reduction in creatinine clearance in patients undergoing parathyroidectomy for primary HPT, but without change in glomerular filtration rate analyzed by the clearance of 51Cr-EDTA8. These accounts led to some questions regarding the frequency of renal changes in patients submitted to parathyroidectomy in tertiary HPT. Would this change occur in kidney transplant patients undergoing other operations in the head and neck? If related to parathyroidectomy, what

PDF Creator - PDF4Free v2.0

http://www.pdf4free.com

3 would be the role of HPT? If related to HPT, what might be expected in patients with primary HPT? The aim of this study was to evaluate the possible fluctuation of renal function after parathyroidectomy. By a retrospective analysis, the frequency of renal changes were compare din different surgical treatment groups, as follows: primary HPT, tertiary HPT after renal

transplantation, non parathyroid related head and neck tumors in kidney transplant patients and patients with normal renal function and non parathyroid related head and neck tumors (oral, larynx, pharynx, thyroid, salivary glands cancer or goiter). PATIENTS AND METHOD Retrospective evaluation of primary HPT of different causes and HPT after successful kidney transplantation (tertiary HPT) submitted to parathyroidectomy at the Department of Head and Neck Surgery of the University of So Paulo Medical School, from 1997 to April, 2007. Kidney transplant patients without HPT submitted to resection of other head and neck tumors under general anesthesia (OKDTx) was analyzed as a control group to patients with tertiary HPT. A random sample of patients with normal renal function undergoing surgical treatment for goiter, thyroid cancer or other head and neck tumors (OHN) was considered as a control group for primary HPT patients. Available data of preoperative creatinine and postoperative results were investigated at the patients charts, from the surgical notes of the first author or available at the electronic system from the laboratory database from the institution. The most recent available preoperative creatinine result was considered in relation to highest postoperative level observed. A subtraction of the preoperative level from the postoperative was calculated and then, this difference was divided by the preoperative level. The percentual variation was estimated. This probably reflects changes in renal function. A negative result was due to a decrease in creatinine reflecting an improvement in renal function. On the other hand, a positive result indicated an elevation of creatinine and, consequently, a decreased renal function. After parathyroidectomy, the change in renal function was considered if superior to 10%. This restriction tried to avoid variations related to measurement of creatinine, according to the

PDF Creator - PDF4Free v2.0

http://www.pdf4free.com

4 variation coefficient from previous studies, about 4%9. The change was stratified to estimate the magnitude of variation. If a 30% increase from preoperative level was observed, this was considered a significant change. 6 During the period of study, laboratory employed different methods. Early measurements were reported as serum automatized colorimetric (normal range 0.6 to 1.4 mg/dl). Later, an automatized kinetic was employed (normal ranges 0.4 to 0.9 for women and 0.7 to 1.2 form men). Each patient comparison was done only with the same method. STATISTICAL ANALYSIS Descriptive statistics included mean, median, standard deviation (SD), and standard error of the mean (SEM). For statistical inference, parametric or non-parametric tests were employed according to the normality test. A dichotomy of values of less or equal to 10%, or superior to 10% was checked with the Qui-square test. Kruskal-Wallis, Dunns Multiple comparison, Mann-Whitney and non-paired student were employed. Calculated descriptive value (p) was considered significant if inferior to 5%. RESULTS In the established 10 year period, 168 primary HPT cases were operated at the institution. Standard surgical technique was bilateral parathyroid exploration. In 105, creatinine levels could be compared right after the operation. They were studied as primary HPT group. Data from 38 kidney transplant patients with HPT submitted to surgery were available, and also from seven transplanted patients without HPT operated on head and neck tumors. In 25 patients undergoing thyroidectomy, comparative creatinine was available. Of these, three were submitted to thyroid lobectomy only and one patient with a previous thyroidectomy in the past underwent a central neck dissection. Total thyroidectomy or completion thyroidectomy was the operation of the remaining 21 patients. Of these, seven were associated with central neck dissection. Table 1 shows the count of cases with creatinine increase superior to 10%, according to each group.

PDF Creator - PDF4Free v2.0

http://www.pdf4free.com

5 Table 1 Counts of creatinine increase superior to 10%, according to different groups.

Creatinine Increase Negative or <10% > 10% Total Primary HPT Tertiary HPT OKDTx Lobectomy Total Thyroidectomy OHN

28 77 105

6 32 38

6 1 7

3 0 3

11 11 22

15 3 18

Comparison of the groups of Table 1 by qui-square test yielded p<0.001. Indeed, a predominant reduction in postoperative creatinine value was observed in patients with preoperative normal renal function undergoing major head and neck cancer surgery and in renal transplant patients undergoing non parathyroid surgery (OKDTx). Table 2 shows details of percent change of creatinine in different groups. In two patients submitted to thyroid lobectomy, a reduction of creatinine was observed and an increase of 8.4% was observed in the third case of this subgroup. Table 2 Estimated postoperative renal function change
percent postoperative creatinine change Primary HPT n=105(100%) Tertiary HPT n=38(100%) OKDTx n=7(100%) Total Thyroidectomy n= 22(100%) OHN n=18(100%)

Improved (negative value) 0% 0.1 to 10% 11 to 30% 31 to 50% > 50%

13 (12.4%) 7 (6.7%) 8 (7.6%) 31 (29.5%) 28 (26.7%) 18 (17.1%)

3 (7.9%) 2 (5.3%) 1 (2.6%) 14 (36.8%) 9 (23.7%) 9 (23.7%)

4 (57.1%) 1 (14.3%) 1 (14.3%) 0 (0%) 1 (14.3%) 0 (0%)

7 (31.8%) 2 (9.1%) 2 (9.1%) 4 (13.6%) 4 (18.2%) 3 (13.6%)

14 (77.8%) 1 (5.6%) 0 (0%) 2 (11.1%) 1 (5.6%) 0 (0%)

PDF Creator - PDF4Free v2.0

http://www.pdf4free.com

6 Table 3 shows descriptive statistics observed in different groups. Table 3 Creatinine variation in different groups. Tertiary HPT OKDTx Primary HPT Total thyroidectomy OHN minimum maximum mean median SEM SD Normality test -33.3% +172.5% +39.5% +28.3% 6.4% 39.2% passed -28.0% +38.0% -2.7% -6.0% 8.4% 22.2% passed -20.2% +304.5% +30.8% +25.0% 4.1% 41.8% failed -29.6% +88.9% +18.7% +11.25% 6.8% 31.7% passed -33.3% +43.4% -6.4% -7.5% 4.1% 17.5% passed

According to creatinine increase, multiple group comparison did show a significant difference (p<0.0001, Kruskal-Wallis test). When groups were compared on pairs, by the Dunns Multiple comparison test, a significant difference was disclosed between tertiary HPT and OKDTx (p<0.05) (Graphic 1), between tertiary HPT and OHN (p<0.001) and primary HPT and OHN (p <0.001).

Graphic 1 Distribution of postoperative creatinine change in tertiary HPT (Tx Renal PTX) and OKDTx (Tx Renal No PTX).
On ordinate axis (y) the scale is the percent postoperative change of creatinine (% variao da creatinina).

PDF Creator - PDF4Free v2.0

http://www.pdf4free.com

7 Graphic 2 shows that no statistical difference was observed in postoperative creatinine change between tertiary and primary HPT. The distributions of creatinine changes in primary HPT and OHN are depicted in graphic 3.

Graphic 2 Percent change of creatinine after parathyroidectomy (% variao da creatinina) in tertiary

(Tx Renal PTX) and primary HPT (HPT primrio).

PDF Creator - PDF4Free v2.0

http://www.pdf4free.com

Graphic 3 Distribution of postoperative creatinine change in primary HPT (HPT primrio) and OHN (CEC CCP).

These observations suggested two other comparisons. The first one between patients undergoing parathyroidectomy for primary HPT and those submitted to total thyroidectomy with or without central neck dissection, but a demonstrated reduction of postoperative parathyroid hormone level. No statistical difference was observed (p=0.97, Mann-Whitney test), as shown is graphic 4.

PDF Creator - PDF4Free v2.0

http://www.pdf4free.com

Graphic 4 Postoperative change of creatinine (% variao da creatinina no PO) in patients with

primary HPT (HPT primrio) and total thyroidectomy with hypocalcemia (hipocalcemia PO).

The second comparison tried to answer if a difference between those with presumed hypoparathyroidism after thyroidectomy could exist when they were compared to those without postoperative reduction in parathyroid activity. In this condition, patients submitted to thyroid lobectomy were included in the group of those without postoperative hypoparathyroidism. When thyroidectomy patients were stratified according to presumed hypoparathyroidism a significant difference was noted. Mean percent creatinine increase was + 28.5% (SEM 9%) in those with presumed hypoparathyroid and it was + 1.2% (SEM 5%) in those without evidence of postoperative hypoparathyroidism. (p=0.02, non paired t test, Graphic 5).

PDF Creator - PDF4Free v2.0

http://www.pdf4free.com

10

Graphic 5 Comparison after thyroidectomy with presumed hypoparathyroidism (hipocalcemia) and

without evidence of postoperative parathyroid dysfunction (sem hipocalcemia).

In most cases, creatinine levels return to basal in few days. Graphic 6 illustrates one patient submitted to total thyroidectomy. She has received supplemental calcium after the thyroidectomy and the medical team in charge had sampled calcium, parathyroid hormone and creatinine in the postoperative period. This case also illustrates that creatinine variation is not associated with serum calcium values, as many patients have received supplemental calcium.

PDF Creator - PDF4Free v2.0

http://www.pdf4free.com

11

C r e at in in e va r ia tio n aft e r t h yr o id e ct o m y in o n e c as e C r e at in in e ( m g /d l) 1,2 1 0,8 0,6 0,4 0,2 0 p r e o p e r a tive o p e r at io n 1 PO 3PO 9 PO T im e PT H <11 p g /m l PT H 15 p g /m l

(e s tim a te d va lue )

0 ,9 1

1 ,0 6

0 ,7 6 C a =9 ,5 C a = 8 ,9 0 ,6 9

0 ,7 3

C a = 9 ,3 C a = 8 ,7

Graphic 6 Creatinine, total calcium in mg/dl(Ca) and some parathyroid hormone (PTH) levels in a
patient submitted to total thyroidectomy, with transient hypoparathyroidism.

DISCUSSION The results presented point to a quick change in renal function after operations that might interfere with parathyroid glands function. This change is expressive in some patients, but fugacious in the majority, returning to normal levels few days after the operation. (complete data not presented) Initially observed in patients with HPT, a hypothesis of low expression of parathyroid hormone receptors in cells related to the control of glomerular flow was considered, in response to elevated levels of circulating parathyroid hormone. The sharp reduction of this concentration after parathyroidectomy could explain the changes observed, until a rearrange in receptors could occur. Notwithstanding, the observation of the same phenomenon in persons without previous HPT but with a probable postoperative hypoparathyroidism make that hypothesis less convenient. Another question involves creatinine changes related to variation of calcium levels, but there was no relationship of measured calcium level and creatinine increase (data not presented), which make less plausible that creatinine increase was directly related to changes in serum calcium, although intracellular calcium may play some role.

PDF Creator - PDF4Free v2.0

http://www.pdf4free.com

12 Through a clinical observation, the present study seems to demonstrate a parathyroid hormone hemodynamic effect on the kidney as suggested by some previous animal studies where a decline in glomerular filtration was observed after parathyroidecotmy10,11. These animals did not have preoperative elevated levels of parathyroid hormone as some thyroid patients of the present study. A creatinine change as consequence of blood pressure changes in anesthesia seems not probable to explain all cases, as patients with head and neck neoplasms undergo more extensive operations, with more pronounced fluid loss, and in many of them creatinine levels decreased. Evaluation of renal function by creatinine measurement is questionable, but it is still a reality in clinical practice12. The possible interference of drugs, as cephalosporins or increase in bilirubin13, is apparently less probable in these cases. There is an observation that creatinine clearance is overestimated in some patients with HPT8, suggesting that the creatinine increase is not a real change in renal function. However, how can one explain creatinine increase in some thyroidectomy patients, without previous HPT? The retrospective nature of this study is associated with many doubts and caution in interpretation of these observations is advised. Clearly, a prospective study, with other markers of renal function, as cystatin C, would be of interest. Even measurement of bilirubin would be justified, as parathyroid hormone affected hepatic flow in an experimental study14. There is evidence that renal disease is a world problem of public health, affecting 5% to 10% of population, with progressive loss of kidney function, cardiovascular disease and early death 15. The knowledge of nephrotoxic drugs (anti-inflammatory, antibiotics and radiological contrasts) make their use selective, with protective measures, lowering their risk of renal complications. Recognizing that the surgical treatment of the parathyroid glands by itself may interfere with renal function is of clinical value. Patient counseling before the operation and careful preoperative evaluation of renal function are necessary. Postoperative care is also recommended as the present authors observed a few patients with a permanent or a progressive loss of renal function after the parathyroidectomy. Indeed, Edvall showed renal alterations due to HPT 16. Some are functional and revert after excision of hyperactive parathyroid tissue. However, in some cases, HPT seems to promote an organic

PDF Creator - PDF4Free v2.0

http://www.pdf4free.com

13 tubular lesion that is irreversible. In advanced disease, parathyroidectomy may represent the loss of compensatory mechanism16. Special attention should be directed to patients with single kidney, to those with a previous compromise in renal function, and to those at risk groups, as diabetics and hypertensive patients. REFERENCES
1. Wells Jr SA, Doherty GM. The surgical management of hyperparathyroidism. In: Bilezikian JP, Marcus R, Levine MA, eds. The Parathyroids. 2nd ed. San Diego: Academic Press; 2001. p.487-97. 2. Ianhez LE. Transplante Renal. Seguimento a longo prazo. So Paulo: Lemos Editorial; 2002. p.37. 3. Tzanakis I, Alifieris E, Kagia S, Spantidakis V, Girousis N, Galis A, Kallivretakis N. Does parathyroidectomy affect residual diuresis in hemodialysis patients? Nephron. 2000;86(3):402-3. 4. Schwarz A, Rustien G, Merkel S, Radermacher J, Haller H. Decreased renal transplant function after parathyroidectomy. Nephrol Dial Transplant. 2007;22(2):584-91. 5. Evenepoel P, Claes K, Kuypers D, Maes B, Vanrenterghem Y. Impact of parathyroidectomy on renal graft function, blood pressure and serum lipids in kidney transplant recipients: a single centre study. Nephrol Dial Transplant. 2005;20(8):1714-20. 6. Rostaing L, Moreau-Gaudry X, Baron E, Cisterne JM, Bernadet-Monrozies P, Durand D. Changes in blood pressure and renal function after subtotal parathyroidectomy in renal transplant patients presenting persistent hypercalcemic hyperparathyroidism. Transplant Proc. 1997;29(1-2):204-6. 7. Jones DB, Jones JH, Lloyd HJ, Lucas PA, Wilkins WE, Walker DA. Changes in blood pressure and renal function after parathyroidectomy in primary hyperparathyroidism. Postgrad Med J. 1983;59(692):350-3. 8. Salahudeen AK, Thomas TH, Sellars L, Tapster S, Keavey P, Farndon JR, Johnston ID, Wilkinson R. Hypertension and renal dysfunction in primary hyperparathyroidism: effect of parathyroidectomy. Clin Sci (Lond). 1989;76(3):289-96. 9. Myers GL, Miller WG, Coresh J, Fleming J, Greenberg N, Greene T, Hostetter T, Levey AS, Panteghini M, Welch M, Eckfeldt JH; National Kidney Disease Education Program Laboratory Working Group. Recommendations for improving creatinine serum measurement: a report from the Laboratory Working Group of the National Kidney Education Program. Clin Chem. 2006;52(1):5-18. 10. Zaladek-Gil F, Costa-Silva VL, Malnic G. Effects of parathyroid hormone on urinary acidification in the rat. Braz J Med Biol Res. 1991;24(10):1063-6. 11. Zaladek Gil F, Nascimento Gomes G, Cavanal MF, Cesar KR, Magaldi AJ. Influence of parathyroidectomy and calcium on rat renal function. Nephron. 1999;83(1):59-65. 12. Pecoits-Filho R. Diagnstico de doena renal crnica: avaliao da funo renal. J Bras Nefrol. 2004;26(Supl.1):4-5.

PDF Creator - PDF4Free v2.0

http://www.pdf4free.com

14
13. Weber JA, van Zanten AP. Interferences in current methods for measurements of creatinine. Clin Chem. 1991;37(5):695-700. 14. Charbon GA, Hulstaert PF. Augmentation of arterial hepatic and renal flow by extracted and synthetic parathyroid hormone. Endocrinology. 1974;96(2):621-6. 15. Moe SM, Dreke T, Lameire N, Eknoyan G. Chronic kidney disease-mineral-bone disorder: a new paradigm. Adv Chronic Kidney Dis. 2007;14(1):3-12. 16. Edvall CA. Renal function in hyperparathyroidism: a clinical study of 30 cases with special reference to selective renal clearance and renal vein catheterization. Acta Chirur Scand Suppl. 1958;114(Suppl 229):1-56.

PDF Creator - PDF4Free v2.0

http://www.pdf4free.com