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Living Kidney Donors With Adrenal Incidentalomas: Are They Appropriate Donors?
Accepted Manuscript Title: Living Kidney Donors with Adrenal Incidentalomas: are They Appropriate Donors Author: Emre Arpali, Atilla Aslan, Joseph Scalea, Cihan Karatas, Serkan Akinci, Mert Altinel, Burak Kocak PII: DOI: Reference:
S0090-4295(15)00940-1 http://dx.doi.org/doi: 10.1016/j.urology.2015.10.004 URL 19428
To appear in:
Urology
Received date: Accepted date:
26-6-2015 1-10-2015
Please cite this article as: Emre Arpali, Atilla Aslan, Joseph Scalea, Cihan Karatas, Serkan Akinci, Mert Altinel, Burak Kocak, Living Kidney Donors with Adrenal Incidentalomas: are They Appropriate Donors, Urology (2015), http://dx.doi.org/doi: 10.1016/j.urology.2015.10.004. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
LIVING KIDNEY DONORS WITH ADRENAL INCIDENTALOMAS: ARE THEY APPROPRIATE DONORS Running title: Living kidney donors with adrenal incidentalomas
Key Words: Adrenal incidentaloma, laparoscopic donor nephrectomy, kidney transplant
Contributors 1. Emre Arpali, M.D. Department of Organ Transplantation, Memorial Sisli Hospital, Istanbul, Turkey 2. Atilla Aslan, M.D. Department of Radiology, Memorial Sisli Hospital, Istanbul, Turkey 3. Joseph Scalea, M.D. Division of Transplantation, Department of Surgery and Urology, University of Wisconsin 4. Cihan Karatas, M.D. Department of Organ Transplantation, Memorial Sisli Hospital, Istanbul, Turkey 5. Serkan Akinci,M.D. Department of Organ Transplantation, Turkish Kidney Foundation Hizmet Hospital, Istanbul, Turkey 6. Mert Altinel, M.D. Department of Urology, Turkish Kidney Foundation Hizmet Hospital, Istanbul, Turkey 7. Burak Kocak, M.D. Department of Organ Transplantation, Memorial Sisli Hospital, Istanbul, Turkey
Corresponding author: Emre Arpali,MD Current address: Division of Transplantation, Department of Surgery and Urology, University of Wisconsin. 600 Highland Avenue, H4/780, WI 53702. E-mail: [email protected]
Disclosures: The authors have no financial disclosures
Page 1 of 12
Abstract: Objective: To determine the incidence of adrenal incidentalomas in a single-center series of living renal donors, to describe an evaluation algorithm for adrenal incidentalomas in this patient population, and to compare the complication rates of hand-assisted laparoscopic donor nephrectomy (HALDN) with those of combined HALDN and adrenalectomy. Methods: We performed a single center, retrospective study of consecutive living kidney donors who underwent laparoscopic nephrectomy for transplantation, with or without simultaneous ipsilateral adrenalectomy, between January 2008 and September 2014. Results: During the study period, adrenal incidentalomas were detected in 18 of 1033 potential living renal donors who underwent computerized tomographic angiography. Application of additional donor selection criteria and of an adrenal mass assessment algorithm resulted in 849 HALDN of which 13 were combined with simultaneous adrenalectomy. The hospital length of stay (2.4 vs 2.6 days), perioperative (0.025 vs 0.077), early (0.073 vs 0.077) and late (0.014 vs 0.077) postoperative complication rates, and conversion to open donor nephrectomy (0.008 vs 0.00) were not significantly different. Mean operative time was significantly longer in the adrenalectomy group. None of the adrenal masses were malignant. Conclusions: Here, we presented our algorithm to manage the living kidney donors with AIs. Although donor population with AIs was relatively small in number, simultaneous adrenalectomy and ipsilateral nephrectomy seemed to be technically safe and conferred no identifiable increased risk of malignancy for the kidney transplant donor, when the incidentaloma is nonfunctional and less than or equal to 4 cm as assessed by preoperative imaging.
Page 2 of 12
LIVING KIDNEY DONORS WITH ADRENAL INCIDENTALOMAS: ARE THEY APPROPRIATE DONORS? Introduction Although the definition varies between authors and institutions, an incidentally discovered adrenal mass by means of an imaging modality which is usually performed for another indication is considered an adrenal incidentaloma (AI) [1, 2]. The majority of the incidentalomas are found to be benign nonfunctional lesions depending on the size [1, 3, 4]. The prevalence of incidentalomas, detected on thoracic and abdominal CT scans, is reported to be between 0.8% and 5% depending on the inclusion criteria [5]. Therefore, it should not be surprising to transplant surgeons that incidentalomas are encountered during the candidate work up for potential living kidney donation especially in high volume transplant centers. But, whether the incidence of AI in kidney donors is different than the normal population is not known. Here, we presented a single-center series of living kidney donors with adrenal masses and their preoperative evaluation and operative management are reviewed. As it has not been studied, we sought to determine the incidence and risk of AI and to propose an evaluation algorithm for potential living kidney donors with AI. We had also compared the complication rates of hand-assisted laparoscopic donor nephrectomy (HALDN) with those of combined HALDN and adrenalectomy to find out if combined, simultaneous adrenalectomy and living kidney donor nephrectomy was safe.
Methods Patient selection: All consecutive HALDN were identified from cases performed between January 2008 and September 2014. Patient data were obtained from a combination of medical record reviews, clinic visits, and telephone communications. Demographics including donor sex, age, weight, height, body mass index (BMI), operative time, transfusion requirement, length of postoperative hospital stay, donor serum creatinine levels before and one week after the surgery, donor hemoglobin levels before, immediately after and one week after the surgery, intraoperative complications, postoperative recovery and complications were collected. No patients who underwent adrenalectomy and following pathologic diagnosis of cancer underwent a subsequent interval nephrectomy were considered in this analysis.
Page 3 of 12
Donor imaging: The presence of two functional kidneys and an assessment of vascular anatomy were determined by high resolution computed tomographic angiography (CTA). Incidentaloma were detected during the routine preoperative donor evaluation. Algorithm: It is our practice to thoroughly evaluate all adrenal masses in potential donors. According to our algorithm (Figure-1) all patients with adrenal masses should be screened with 24-hr urine free cortisol level, plasma ACTH level, plasma free metanephrine/normetanephrine levels, plasma aldosterone concentration and plasma renin activity measurement in order to interrogate the activity of the adrenal masses. Patients are not allowed to proceed to donation if they demonstrated elevations in these adrenal markers. If the radiologic signs of malignancy are found in kidney donor candidates donation is cancelled. For patients with masses greater than 4 cm on imaging, adrenalectomy is recommended without nephrectomy for organ donation. Kidneys ipsilateral to the adrenal masses are chosen for donation providing that both kidneys are volumetrically and anatomically equivalent based on preoperative imaging. If there is a reason which obligates to choose the contralateral kidney, the donation will not proceed.
Complications: Complications were defined as untoward events within the perioperative period that altered patient recovery, prolonged hospital stay, or represented technical deviations during the surgical procedure. Mean postoperative pain score was calculated based on a previously validated, patientreported pain scale ranging from 1 to 10 [6, 7]. Operative technique: The operative technique for LDN (2-3 laparoscopic ports, left/right lower quadrant extraction incision) has been described in prior reports [8]. In all cases, a pneumatic sleeve (Gelport®, Applied Medical) was used to allow hand-assisted nephrectomy. Generally, nephrectomy was performed through two ports for a left nephrectomy and three ports for a right nephrectomy. Adrenalectomy: When required, adrenalectomy was performed in all patients prior to donor nephrectomy. Frozen section was obtained intraoperatively and was read immediately by a senior oncologic pathologist. After the plane between the kidney and adrenal gland was developed, the adrenal vein was dissected, ligated, and divided. The posterior and inferior aspect of the gland was mobilized over the psoas muscle. Finally, the upper pole of the adrenal gland was dissected off the
Page 4 of 12
pancreas and spleen on the left side and off the liver on the right side. All dissections were completed with the use of dissection/tissue sealing instrument (Ligasure™, Valley Lab). Statistics: Statistical analyses were done using commercially available software, postoperative hospitalization duration, operative time, body mass index (BMI), visual pain score and perioperative and postoperative complication incidences were compared. The Chi-Square test and Mann-Whitney U test were applied when necessary. A p<0.05 was accepted as statistically significant.
Results Incidentaloma diagnosis in kidney donor candidates: One thousand twelve patients presented for living donor evaluation during the study period (Figure 1). Of these, 179 (14.7%) patients had preexisting diseases and were excluded from proceeding to donor evaluation without CT scan. Eighteen (1.74%) of the remaining 1033 patients who underwent CT scanning, were observed to have an adrenal incidentaloma. None of the patients with incidentaloma were excluded from proceeding to donation based on the concern for malignancy. Of the 18 patients with incidentalomas, 13 (72%) proceeded to living kidney donation. Application of additional donor selection criteria and an adrenal assessment algorithm resulted in 849 HALDN of which 13 were combined with simultaneous adrenalectomy. Five patients with adrenal incidentalomas were excluded from kidney donation. Of these, one patient had hormonally active adrenal mass and the other 4 patients had other medical problems, precluding kidney donation (Figure 2). Demographics of kidney donors: Patient demographics are presented in Table 1. Patients with incidentalomas were older than those without incidentalomas (p=0.009). The mean BMI for patients with incidentalomas versus without incidentalomas was 30 ± 2.7 versus 27.4 ± 4.8, respectively (p=0.016). None of the 13 incidentalomas were functional. Adrenal incidentalomas were measured at a mean of 16.5 ± 5.1 mm on preoperative imaging studies. Of those with adrenal masses, 30.7 % required additional imaging prior to surgery. Operative time: Mean operative time was 82±23.1 minutes for those who underwent laparoscopic donor nephrectomy alone. In contrast, Mean operative time was 97.6±20.4 minutes for patients in whom adrenalectomy was also performed (p=0.021).
Page 5 of 12
Intraoperative complications: There were no deaths. A single operative complication (1/13, 7.7%) was observed in adrenalectomy group. There was no difference in length of stay or pain score at 24 hours between the two groups (Table 1). The rate of conversion from laparoscopic to open surgery was 0.00% and 0.83% (0.74, n=7) with and without adrenalectomy, respectively. Reasons for conversion to open are presented in table 2. There were one (0.82%) patient in the adrenalectomy group with major renovascular complications but did not require open conversion. Two of the seven (28.6%) open conversions in donors without adrenalectomy were due to vascular injuries which included renal arterial injury and inferior vena cava injuries. In addition, vascular stapler failure was the cause of open conversion in three patients. Post-operative complications: There was no difference in overall inpatient post-operative complication rate between two groups. Regarding presentation of complication after discharge, we identified 7.7% and 1.4% of complications with and without adrenalectomy, respectively. All patients with prolonged ileus were managed by medical treatment. A single patient required re-operation due to bleeding for which laparoscopic exploration was performed. Ten patients of 849 (1.2%) who were initially discharged to home were re-hospitalized for prolonged ileus, urinary tract infection, chylous ascites, shortness of breath or dehydration. The patient with chylous ascites required percutaneous drainage and dietary modification. No patients in the adrenalectomy group required readmission and hospitalization after discharge from the primary operation following adrenalectomy and nephrectomy. A single incisional hernia was observed in one patient (7.7%) six months after simultaneous adrenalectomy and nephrectomy. Two additional patients with hernias were diagnosed one year following nephrectomy alone (0.24%; p<0.05). Pathology and recipient follow up: Of the donors in whom adrenalectomy was performed, none were determined to be malignant. No atypical changes were seen. Regarding the donors, at a follow up of 2.3 ±1.6 years there were no cases of significant medical problems including symptoms or signs of adrenal insufficiency.
Page 6 of 12
Discussion Most of AIs are benign nonfunctional lesions, leaving a small but important proportion of them being malignant or functioning masses [9]. The probability of malignancy or hormonal activity poses a significant risk that cannot be ignored in living kidney donor candidates. Although majority of the adrenal incidentalomas have no clinical significance, two main issues should be kept in mind when evaluating a kidney donor candidate with an adrenal incidentaloma: A malignant lesion and a functionally active mass. Tumors over-producing cortisol, catecholamines or mineralocorticoids are the most common forms of hormonally active masses and the patients may not have any overt clinical manifestations [10]. For instance, many of the pheochromocytomas progress insidiously for long periods of time until clinical manifestations like headache, palpitations, and paroxysmal hypertension occur. Operation without proper preparation during this silent period may cause unpredictable fatal consequences [11]. Thus, the first step which should be taken into account during the evaluation of a candidate with AI is the hormonal activity status and patients with hypersecretory masses should not proceed to kidney donation. They should be treated with surgery, in addition to medical management depending on the hormones secreted [2]. In our series, only one the 18 patients (5.5%) with adrenal incidentaloma had a hypersecretory mass. His clinical evaluation revealed subclinical Cushing’s syndrome and he was excluded from kidney donation. Once the diagnosis of a non-functioning adrenal mass is made, the question that arises is one of medical suitability for live kidney donation. By definition living kidney donor is a “Healthy person”. Actually, the question to be answered should be if a person with a non-functioning adrenal mass is a healthy person or not? The size of the adrenal mass will generally inform the solution to this question. The size of the AI is an important risk factor for the malignancy and for poor prognosis [1, 2]. Previous reports have shown that 25% of lesions larger than 6 cm were found to be malignant whereas the incidence of malignancy in lesions smaller than 4 cm was only 2% [1, 12]. Therefore, for live donor candidates with adrenal lesions more than 4 cm, these lesions warrant adrenalectomy and the kidney donation should be declined. It would not be wrong to conclude that smaller lesions have lower risk of malignancy. However, even if the lesion is smaller than 2 cm, the risk of malignancy is not zero, and the risk of malignancy should be minimized as much as possible [12]. For patients with these smaller masses, a through radiologic evaluation is mandatory, yet histologic diagnosis is the gold standard.
Page 7 of 12
Enhancement and washout characteristics of the adrenal masses found in enhanced CT may give important clues about the nature of the lesions. However, the reliability of an evaluation protocol depending on only radiologic findings to rule out malignancy has not been validated [13-15]. Hence, in order to reduce risk of malignancy (to a degree that is possible by frozen section) and to learn histologic diagnosis, we have included laparoscopic adrenalectomy and frozen section examination of the adrenal mass to our routine algorithm. If frozen section examination of the adrenal mass suggests a nonmalignant process, we think that it is safe to proceed with donor nephrectomy. In our series all adrenalectomies and frozen section examinations were performed prior to proceeding donor nephrectomies. Accuracy of the frozen section may be another concern as we are unware of any large scale studies investigating the reliability of frozen section diagnosis of adrenal masses have been performed and misdiagnosis of a malignant lesion in preoperative evaluation and frozen section examination may happen theoretically. Our results suggest that the rate of such an event is very low, although a cohort of 13 patients remains a very small number to draw meaningful conclusions. The alternative diagnostic strategy, the preoperative percutaneous biopsy, is both inconvenient and unsafe with high major complication rates [16-18]. Besides it was mentioned that it had no advantage in defining the nature of the adrenal masses. Therefore we find it a reasonable way to do the adrenalectomy first and proceed with donor nephrectomy if the frozen section examination reveals a benign lesion. The validity of our approach to living kidney donors with adrenal incidentalomas can be questioned and performing adrenalectomy to these patients may be regarded as over treatment. These are the patients who would be followed on active surveillance rather than receive surgery for their adrenal lesions outside of the context of donor nephrectomy. The interesting question here would have been "why remove these adrenal glands at the time of donor nephrectomy if they would not normally be removed under other circumstances?" The American Association of Clinical Endocrinologists and Association of Endocrine Surgeons guidelines recommend follow-up for incidentalomas smaller than 4 cm and for radiologic findings consistent with benign lesions [19]. Accordingly, radiological reevaluation should be performed in any hormonally inactive patient with a lesion smaller than 4 cm at 3 to 6 months and then annually for 2 years. Hormonal evaluation should also be performed at the time of diagnosis and every year for 5 years. This
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is the standard approach for any patient diagnosed with AI. We think that there are downsides to this approach in the potential kidney donor. Notably, one would not be able to rule out any potential malignancy even though the lesion is even less than 2 cm and this would make the donation process unsafe. Moreover, the risk of increment in size during the following 1st, 2nd and 5th years were estimated to be 6%, 14% and 29% respectively. The risk of transition into a hormonally active form during the same periods of time has been reported to be 17%, 29% and 47%, respectively [20]. There are no well-defined risk factors that show which masses will gain function or have malignant degeneration in long term. Thus, a donor may have to suffer a second operation in the future. In this case, having a laparoscopic adrenal surgery will be more challenging giving the fact that the patient has already had an ipsilateral previous donor nephrectomy. We believe adrenalectomy concomitant with ipsilateral donor nephrectomy is a viable option in potential donors with AI.
Conclusion In our study we have observed that although, the addition of the laparoscopic adrenalectomy to laparoscopic donor nephrectomy increases the operative time, it does not increase the intraoperative complication rates. A safe surgery for a donor operation is of paramount importance and adding an adrenalectomy to the donor operation does not jeopardize the safety of the donor operation and does not increase the morbidity of the operation. However, justification of concomitant adrenalectomy should be argued to the patients and follow-up option could be discussed in detail with its own risks. In our cases all patients with adrenal incidentaloma rejected the follow-up option. Although our study was conducted on a small group of patients in a retrograde fashion, there are no retrospective or prospective randomized studies in the literature evaluating long term results of performing adrenalectomy versus follow up in living kidney donor population with AI. At the very least,
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we suppose, this work should provide a published precedent for not excluding donor candidates solely based on the presence of a small, nonfunctional adrenal incidentaloma suitable for active surveillance.
References 1.
Aron, D., M. Terzolo, and T.J. Cawood, Adrenal incidentalomas. Best Pract Res Clin Endocrinol
Metab, 2012. 26(1): p. 69-82. 2.
Bittner, J.G.t. and L.M. Brunt, Evaluation and management of adrenal incidentaloma. J Surg
Oncol, 2012. 106(5): p. 557-64. 3.
Terzolo, M., et al., Prevalence of adrenal carcinoma among incidentally discovered adrenal
masses. A retrospective study from 1989 to 1994. Gruppo Piemontese Incidentalomi Surrenalici. Arch Surg, 1997. 132(8): p. 914-9. 4.
Barzon, L., et al., Prevalence and natural history of adrenal incidentalomas. Eur J Endocrinol,
2003. 149(4): p. 273-85. 5.
Davenport, C., et al., The prevalence of adrenal incidentaloma in routine clinical practice.
Endocrine, 2011. 40(1): p. 80-3. 6.
Price, D.D., et al., The validation of visual analogue scales as ratio scale measures for chronic and
experimental pain. Pain, 1983. 17(1): p. 45-56. 7.
Tiplady, B., et al., Validity and sensitivity of visual analogue scales in young and older healthy
subjects. Age Ageing, 1998. 27(1): p. 63-6. 8.
Leventhal, J.R., et al., Laparoscopic live donor nephrectomy--is it safe? Transplantation, 2000.
70(4): p. 602-6. 9.
Anagnostis, P., et al., Long term follow-up of patients with adrenal incidentalomas--a single
center experience and review of the literature. Exp Clin Endocrinol Diabetes, 2010. 118(9): p. 610-6. 10.
Arnaldi, G., et al., Adrenal incidentaloma. Braz J Med Biol Res, 2000. 33(10): p. 1177-89.
Page 10 of 12
11.
Kopetschke, R., et al., Frequent incidental discovery of phaeochromocytoma: data from a
German cohort of 201 phaeochromocytoma. Eur J Endocrinol, 2009. 161(2): p. 355-61. 12.
Else, T., et al., Adrenocortical carcinoma. Endocr Rev, 2014. 35(2): p. 282-326.
13.
Slattery, J.M., et al., Adrenocortical carcinoma: contrast washout characteristics on CT. AJR Am J
Roentgenol, 2006. 187(1): p. W21-4. 14.
Bharwani, N., et al., Adrenocortical carcinoma: the range of appearances on CT and MRI. AJR Am
J Roentgenol, 2011. 196(6): p. W706-14. 15.
Park, B.K., C.K. Kim, and B. Kim, Adrenal incidentaloma detected on triphasic helical CT:
evaluation with modified relative percentage of enhancement washout values. Br J Radiol, 2008. 81(967): p. 526-30. 16.
Quayle, F.J., et al., Needle biopsy of incidentally discovered adrenal masses is rarely informative
and potentially hazardous. Surgery, 2007. 142(4): p. 497-502; discussion 502-4. 17.
Williams, A.R., G.D. Hammer, and T. Else, Transcutaneous biopsy of adrenocortical carcinoma is
rarely helpful in diagnosis, potentially harmful, but does not affect patient outcome. Eur J Endocrinol, 2014. 170(6): p. 829-35. 18.
Mazzaglia, P.J. and J.M. Monchik, Limited value of adrenal biopsy in the evaluation of adrenal
neoplasm: a decade of experience. Arch Surg, 2009. 144(5): p. 465-70. 19.
Zeiger, M.A., et al., The American Association of Clinical Endocrinologists and American
Association of Endocrine Surgeons medical guidelines for the management of adrenal incidentalomas. Endocr Pract, 2009. 15 Suppl 1: p. 1-20. 20.
Libe, R., et al., Long-term follow-up study of patients with adrenal incidentalomas. Eur J
Endocrinol, 2002. 147(4): p. 489-94.
Figure-1 Our Algorithm for managing living donor candidates with adrenal incidentalomas Figure-2 Distribution of the living kidney donor candidates
Page 11 of 12
Table-1 Patient demographics and postoperative complication rates
AGE GENDER (M/F) BMI OPERATIVE TIME (MIN) POSTOP STAY (DAYS) PEROPERATIVE COMP. POSTOP EARLY COMP. POSTOP LATE COMP. CONVERSION (MIN)
DONORS WITHOUT ID 46 ± 13.2 375/461 27.4 ± 4.8 82 ± 23.1
DONOR WITH ID
P VALUE
56 ± 11.7 4/9 30 ± 2.7 97.6 ± 20.4
0.009 0.31 0.016 0.021
2.35 ± 0.79
2.6 ± 1.64
0.82
21/836
1/13
0.24
61/836
1/13
0.95
12/836
1/13
0.68
7/836
0/13
0.74
Table-2 Reasons for conversion to open surgery Reason for conversion to open surgery Bleeding from adrenal gland Vascular stapler failure Renal vein injury Renal artery injury
Number of the patient 2 3 1 1
Page 12 of 12
S0090-4295(15)00940-1 http://dx.doi.org/doi: 10.1016/j.urology.2015.10.004 URL 19428
To appear in:
Urology
Received date: Accepted date:
26-6-2015 1-10-2015
Please cite this article as: Emre Arpali, Atilla Aslan, Joseph Scalea, Cihan Karatas, Serkan Akinci, Mert Altinel, Burak Kocak, Living Kidney Donors with Adrenal Incidentalomas: are They Appropriate Donors, Urology (2015), http://dx.doi.org/doi: 10.1016/j.urology.2015.10.004. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
LIVING KIDNEY DONORS WITH ADRENAL INCIDENTALOMAS: ARE THEY APPROPRIATE DONORS Running title: Living kidney donors with adrenal incidentalomas
Key Words: Adrenal incidentaloma, laparoscopic donor nephrectomy, kidney transplant
Contributors 1. Emre Arpali, M.D. Department of Organ Transplantation, Memorial Sisli Hospital, Istanbul, Turkey 2. Atilla Aslan, M.D. Department of Radiology, Memorial Sisli Hospital, Istanbul, Turkey 3. Joseph Scalea, M.D. Division of Transplantation, Department of Surgery and Urology, University of Wisconsin 4. Cihan Karatas, M.D. Department of Organ Transplantation, Memorial Sisli Hospital, Istanbul, Turkey 5. Serkan Akinci,M.D. Department of Organ Transplantation, Turkish Kidney Foundation Hizmet Hospital, Istanbul, Turkey 6. Mert Altinel, M.D. Department of Urology, Turkish Kidney Foundation Hizmet Hospital, Istanbul, Turkey 7. Burak Kocak, M.D. Department of Organ Transplantation, Memorial Sisli Hospital, Istanbul, Turkey
Corresponding author: Emre Arpali,MD Current address: Division of Transplantation, Department of Surgery and Urology, University of Wisconsin. 600 Highland Avenue, H4/780, WI 53702. E-mail: [email protected]
Disclosures: The authors have no financial disclosures
Page 1 of 12
Abstract: Objective: To determine the incidence of adrenal incidentalomas in a single-center series of living renal donors, to describe an evaluation algorithm for adrenal incidentalomas in this patient population, and to compare the complication rates of hand-assisted laparoscopic donor nephrectomy (HALDN) with those of combined HALDN and adrenalectomy. Methods: We performed a single center, retrospective study of consecutive living kidney donors who underwent laparoscopic nephrectomy for transplantation, with or without simultaneous ipsilateral adrenalectomy, between January 2008 and September 2014. Results: During the study period, adrenal incidentalomas were detected in 18 of 1033 potential living renal donors who underwent computerized tomographic angiography. Application of additional donor selection criteria and of an adrenal mass assessment algorithm resulted in 849 HALDN of which 13 were combined with simultaneous adrenalectomy. The hospital length of stay (2.4 vs 2.6 days), perioperative (0.025 vs 0.077), early (0.073 vs 0.077) and late (0.014 vs 0.077) postoperative complication rates, and conversion to open donor nephrectomy (0.008 vs 0.00) were not significantly different. Mean operative time was significantly longer in the adrenalectomy group. None of the adrenal masses were malignant. Conclusions: Here, we presented our algorithm to manage the living kidney donors with AIs. Although donor population with AIs was relatively small in number, simultaneous adrenalectomy and ipsilateral nephrectomy seemed to be technically safe and conferred no identifiable increased risk of malignancy for the kidney transplant donor, when the incidentaloma is nonfunctional and less than or equal to 4 cm as assessed by preoperative imaging.
Page 2 of 12
LIVING KIDNEY DONORS WITH ADRENAL INCIDENTALOMAS: ARE THEY APPROPRIATE DONORS? Introduction Although the definition varies between authors and institutions, an incidentally discovered adrenal mass by means of an imaging modality which is usually performed for another indication is considered an adrenal incidentaloma (AI) [1, 2]. The majority of the incidentalomas are found to be benign nonfunctional lesions depending on the size [1, 3, 4]. The prevalence of incidentalomas, detected on thoracic and abdominal CT scans, is reported to be between 0.8% and 5% depending on the inclusion criteria [5]. Therefore, it should not be surprising to transplant surgeons that incidentalomas are encountered during the candidate work up for potential living kidney donation especially in high volume transplant centers. But, whether the incidence of AI in kidney donors is different than the normal population is not known. Here, we presented a single-center series of living kidney donors with adrenal masses and their preoperative evaluation and operative management are reviewed. As it has not been studied, we sought to determine the incidence and risk of AI and to propose an evaluation algorithm for potential living kidney donors with AI. We had also compared the complication rates of hand-assisted laparoscopic donor nephrectomy (HALDN) with those of combined HALDN and adrenalectomy to find out if combined, simultaneous adrenalectomy and living kidney donor nephrectomy was safe.
Methods Patient selection: All consecutive HALDN were identified from cases performed between January 2008 and September 2014. Patient data were obtained from a combination of medical record reviews, clinic visits, and telephone communications. Demographics including donor sex, age, weight, height, body mass index (BMI), operative time, transfusion requirement, length of postoperative hospital stay, donor serum creatinine levels before and one week after the surgery, donor hemoglobin levels before, immediately after and one week after the surgery, intraoperative complications, postoperative recovery and complications were collected. No patients who underwent adrenalectomy and following pathologic diagnosis of cancer underwent a subsequent interval nephrectomy were considered in this analysis.
Page 3 of 12
Donor imaging: The presence of two functional kidneys and an assessment of vascular anatomy were determined by high resolution computed tomographic angiography (CTA). Incidentaloma were detected during the routine preoperative donor evaluation. Algorithm: It is our practice to thoroughly evaluate all adrenal masses in potential donors. According to our algorithm (Figure-1) all patients with adrenal masses should be screened with 24-hr urine free cortisol level, plasma ACTH level, plasma free metanephrine/normetanephrine levels, plasma aldosterone concentration and plasma renin activity measurement in order to interrogate the activity of the adrenal masses. Patients are not allowed to proceed to donation if they demonstrated elevations in these adrenal markers. If the radiologic signs of malignancy are found in kidney donor candidates donation is cancelled. For patients with masses greater than 4 cm on imaging, adrenalectomy is recommended without nephrectomy for organ donation. Kidneys ipsilateral to the adrenal masses are chosen for donation providing that both kidneys are volumetrically and anatomically equivalent based on preoperative imaging. If there is a reason which obligates to choose the contralateral kidney, the donation will not proceed.
Complications: Complications were defined as untoward events within the perioperative period that altered patient recovery, prolonged hospital stay, or represented technical deviations during the surgical procedure. Mean postoperative pain score was calculated based on a previously validated, patientreported pain scale ranging from 1 to 10 [6, 7]. Operative technique: The operative technique for LDN (2-3 laparoscopic ports, left/right lower quadrant extraction incision) has been described in prior reports [8]. In all cases, a pneumatic sleeve (Gelport®, Applied Medical) was used to allow hand-assisted nephrectomy. Generally, nephrectomy was performed through two ports for a left nephrectomy and three ports for a right nephrectomy. Adrenalectomy: When required, adrenalectomy was performed in all patients prior to donor nephrectomy. Frozen section was obtained intraoperatively and was read immediately by a senior oncologic pathologist. After the plane between the kidney and adrenal gland was developed, the adrenal vein was dissected, ligated, and divided. The posterior and inferior aspect of the gland was mobilized over the psoas muscle. Finally, the upper pole of the adrenal gland was dissected off the
Page 4 of 12
pancreas and spleen on the left side and off the liver on the right side. All dissections were completed with the use of dissection/tissue sealing instrument (Ligasure™, Valley Lab). Statistics: Statistical analyses were done using commercially available software, postoperative hospitalization duration, operative time, body mass index (BMI), visual pain score and perioperative and postoperative complication incidences were compared. The Chi-Square test and Mann-Whitney U test were applied when necessary. A p<0.05 was accepted as statistically significant.
Results Incidentaloma diagnosis in kidney donor candidates: One thousand twelve patients presented for living donor evaluation during the study period (Figure 1). Of these, 179 (14.7%) patients had preexisting diseases and were excluded from proceeding to donor evaluation without CT scan. Eighteen (1.74%) of the remaining 1033 patients who underwent CT scanning, were observed to have an adrenal incidentaloma. None of the patients with incidentaloma were excluded from proceeding to donation based on the concern for malignancy. Of the 18 patients with incidentalomas, 13 (72%) proceeded to living kidney donation. Application of additional donor selection criteria and an adrenal assessment algorithm resulted in 849 HALDN of which 13 were combined with simultaneous adrenalectomy. Five patients with adrenal incidentalomas were excluded from kidney donation. Of these, one patient had hormonally active adrenal mass and the other 4 patients had other medical problems, precluding kidney donation (Figure 2). Demographics of kidney donors: Patient demographics are presented in Table 1. Patients with incidentalomas were older than those without incidentalomas (p=0.009). The mean BMI for patients with incidentalomas versus without incidentalomas was 30 ± 2.7 versus 27.4 ± 4.8, respectively (p=0.016). None of the 13 incidentalomas were functional. Adrenal incidentalomas were measured at a mean of 16.5 ± 5.1 mm on preoperative imaging studies. Of those with adrenal masses, 30.7 % required additional imaging prior to surgery. Operative time: Mean operative time was 82±23.1 minutes for those who underwent laparoscopic donor nephrectomy alone. In contrast, Mean operative time was 97.6±20.4 minutes for patients in whom adrenalectomy was also performed (p=0.021).
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Intraoperative complications: There were no deaths. A single operative complication (1/13, 7.7%) was observed in adrenalectomy group. There was no difference in length of stay or pain score at 24 hours between the two groups (Table 1). The rate of conversion from laparoscopic to open surgery was 0.00% and 0.83% (0.74, n=7) with and without adrenalectomy, respectively. Reasons for conversion to open are presented in table 2. There were one (0.82%) patient in the adrenalectomy group with major renovascular complications but did not require open conversion. Two of the seven (28.6%) open conversions in donors without adrenalectomy were due to vascular injuries which included renal arterial injury and inferior vena cava injuries. In addition, vascular stapler failure was the cause of open conversion in three patients. Post-operative complications: There was no difference in overall inpatient post-operative complication rate between two groups. Regarding presentation of complication after discharge, we identified 7.7% and 1.4% of complications with and without adrenalectomy, respectively. All patients with prolonged ileus were managed by medical treatment. A single patient required re-operation due to bleeding for which laparoscopic exploration was performed. Ten patients of 849 (1.2%) who were initially discharged to home were re-hospitalized for prolonged ileus, urinary tract infection, chylous ascites, shortness of breath or dehydration. The patient with chylous ascites required percutaneous drainage and dietary modification. No patients in the adrenalectomy group required readmission and hospitalization after discharge from the primary operation following adrenalectomy and nephrectomy. A single incisional hernia was observed in one patient (7.7%) six months after simultaneous adrenalectomy and nephrectomy. Two additional patients with hernias were diagnosed one year following nephrectomy alone (0.24%; p<0.05). Pathology and recipient follow up: Of the donors in whom adrenalectomy was performed, none were determined to be malignant. No atypical changes were seen. Regarding the donors, at a follow up of 2.3 ±1.6 years there were no cases of significant medical problems including symptoms or signs of adrenal insufficiency.
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Discussion Most of AIs are benign nonfunctional lesions, leaving a small but important proportion of them being malignant or functioning masses [9]. The probability of malignancy or hormonal activity poses a significant risk that cannot be ignored in living kidney donor candidates. Although majority of the adrenal incidentalomas have no clinical significance, two main issues should be kept in mind when evaluating a kidney donor candidate with an adrenal incidentaloma: A malignant lesion and a functionally active mass. Tumors over-producing cortisol, catecholamines or mineralocorticoids are the most common forms of hormonally active masses and the patients may not have any overt clinical manifestations [10]. For instance, many of the pheochromocytomas progress insidiously for long periods of time until clinical manifestations like headache, palpitations, and paroxysmal hypertension occur. Operation without proper preparation during this silent period may cause unpredictable fatal consequences [11]. Thus, the first step which should be taken into account during the evaluation of a candidate with AI is the hormonal activity status and patients with hypersecretory masses should not proceed to kidney donation. They should be treated with surgery, in addition to medical management depending on the hormones secreted [2]. In our series, only one the 18 patients (5.5%) with adrenal incidentaloma had a hypersecretory mass. His clinical evaluation revealed subclinical Cushing’s syndrome and he was excluded from kidney donation. Once the diagnosis of a non-functioning adrenal mass is made, the question that arises is one of medical suitability for live kidney donation. By definition living kidney donor is a “Healthy person”. Actually, the question to be answered should be if a person with a non-functioning adrenal mass is a healthy person or not? The size of the adrenal mass will generally inform the solution to this question. The size of the AI is an important risk factor for the malignancy and for poor prognosis [1, 2]. Previous reports have shown that 25% of lesions larger than 6 cm were found to be malignant whereas the incidence of malignancy in lesions smaller than 4 cm was only 2% [1, 12]. Therefore, for live donor candidates with adrenal lesions more than 4 cm, these lesions warrant adrenalectomy and the kidney donation should be declined. It would not be wrong to conclude that smaller lesions have lower risk of malignancy. However, even if the lesion is smaller than 2 cm, the risk of malignancy is not zero, and the risk of malignancy should be minimized as much as possible [12]. For patients with these smaller masses, a through radiologic evaluation is mandatory, yet histologic diagnosis is the gold standard.
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Enhancement and washout characteristics of the adrenal masses found in enhanced CT may give important clues about the nature of the lesions. However, the reliability of an evaluation protocol depending on only radiologic findings to rule out malignancy has not been validated [13-15]. Hence, in order to reduce risk of malignancy (to a degree that is possible by frozen section) and to learn histologic diagnosis, we have included laparoscopic adrenalectomy and frozen section examination of the adrenal mass to our routine algorithm. If frozen section examination of the adrenal mass suggests a nonmalignant process, we think that it is safe to proceed with donor nephrectomy. In our series all adrenalectomies and frozen section examinations were performed prior to proceeding donor nephrectomies. Accuracy of the frozen section may be another concern as we are unware of any large scale studies investigating the reliability of frozen section diagnosis of adrenal masses have been performed and misdiagnosis of a malignant lesion in preoperative evaluation and frozen section examination may happen theoretically. Our results suggest that the rate of such an event is very low, although a cohort of 13 patients remains a very small number to draw meaningful conclusions. The alternative diagnostic strategy, the preoperative percutaneous biopsy, is both inconvenient and unsafe with high major complication rates [16-18]. Besides it was mentioned that it had no advantage in defining the nature of the adrenal masses. Therefore we find it a reasonable way to do the adrenalectomy first and proceed with donor nephrectomy if the frozen section examination reveals a benign lesion. The validity of our approach to living kidney donors with adrenal incidentalomas can be questioned and performing adrenalectomy to these patients may be regarded as over treatment. These are the patients who would be followed on active surveillance rather than receive surgery for their adrenal lesions outside of the context of donor nephrectomy. The interesting question here would have been "why remove these adrenal glands at the time of donor nephrectomy if they would not normally be removed under other circumstances?" The American Association of Clinical Endocrinologists and Association of Endocrine Surgeons guidelines recommend follow-up for incidentalomas smaller than 4 cm and for radiologic findings consistent with benign lesions [19]. Accordingly, radiological reevaluation should be performed in any hormonally inactive patient with a lesion smaller than 4 cm at 3 to 6 months and then annually for 2 years. Hormonal evaluation should also be performed at the time of diagnosis and every year for 5 years. This
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is the standard approach for any patient diagnosed with AI. We think that there are downsides to this approach in the potential kidney donor. Notably, one would not be able to rule out any potential malignancy even though the lesion is even less than 2 cm and this would make the donation process unsafe. Moreover, the risk of increment in size during the following 1st, 2nd and 5th years were estimated to be 6%, 14% and 29% respectively. The risk of transition into a hormonally active form during the same periods of time has been reported to be 17%, 29% and 47%, respectively [20]. There are no well-defined risk factors that show which masses will gain function or have malignant degeneration in long term. Thus, a donor may have to suffer a second operation in the future. In this case, having a laparoscopic adrenal surgery will be more challenging giving the fact that the patient has already had an ipsilateral previous donor nephrectomy. We believe adrenalectomy concomitant with ipsilateral donor nephrectomy is a viable option in potential donors with AI.
Conclusion In our study we have observed that although, the addition of the laparoscopic adrenalectomy to laparoscopic donor nephrectomy increases the operative time, it does not increase the intraoperative complication rates. A safe surgery for a donor operation is of paramount importance and adding an adrenalectomy to the donor operation does not jeopardize the safety of the donor operation and does not increase the morbidity of the operation. However, justification of concomitant adrenalectomy should be argued to the patients and follow-up option could be discussed in detail with its own risks. In our cases all patients with adrenal incidentaloma rejected the follow-up option. Although our study was conducted on a small group of patients in a retrograde fashion, there are no retrospective or prospective randomized studies in the literature evaluating long term results of performing adrenalectomy versus follow up in living kidney donor population with AI. At the very least,
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we suppose, this work should provide a published precedent for not excluding donor candidates solely based on the presence of a small, nonfunctional adrenal incidentaloma suitable for active surveillance.
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Figure-1 Our Algorithm for managing living donor candidates with adrenal incidentalomas Figure-2 Distribution of the living kidney donor candidates
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Table-1 Patient demographics and postoperative complication rates
AGE GENDER (M/F) BMI OPERATIVE TIME (MIN) POSTOP STAY (DAYS) PEROPERATIVE COMP. POSTOP EARLY COMP. POSTOP LATE COMP. CONVERSION (MIN)
DONORS WITHOUT ID 46 ± 13.2 375/461 27.4 ± 4.8 82 ± 23.1
DONOR WITH ID
P VALUE
56 ± 11.7 4/9 30 ± 2.7 97.6 ± 20.4
0.009 0.31 0.016 0.021
2.35 ± 0.79
2.6 ± 1.64
0.82
21/836
1/13
0.24
61/836
1/13
0.95
12/836
1/13
0.68
7/836
0/13
0.74
Table-2 Reasons for conversion to open surgery Reason for conversion to open surgery Bleeding from adrenal gland Vascular stapler failure Renal vein injury Renal artery injury
Number of the patient 2 3 1 1
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