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Synchronous renal and adrenal masses: an analysis of 80 cases
Armita Bahrami MDa, Luan D. Truong MDa, b, Steven S. Shen MD, PhDb and Bhuvaneswari Krishnan MDa, c, Corresponding Author Contact Information, E-mail The Corresponding Author
aBaylor College of Medicine, Houston, TX, USA
bThe Methodist Hospital, Weill Medical College of Cornell University, Houston, TX, USA
cMichael E. DeBakey VA Medical Center, Houston, TX, USA
Available online 5 September 2008.
Abstract
Synchronous renal and adrenal masses are uncommon. Although adrenal masses in the context of renal cell carcinoma (RCC) are often suspected as metastasis, other adrenal lesions with different therapeutic and prognostic implications may coexist with RCC. In a retrospective review of 550 radical nephrectomies with ipsilateral adrenalectomy, 80 cases of coexisting renal and adrenal masses were identified. The renal masses included 76 RCCs, 3 oncocytomas, and 1 malignant pheochromocytoma of adrenal gland involving the kidney. Although the gross pathologic impression of adrenal masses in the presence of RCC was metastasis, on histologic examination, 56% of them were found to be benign lesions (mostly adrenal adenoma/hyperplasia), whereas malignant involvement from RCC was seen in 43%. The benign and malignant nature of the adrenal lesions in the context of RCC could not be discriminated based on the size of adrenal mass. Because of the prognostic implication of direct or metastatic involvement of adrenal gland in the setting of RCC and the possibility of finding small metastatic foci, a meticulous gross and microscopic examination of adrenal glands is emphasized. Rare unusual combinations of renal and adrenal lesions such as RCC and adrenal histoplasmosis, RCC and adrenal myelolipoma, renal oncocytoma, and adrenal pheochromocytoma are also described.
Keywords: Renal cell carcinoma; Adrenal tumors; Synchronous renal and adrenal tumors; Renal tumors; Benign adrenal tumors; Malignant adrenal tumors; Adrenal metastasis
Article Outline
1. Introduction
2. Materials and methods
3. Results
4. Discussion
References
1. Introduction
Simultaneous renal and adrenal masses at presentation are uncommon. Because approximately 80% to 85% of isolated renal masses represent renal cell carcinomas (RCCs), the detection of both adrenal and renal masses is generally considered metastatic RCC in the adrenal gland. On the other hand, a high prevalence of asymptomatic adrenal tumors has been reported in autopsy series where adrenal adenomas greater than 1 cm were seen in 1.5% to 7% of cases [1]. With the advent of sensitive imaging techniques and their increased clinical utility, small lesions of both the kidney and adrenal gland are often discovered. In view of the common existence of benign adrenal masses, the likelihood of metastasis in the setting of simultaneous renal and adrenal masses has not been previously analyzed.
2. Materials and methods
The pathology reports of 550 radical nephrectomy specimens performed at The Methodist Hospital and Michael E. DeBakey VA Medical Center in Houston, Tex, between January 1988 and August 2006 were reviewed for synchronous renal and adrenal lesions. Only grossly and/or radiologically detected lesions, which on subsequent microscopic examination were found to represent distinct pathological entities, were considered for the study. The demographic data and pathological characteristics of these cases were subsequently reviewed.
3. Results
Of the 550 radical nephrectomy specimens, 80 (15%) had simultaneous adrenal and renal lesions. The patients included 67 men and 13 women, ranging from 35 to 77 years of age (mean, 63 years). The incidence of primary benign lesions of the adrenal gland was 8.1% (45/550), whereas the incidence of metastatic tumor and direct extension from RCC were 3.5% (19/550) and 2.7% (15/550), respectively.
The most frequent combinations of renal/adrenal lesions included RCC and adenoma/hyperplasia (37/80, 44%), RCC and adrenal metastasis (19/80, 24%), and RCC and contiguous spread to adrenal gland (15/80, 19%). Unusual coexisting renal and adrenal masses were also encountered, including RCC and histoplasmosis of the adrenal gland, RCC and adrenal myelolipoma, oncocytoma and pheochromocytoma, and a malignant pheochromocytoma invading the kidney. The details of these cases are summarized in Table 1.
Table 1.
Histologic characteristics of synchronous renal and adrenal masses
Adrenal masses (no. of cases) [size range] Renal Masses (no. of cases) [size range]
Cortical adenoma or hyperplasia (37) [0.5-3.5 cm] Clear cell (27), papillary (6), chromophobe (2), oncocytoma (2) [2-22 cm]
Metastatic RCC (19) [0.5-9 cm] Clear cell (17), papillary (2) [2.5-12 cm]
Contiguous spread of RCC (15) Clear cell (11), unclassified (2), papillary (1), collecting duct (1) [4-18 cm]
Pheochromocytoma (4) [2.8-3.3 cm] Clear cell (2) [1.5-4.5 cm], oncocytoma (1) [1.8], pheochromocytoma invading kidney (1) [10 cm]
Myelolipoma (1) [6.5 cm] Clear cell (1) [2.5 cm]
Histoplasma infection (1) [8 cm] Clear cell (1) [7.5 cm]
Hemangioma (2) [0.5 cm, 1.6 cm] Clear cell (2) [8 cm, 8.5 cm]
Benign cyst (1) [1.5 cm] Clear cell (1) [4 cm]
Full-size table
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The renal lesions included 62 (79%) conventional clear cell RCC, 9 (11%) papillary RCCs, 2 (2.5%) chromophobe RCCs, 3 (3.75%) oncocytomas, 2 (2.5%) unclassified RCCs, 1 (1%) collecting duct carcinoma, and 1 (1%) adrenal pheochromocytoma with direct extension to the kidney (Table 1). The overall mean size of renal tumor was 8.1 cm (range, 1-22 cm). The average size of RCCs without simultaneous adrenal involvement was 5.3 cm (range, 1-14.9 cm), the mean size of RCCs with adrenal metastasis was 8.7 cm (range, 2.5-12 cm), and the average size of RCCs with direct extension to adrenal gland was 10.5 cm (range, 5-18 cm), which reflects combined measurement of the renal and adrenal tumors. The tumor stage among RCCs included T1a, 22 cases; T1b, 9 cases; T2, 4 cases; T3a, 22 cases; T3a and T3b, 10 cases; T3b alone, 3 cases; T3c, 3 cases; and T4, 3 cases. Interestingly, all the patients with T4 tumors also had direct extension of RCC into the adrenal gland. Among the 3 cases with T3c tumors, 1 case also had direct adrenal invasion (T3a) and 2 cases had adrenal metastasis.
The adrenal lesions included 37 (46%) cases of cortical adenoma or hyperplastic nodule, 19 (24%) metastatic RCCs, 15 (19%) contiguous spread of RCC, 4 (5%) pheochromocytomas, and 5 (6%) other lesions, including 2 hemangiomas, 1 myelolipoma, 1 histoplasma infection, and 1 benign cyst (Table 1). Among 19 patients with metastatic RCC, isolated contralateral and bilateral involvement were seen in 1 and 2 cases, respectively. The average size of benign adrenal tumor was 1.7 cm (range, 0.5-8 cm), and the average size of metastatic RCC was 3.7 cm (range, 0.5-9 cm).
The tumor stages of 35 RCCs associated with adrenal adenoma/hyperplasia were as follows: T1a in 20 cases, T1b in 8 cases, T2 in 1 case, T3a (with perirenal and hilar fat invasion) in 5 cases, and T3b (renal vein invasion) in 1 case. The RCCs in 15 cases with direct adrenal extension (T3a) also showed renal vein invasion in 3 (T3b) inferior vena cava involvement above the diaphragm in one (T3c) and tumor invasion beyond the Gerota fascia in 3 (T4). The details of these cases are shown in Table 2. Among the 19 cases with adrenal metastasis, most of the cases showed higher tumor stage (T3) with invasion of the neoplasm into the perirenal adipose tissue. Of the 19 cases, 10 showed invasion of the RCC into the renal vein/inferior vena cava. There was only one T2 and one T1a stage tumor with metastatic adrenal tumor. The details of these cases are shown in the Table 3.
Table 2.
Renal cell carcinomas with direct extension into the adrenal glands
RCC variant Tumor size Tumor stage Tumor grade
Clear cell 5 cm T3a G2
Clear cell 12 cm T3a and T3b G4
Clear cell 17.5 T3a G3
Collecting duct carcinoma 6 cm T3a G4
Clear cell 18 T3a G3
Clear cell 12 T3a, also lung metastasis G4
Papillary type 2 10 cm T4 G4
RCC, unclassified 10.1 cm T3a and T3c G3
RCC, unclassified 8.5 cm T4 G4
Clear cell 9.5 cm T3a G4
Clear cell 8.4 cm T3a G4
Clear cell 9.1 cm T3a, T3b G3
Clear cell 11 cm T3a G3
Clear cell N/A T4 G3
Clear cell 8.3 cm T3a, T3b, lymph node metastasis G3
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Table 3.
Cases of RCC with adrenal metastasis
RCC variant RCC size Adrenal mass Tumor stage Nuclear grade
Clear cell 2.5 0.6 T3a G2
Clear cell 8.5 5 T3a and T3b G3
Clear cell 12 N/A T3a and T3b G3
Clear cell 10.5 N/A T3c G2
Clear cell 12 0.5 T3c G2
Clear cell 4.2 2.2 T3a,T3b, omental metastasis G4
Clear cell 11.7 8.5 T3a andT3b G4
Clear cell 11 3.5 T3a G4
Clear cell 8.5 3.7 T3a G4
Clear cell 11.5 2 T3a G3
Clear cell 11 0.8 T3a and T3b G3
Clear cell 4 0.9 T1a G4
Clear cell 9a N/A T3a and T3b G3
Clear cell 11b N/A T3a and T3b G3
Clear cell 6 0.5 T3a and T3b G3
Clear cell 10.5 9 T3a also lung metastasis G3
Papillary 5.5 0.7c T3a G3
Clear cell 9.8b 7 and 2 cm T2 G3
Papillary Multiple 2-3 cm N/A T3a, lymph node metastasis G3
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a Isolated contralateral adrenal metastasis.
b Metastasis also to contralateral adrenal gland.
c Hemorrhagic mass with foci of micrometastasis.
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4. Discussion
Ipsilateral adrenal metastasis has been reported in 1.2% to 10% of RCCs [2], [3], [4], [5], [6], [7], [8], [9], [10] and [11]. Although ipsilateral adrenal removal has been traditionally performed routinely in conjunction with radical nephrectomy, the benefit of this practice has long been under scrutiny [3], [5], [7] and [12]. Several authors have advocated against concomitant adrenalectomy as a standard procedure for smaller renal tumors with grossly normal adrenal gland and without radiographic evidence of adrenal disease. These conclusions were based on the low incidence of malignant involvement on pathologic examination of grossly unremarkable adrenal glands and the relatively high sensitivity of imaging modalities in detecting adrenal lesions [3], [4], [5], [13], [14], [15] and [16]. The habitual practice of unilateral adrenalectomy in renal surgery has also been discouraged due to the likelihood of irreversible impairment of the adrenocortical functional reserve [17]. Based on these observations, most authors advise adrenal sparing nephrectomy, unless there is a clear indication, including positive radiography for adrenal involvement, a large upper pole renal tumor, or a gross adrenal lesion seen at the time of nephrectomy [2], [3], [5], [6], [7], [12], [16], [18], [19] and [20] R. von Knobloch, F. Seseke and H. Riedmiller et al., Radical nephrectomy for renal cell carcinoma: is adrenalectomy necessary?, Eur Urol 36 (1999), pp. 303–308. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (34)[20].
Although detecting a gross adrenal mass during renal surgery is a clear indication for concomitant ipsilateral adrenalectomy, the odds of adrenal malignant involvement by RCC when a gross lesion is discerned has not been previously discussed. Although in our series, the gross pathologic impression of adrenal masses in the presence of a primary renal neoplasm was mainly metastasis from RCC, histologically, we found that most of these lesions (43/77, 56%) represented other entities, among which adrenal adenoma/hyperplasia was the most common. On the other hand, malignant invasion, either as a direct extension or as a result of hematogenous spread, accounted for less than half of the cases (43%).
As demonstrated in Table 1, there was no correlation between the size of adrenal lesions and their benign or malignant nature. Of note, in 2 of the adrenal metastatic tumors, the size of gross lesions was only 0.5 cm in diameter, supporting the notion that careful examination of any suspicious adrenal lesion, regardless of its size, is essential. In addition, because of the lack of reliable distinctive gross features, microscopic evaluation is mandatory to determine the nature of these lesions. Although the initial design of our study specifies inclusion of only cases of grossly and/or radiologically detectable adrenal lesions, we did not find any cases of metastasis detected by microscopic examination that was not observed on gross examination.
The likelihood of adrenal metastasis has been shown to be higher in RCCs of higher stage and larger size. In a study of 511 patients undergoing radical nephrectomy with ipsilateral adrenalectomy for RCC, the probability of adrenal spread correlated with tumor stage, with T4, T3, and T1-T2 tumors accounting for 40%, 7.8%, and 0.6% of cases, respectively [3]. Consistent with these findings, in our series, 17 of the 19 cases with adrenal metastasis were stage T3 RCCs; whereas only 1 case of T2 lesion and 1 case of T1a lesion showed metastasis, the latter in fact was a Fuhrman's nuclear grade 4 RCC. In our case series, the mean size of renal tumor with adrenal metastasis was 8.7 cm, which was significantly larger than the mean size of tumors without adrenal involvement (5.3 cm) (P value<.01). Li et al [8] in their study of 129 RCCs found no adrenal invasion by tumors of less than 5 cm in diameter. All the patients with adrenal involvement were either grade 3 or 4 with pT2 or T3 lesions. In our series, 3 of the 19 adrenal metastases were derived from RCCs smaller than 5 cm in diameter; the smallest of which was a 2.5 cm RCC associated with a 0.6-cm focus of adrenal metastasis. In 2 of these cases, although the tumors were small (2.5 and 4.2 cm), they were T3a lesions with invasion into the perirenal fat, and one of them also had vena cava invasion (T3b). The third case was a T1a lesion but showed a nuclear grade of 4 (Table 3). Our findings indicate that the nuclear grade and tumor stage are better predictors of adrenal metastasis than simply the size of tumor.
Adrenal involvement in the setting of RCC has important prognostic implications. Ipsilateral adrenal invasion by direct extension is classified as a pT3a in the American Joint Committee on Cancer staging system, whereas involvement by hematogenous route defines a stage IV or metastatic tumor. In general, the presence of adrenal metastasis has been shown to be associated with a poor outcome in patients with RCC [4], [5], [6] and [10]. In the follow-up on 4 of our patients with adrenal metastasis, 3 patients died of disease within 1 to 2 years of diagnosis, whereas 1 patient with a T3a tumor and a very small (0.9 cm) adrenal metastasis was alive with no evidence of disease, 15 years after the nephrectomy. Although a number of studies have found some improvement in the survival of a subset of patients with RCC who had an isolated adrenal metastasis and underwent metastasis removal [18], [21], [22] and [23], others experienced no significant benefit in patients' survival from ipsilateral adrenalectomy [14] and [19].
In the current American Joint Committee on Cancer staging system RCC, invasion into the perirenal fat, renal sinus, and direct invasion of the adrenal gland are considered as pT3a tumors. There is significant controversy about combining all 3 in 1 category as pT3a tumors. Han et al [24] have shown that direct invasion of RCC into the adrenal gland has a worse prognosis than perinephric fat or renal sinus invasion. They suggested considering direct extension of RCC into the adrenal gland as a T4 tumor instead of T3a because its prognostic characteristics were similar to that of T4 tumors [24]. In addition, tumors with renal sinus invasion showed more aggressive behavior than those with perinephric fat invasion [25] and [26]. From these studies, it appears that the T3a tumors are heterogeneous and should be further subclassified based on the site of invasion.
The incidence of adrenal gland involvement by RCC is very low. In our study of 550 RCCs, there was a 2.7% incidence of direct extension of RCC and a 3.5% incidence of adrenal metastasis. Given the fact that the patients with both direct adrenal invasion and metastasis had dismal prognosis, a large number of cases must be studied to determine if there is any difference in the prognosis in these groups.
We found an overall higher incidence of adrenal pathologic abnormalities (15%) compared with the 6.5% incidence reported from Antonelli et al [22], in a study of 914 radical nephrectomy specimens. This discrepancy may be due to inclusion of both gross and/or radiological abnormalities in our study and the inclusion of only radiologically detected adrenal lesions in their study. The patients' mean age in their series (61.5 years) was comparable to that in our study (62 years). The prevalence of benign pathologic entities of the adrenal gland and the incidence of metastatic adrenal and direct infiltration from a renal primary in their study were reportedly 3%, 2.7%, and 0.8%, respectively.
We observed some uncommon findings in our series, including a case of an isolated contralateral metastasis to the left adrenal gland from a 9-cm right RCC. Very few examples of contralateral adrenal metastasis from RCC have been reported in the literature. The largest series was reported from the Mayo Clinic of 11 patients, 2 with synchronous and 9 with metachronous metastases [8], [27], [28] and [29]. Although the most common sites of metastatic RCC are the lungs, abdominal organs, bones, and brain [30], the contralateral adrenal gland is the sole metastatic site in only 2.5%, according to an autopsy study of more than 400 patients with RCC [31]. Our series also included 2 cases of an uncommon bilateral involvement of adrenal glands [32] and [33] from a 7-cm and an 11-cm RCC.
There were also a number of uncommon coexisting renal and adrenal lesions in our series. Although only a handful of ipsi- or contralateral adrenal myelolipoma associated with RCC have been reported in the literature [34], [35], [36], [37] and [38], our report adds 2 additional examples: a case of adrenal myelolipoma presenting as a 6.5-cm lesion in association with a 2.5-cm RCC (Fig. 1A-C) and another case of an incidental microscopic focus of adrenal myelolipoma. The later was, however, not included in the study because no gross abnormalities were seen in the adrenal gland. Myelolipoma can be an incidentaloma of the adrenal gland or can also present as a large mass. Hemorrhage is a complication of large myelolipomas. The pathogenesis of myelolipoma is not definitively known, but recently, a clonal proliferation of both hematopoietic elements and adipose tissue has been demonstrated in this entity [39].
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Fig. 1. (A) Gross photograph of radical nephrectomy containing a partly cystic RCC and a myelolipoma in the adrenal gland. (B) The neoplasm in the kidney showing clear cell RCC, with rich vascularity and the neoplastic cells with clear cytoplasm. (C) The concomitant adrenal mass showing myelolipoma in the ipsilateral adrenal gland. Myeloid and erythroid precursors admixed with megakaryocytes and scant adipose tissue is present.
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One of the nephrectomy contained a 7.5-cm RCC and an 8-cm histoplasma granuloma in the ipsilateral adrenal gland, characterized by a granulomatous inflammation associated with histoplasma organisms. Although an infrequent cause of adrenal mass, adrenal histoplasmosis may unusually affect immunocompetent hosts and exhibit variable imaging features [40]. They can present as unilateral or bilateral adrenal masses and rarely cause adrenal insufficiency. Histoplasmosis, therefore, should be included in the differential diagnosis of incidentally discovered adrenal masses.
The coexistence of RCC and adrenal pheochromocytoma is infrequent. The combination of pheochromocytoma and multiple clear cell RCC in a young patient should always raise the possibility of Von Hippel Lindau (VHL) syndrome. In this study, a 36-year-old man with VHL syndrome had multiple clear cell RCC and bilateral adrenal pheochromocytomas. This combination of multiple RCC and pheochromocytoma is seen in type 2b VHL syndrome (Fig. 2A-B) [41]. Von Hippel Lindau disease is an autosomal dominant hereditary syndrome, characterized by a germline mutation in the VHL gene. The carriers are predisposed to tumors in multiple organs, including hemangioblastoma in the retina and central nervous system, RCC, pheochromocytoma, and islet cell tumors of the pancreas. Clear cell RCC has been found to occur in up to 70% of these patients [42]. In a germline mutation, analysis performed in a large study of 469 families with VHL from North America, Europe, and Japan, the various cancer phenotypes included RCC without pheochromocytoma, RCC with pheochromocytoma, and pheochromocytoma alone [43]. Based on the earlier reports, metastatic RCC has been a common cause of death in patients with VHL [44].
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Fig. 2. Concurrent RCC and adrenal pheochromocytoma. (A) Clear cell RCC in the kidney. The adjacent normal kidney is also seen. (B) The adrenal mass showing a pheochromocytoma with a nested pattern and rich vascularity. Adjacent normal adrenal gland is seen.
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Two other pheochromocytomas in our series were sporadic tumors. One was in a 59-year-old man with a 1.5-cm grade 2 clear cell RCC and a 2.8-cm adrenal pheochromocytoma. The second case was from a 77-year-old man with a 1.8-cm oncocytoma and a 3.3-cm adrenal pheochromocytoma (Fig. 3A-C). This combination of renal and adrenal tumors is extremely rare, and to the best of our knowledge, only 2 such cases have been previously reported [45] and [46]. Our series also included a very rare case of malignant adrenal pheochromocytoma with invasion into the kidney. No primary renal tumor was found in the kidney.
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Fig. 3. Concurrent renal oncocytoma and adrenal pheochromocytoma. (A) Renal oncocytoma showing solid islands and dilated tubules with cells containing eosinophilic granular cytoplasm. A loose scant cellular stroma is present. (B) adrenal pheochromocytoma with a solid pattern. Adjacent normal adrenal gland is present. (C) Higher magnification of the adrenal tumor showing some spindled cells with abundant granular cytoplasm. The cytoplasm has a brownish hue due to the presence of melanin.
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In summary, although less than half of the grossly discovered adrenal lesions in association with RCC in our series were found to represent malignant involvement by RCC, due to the significant prognostic consequence of adrenal metastasis and the possibility of small metastatic foci in adrenal glands, meticulous gross and microscopic examination of adrenal glands removed during renal surgery is crucial. Nevertheless, other pathologic entities, including benign or malignant adrenal primaries, as well as nonneoplastic lesions, should also be included in the differential diagnosis. When the adrenal mass is larger than the renal mass, pathological entities other than metastatic RCC should be considered.
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[28] A. Stein, Y. Mecz and Y. Sova et al., Synchronous and metachronous contralateral adrenal metastases from primary renal cell carcinoma, Urol Int 58 (1997), pp. 58–60. View Record in Scopus | Cited By in Scopus (5)
[29] P. Sapienza, F. Stipa and G. Lucandri et al., Renal carcinoma with a solitary synchronous contralateral adrenal metastasis: a case report, Anticancer Res 17 (1997), pp. 743–747. View Record in Scopus | Cited By in Scopus (9)
[30] J.M. Kozlowski, Management of distant solitary recurrence in the patient with renal cancer. Contralateral kidney and other sites, Urol Clin North Am 21 (1994), pp. 601–624. View Record in Scopus | Cited By in Scopus (42)
[31] H. Saitoh, M. Nakayama, K. Nakamura and T. Satoh, Distant metastasis of renal adenocarcinoma in nephrectomized cases, J Urol 127 (1982), pp. 1092–1095. View Record in Scopus | Cited By in Scopus (74)
[32] F. Masuda, H. Suzuki and M. Suzuki, Bilateral adrenal metastasis from renal cell carcinoma, Hinyokika Kiyo 38 (1992), pp. 933–935. View Record in Scopus | Cited By in Scopus (2)
[33] R. Rabii, A. Joual and K. Naciri et al., Isolated bilateral adrenal metastasis from renal cancer. Case report, Ann Urol (Paris) 33 (1999), pp. 418–420. View Record in Scopus | Cited By in Scopus (1)
[34] K. Matsumoto, O. Takahashi and H. Yajima, A case of adrenal myelolipoma associated with renal cell carcinoma, Hinyokika Kiyo 39 (1993), pp. 29–32. View Record in Scopus | Cited By in Scopus (2)
[35] R. Campagnacci, M. Guerrieri and A. De Sanctis et al., Laparoscopic radiofrequency renal ablation in patients with simultaneous visceral tumors: long-term follow-up, J Endourol 20 (2006), pp. 321–325. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (3)
[36] M.M. El Mekresh, M. Abdel-Gawad and T. El Diasty et al., Clinical, radiological and histological features of adrenal myelolipoma: review and experience with a further eight cases, Br J Urol 78 (1996), pp. 345–350. View Record in Scopus | Cited By in Scopus (17)
[37] G. Hofmockel, J. Dammrich and G.H. Manzanilla et al., Myelolipoma of the adrenal gland associated with contralateral renal cell carcinoma: case report and review of the literature, J Urol 153 (1995), pp. 129–132. Abstract | Article | PDF (920 K) | Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (26)
[38] M.C. Sharma, S. Kashyap and R. Sharma et al., Symptomatic adrenal myelolipoma. Clinicopathological analysis of 7 cases and brief review of the literature, Urol Int 59 (1997), pp. 119–124. View Record in Scopus | Cited By in Scopus (14)
[39] E. Bishop, J.N. Eble and L. Cheng et al., Adrenal myelolipomas show nonrandom X-chromosome inactivation in hematopoietic elements and fat: Support for a clonal origin of myelolipomas, Am J Surg Pathol 30 (2006), pp. 838–843. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (6)
[40] N. Kumar, S. Singh and S. Govil, Adrenal histoplasmosis: clinical presentation and imaging features in nine cases, Abdom Imaging 28 (2003), pp. 703–708. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (14)
[41] R.A. DeLellis, R.V. Lloyd, P.U. Heitz and C. Eng, Pathology and genetics of tumours of endocrine organs, World Health Organization Classification of Tumours, IARC Press, Lyon, France (2004), p. 151.
[42] C.A. Friedrich, Von Hippel-Lindau syndrome. A pleomorphic condition, Cancer 86 (1999), pp. 2478–2482. View Record in Scopus | Cited By in Scopus (48)
[43] B. Zbar, T. Kishida and F. Chen et al., Germline mutations in the Von Hippel-Lindau disease (VHL) gene in families from North America, Europe, and Japan, Hum Mutat 8 (1996), pp. 348–357. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (242)
[44] E.R. Maher, J.R. Yates and R. Harries et al., Clinical features and natural history of von Hippel-Lindau disease, Q J Med 77 (1990), pp. 1151–1163. View Record in Scopus | Cited By in Scopus (287)
[45] M.A. Rado Valazquez, M.A. Correas Gomez and B. Martin Garcia et al., Synchronous renal oncocytoma and asymptomatic pheochromocytoma. Report of a case, Arch Esp Urol 54 (2001), pp. 816–819.
[46] G. Daskalopoulos, D. Delakas and N. Charoulakis et al., Coexisting non-functioning pheochromocytoma and renal oncocytoma: a case report and review of the literature, Eur J Radiol 23 (1996), pp. 138–142. Article | PDF (534 K) | View Record in Scopus | Cited By in Scopus (4)
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Lagi-lagi soal membuat fasilitas Read more.. atau Selengkapnya.. pada template baru (XML), topik ini rupanya yang paling banyak di baca dan di minati oleh para blogger baru. Hal ini terlihat dari banyaknya komentar yang masuk pada artikel tersebut, ada yang girang karena sudah merasa berhasil dan ada juga yang sedikit kecewa karena masih menemui kegagalan.
Dengan masih adanya kegagalan-kegagalan tersebut, maka dapat di tarik kesimpulan bahwa metode yang saya sampaikan ternyata masih kurang untuk di pahami. Dari itu tentu harus di pikirkan cara yang tepat dalam penyampaian suatu panduan. Beberapa waktu yang lalu ada sebuah komentar yang masuk pada salah satu artikel saya (artikel yang mana saya lupa dan sedikit malas untuk membuka dokumen komentar) bahwa metoda penyampaian tersebut sangatlah mudah untuk di pahami, maka pada kesempatan kali ini saya akan mencoba metoda tersebut pada artikel membuat fungsi Read more.. atau Selengkapnya...
adadeh
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French lessons: Leadership in Alzheimer's disease
French lessons: Leadership in Alzheimer's disease
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1. Inauguration Day – Two Translations
It is impossible to forecast anything at the beginning of 2009 about health policy in general, or Alzheimer's disease (AD) specifically, that is not both optimistic and cautionary. Our new President, Barack Obama, who spent the campaign energizing the nation about prospects for change, is hunkered down with advisors tackling our financial and economic crises and remapping the nation's foreign affairs. But if the multiple plans for health insurance reform that have started appearing from Congress are any indication, we may well be in store for serious and sustained leadership on this front in the near term.
However there is something very troubling about this new start on healthcare: it's all become about paying for it. Somewhere over the past few months, it has become impossible -- or at least it seems irresponsible -- to think about healthcare in anything but monetary terms. How will we save Medicare and Medicaid? How will we fight profiteering within the insurance and managed care industries and move to reimbursement that covers more (all) of us? How will business owners, large and small, stay afloat while subsidizing employee health costs? How will American families manage our own stretched healthcare budgets?These are important, fundamental questions to be sure, especially given our domestic and global economic crises, and the burst of governmental spending to manage them. But shouldn't we also be having a simultaneous discussion about prevention of illness and how to provide the actual care – how, in fact, to make the fruits of world leadership in medical research available to more Americans in the form of compassionate care? Before we close the patient file and move on to reimbursement exclusively, are there not other equally fundamental questions about our duty to care?
Any consideration of this complex question—beyond one or two slogans in policy speeches—is now seen as frivolous and not pertinent. In fact, I think these questions are im-pertinent, in the best possible sense. And in the lingo of the day, we can no longer afford not to ask them.
For a study in contrasts, consider another January 2009 Presidential inauguration—that of the President of the Czech Republic, Vaclav Klaus, as rotating President of the European Union. Outgoing EU President, France's Nicolas Sarkozy, will collaborate with Klaus closely on priority issues, as is the custom of the essentially shared European Presidency. And among the EU's top priorities, alongside banking industry reform, will be the first disease-specific pan-EU plan ever – to fight AD.
How AD has risen to the top of European awareness is largely a tribute to President Sarkozy, who tirelessly lobbied for a pan-EU version of what he has accomplished at the national French level: a comprehensive “French Alzheimer's Plan” that integrates brave new initiatives in research, caregiving, and medical and public education in a plan that is already funded by the French government and widely embraced by most of the nation.
Granted, Sarkozy's pan-EU AD proposal still faces a polyglot of political challenges from a loose alliance of diverse nations that, individually, do not share France's passion for a fight against AD. Granted, some steps have already been taken on AD efforts by other individual member nations: Germany has made enormous advances in clinical research; the United Kingdom is developing more supportive care giving and social support services; while Italy, Norway and Finland are also beginning to respond to the coming epidemic. Still, it may be hard to sell France's much more comprehensive approach on the larger European stage. But this just added fire to Sarkozy's passionate argument for a pan-EU plan at a special Presidential meeting of EU legislators and AD leaders from around the world who met in Paris on October 30, 2008.
What emerged at the Paris meeting in detailed reports on the French plan and speculation on a pan-EU version was precisely what we do not hear from any of the healthcare discourse in the US today: Sarkozy's AD plan is about the goal of patient-centered, preventive care, not just the business of funding it. It is also a deeply personal commitment from a national leader about moral duty first and foremost. Stunning.
As Sarkosy explained when he first announced the initial French plan in February, 2008:
We are confronted with a disease that is far more than a dysfunction. Alzheimer's and related diseases are a rupture in human existence.
A rupture because Alzheimer's is alterity that we do not want to see for what it is. It is more comfortable to live in a state of individualism, ignoring others. Alzheimer's disease demands solidarity and not resignation.
A rupture because Alzheimer's disease plays with time. It makes the past unbearable for the sufferer and the present unbearable for carers. When will this illness get the better of my wife, my husband, my mother, my father? Every family asks itself this question every day.
A rupture because Alzheimer's disease seems to resist our dream of being all-powerful. This disease plays hide-and-seek with researchers. The most promising avenues today could be deadends tomorrow.1
But to his credit as a politician, this personal immediacy has been transformed into a compelling political imperative:
It seems that Europe must fully commit itself to the fight against Alzheimer's disease because its values are at stake.
The Charter of Fundamental Rights of the European Union recalls our duty to preserve the dignity of infirm persons. Respecting the dignity of human beings is at the heart of European democratic values. After the horrors which traversed our continent for the duration of the twentieth century, respect of the dignity of the person is an absolute imperative for us all at the dawn of the twenty-first century.
Solidarity is another founding value of Europe. Despite their differences in terms of organisation, our systems of solidarity all rely on the State, on social partners, businesses and individual responsibility. In all European countries there is a system which protects individuals from the vagaries of life. It is a profoundly European value to leave no one behind. The systems of solidarity must evolve in order to be more efficient and to motivate work. But they must be preserved in their ultimate objective. We cannot renounce that which constitutes our fundamental nature as Europeans.2
In an American moment when we too have a new President with enormous personal commitment, what we need is this degree of clarity about why we must change healthcare, not just how we will pay for it.
2. A Master Plan – Unifying the Science
The French Alzheimer's Plan—administered by Sarkozy appointees: Florence Lustman, Inspector General of Finances for France; Philippe Amouyel, Professor of Public Health at the University of Lille; and Raphaël Radanne, special health advisor to President Sarkozy—has authorized 1.6 billion Euros (or a little over $2 billion US) over 5 years, including 200 million Euros for research, 200 million for patient care and 1.2 billion for social and family support.3 Tellingly, it is difficult to compare this figure with a similar grand total for US AD spending primarily because no one is keeping coordinated records on the various efforts, and no one is thinking five years ahead. But clearly the most important piece of the US AD puzzle is the approved 2008 National Institutes of Health commitment of $644 million for research – the lowest NIH spend since 2005.4 We can count on millions more in private research and development, but still what remains absent are the other components of a coordinated plan to address an epidemic in the minds of a nation – an understanding of the patient, care giver support, education, a vision of what will happen if we do nothing, and a commitment to preventing it. Certainly some efforts are being made to address these issues, but not by a centralized force – governmental, private or public – and not with any national priority.
In contrast, the French plan will support 44 specific objectives divided around 10 key measures. Seen as a whole, the plan seeks to provide better treatment and support for patients and caregivers through a single source of contact, and speed up research by creating a Foundation for Scientific Cooperation.5 According to Sarkozy,
The trademark of the French Alzheimer's Plan is to integrate research, treatment and support. Our aim is not only to intensify our effort in each of these separate areas. Our aim is also to develop synergies between each of them in order to improve the quality of life of afflicted persons and their families.6
In an interview with Alzheimer's & Dementia, Sarkozy's principal implementer for the French Alzheimer's plan, Florence Lustman, suggests that this integrative approach will make good use of scientific advances now and in years to come:
Both the United States and Europe can learn from each other. The USA has been a leader in Alzheimer's research since 1978…while the French Alzheimer's plan is the…first one to deal with research. Its originality is to integrate all aspects of the fight against the disease in order to serve better the patients and family carers. In the medium term, research will enable us to delay or treat the disease but in the short term, patients must be helped to cope with an early and supported diagnosis, and their quality of life must be improved with non-pharmacological therapies that can help them stay at home longer.7
The chief architect of the French plan is leading cardiologist Dr. Jöel Ménard, and as a man of science, his first focus was coordinating the best that France already has to offer on a diversity of clinical fronts, seeding new leaders and lines of research, and integrating it all so that it best serves France, the European Union, and beyond. Highlights of the scientific initiative include:
• Reinforcing current strengths by facilitating the work of multi-disciplinary centers with strong previous scientific production and exploiting population cohorts, participation in genome-scan studies, better use of experimental models already developed in France, such as the microcebe.
• Attracting new teams from experts connected with existing teams, and opening new fields, such as cellular biology, systems biology, vascular biology, immunology.
• Attracting forty young researchers per year through a national program and training 10 more PhD and post-doctoral researchers per year.
• Training 1500 additional professionals in clinical epidemiology, etiology, diagnosis, prognostic, therapeutic trials, and meta-analysis.
• Recruiting Associate Professors from the pharmaceutical and diagnostics industries to teach the new generation of AD professionals.8
Already there are new French scientific working groups in controlled clinical trials and prospective studies, neuropsychology and clinical investigation, neuro-imaging, biomarkers, genetics, animal models, cell biology and neuropathology.9 In an interview with Alzheimer's & Dementia, Dr. Ménard explained that these efforts will systematically explore and integrate insights on new technologies as diverse as:
Experimental and cellular models, to the possibilities of performing more sophisticated neuropsychological, biochemical and functional imaging studies in humans…Also, a national Center for Genetic Alzheimer diseases will be created, on the model of what is done for other diseases, such as mucoviscidose, myopathies, and others.10
And to assure that the new advances are efficiently shared to expedite clinical application, Dr. Ménard has planned:
…a global information system to have the most comprehensive database on issues like Alzheimer's-related hospitalization causes and duration of hospital stays, practices for attributing mortality to Alzheimer's on death certificates, population and incidence studies, prediction models on prevalence and incidence special cohort studies, best practices on structure for standardized and computerized medical dossiers, surveys of awareness and perceptions of AD among the general population, research applications, and synthesis of research results11
3. La Condition humaine
Just as systematic as its scientific infrastructure is France's commitment to refocusing care on the patient throughout the process. The planned systems of psycho-social support start at point of diagnosis and respect the wide range of needs implicit in AD care through the entire disease cycle. Under the French Plan, family interventions begin at diagnosis and every effort is being made to make those assessments earlier and earlier. Primary care physicians are actively engaged in diagnosis as well as long term supervision of care. According to Sarkozy:
Faced with a disease for which there is often no real treatment, it is a duty to explain, reassure and guide the patient and his/her loved ones…The [diagnosis] must go hand in hand with informing the patient about available support. This is why we will be creating Centres for the Autonomy and Integration of Alzheimer's Patients. These centres will be an anchor point for families.12
The value of this approach to a care continuum will be clear to anyone running the care giving gauntlet in the US. Here, a patient and family are given a diagnosis, usually two years after onset, and then left to find their way through loosely linked social service networks that hand off patient and family in an uncoordinated fashion that often ends up compromising both patient and caregiver, leaving essential issues unresolved.
And finally, growing from the same understanding of the central role of the patient and family, Sarkozy has called for a Europe-wide reevaluation of the “ethics of Alzheimer's,” by which he means the rights of the patient, the family and the nation: legal status of AD patients in institutions, informed consent around end-of-life decisions, treatments, and clinical trials. Sarkozy asks:
How should we obtain the consent of a person to enter a nursing home? How can we reconcile the respect of the patient's autonomy and their security? What attitude is appropriate with regard to a person who has lost all their usual means of communicating? How can we adapt treatment to a person's preferences? What role can carers play to assist the patient in expressing their choice?
These are all concrete questions for which we must find ethical answers. Faced with such questions, we cannot settle for purely technical replies, nor is it possible either to confine ourselves to a purely compassionate register. Legislation must help in clarifying certain situations. However, it is the behaviour of each one of us faced with suffering and the gradual disappearance of the afflicted person's autonomy that takes precedence. Well-informed behaviour, based in every circumstance on the respect for the dignity of the person, is essential. There are no universal rules in this area. While the principle of the respect of dignity is universal, its concrete application depends on the situation of the afflicted person, their family and their environment.13
4. Toward a Global AD Plan
Sarkozy and his team are already looking beyond a pan-EU AD plan in some of the world's first realistic overtures toward a global approach. At the moment, these are overtures to learn from the different ways AD is managed in different cultures. Sarkozy's special health advisor, Raphaël Radanne, talked with us about some of the more apparent opportunities:
A fruitful collaboration could certainly engage between Europe and the USA concerning research (for instance on the subjects currently being identified for European cooperation such as large intervention studies, studies on young onset dementia patients, genome wide association studies…) but also exchange of good practices or definition of standards for care or ethics14
Marc Wortmann, Executive Director of Alzheimer's Disease International, addressed the Paris conference and cited a new global dementia incidence figure of 30 million, but he also suggests that we must quantify the economic scale of the epidemic if we are to rally worldwide attention:
At the moment, most people have no idea at all of the economic impact. So we have to tell this over and over again. You need a solid, research based report to really convince the media and policy makers. That's how it went in Australia, UK and Netherlands for instance. After publication of the reports, governments started to act – they could not neglect the problem anymore. The report is essential, but not enough. We also need a global awareness campaign.15
George Vradenburg, President of the Vradenburg Foundation and leading AD advocate in the US, argues for a broad-based collaboration on global AD:
With the global incidence of Alzheimer's now approaching or exceeding that of HIV/AIDS, the global community must marshal the same unrelenting focus and large-scale resources as the HIV/AIDS community in order to prevent the social and economic agony of what is quickly becoming a global Alzheimer's pandemic.16
Vradenburg traveled to Sarkozy's Paris summit in October at the behest of the Alzheimer's Study Group (ASG), which is currently mounting, in consultation with Leon Thal Symposium scientists, and disease-specific advocacy organizations, one of the only efforts toward a consolidated US response to Alzheimer's. ASG is also now considering specific ways to collaborate with the French government on global efforts.
5. The Ugly American?
France's efforts at home, on the EU stage, and even globally are significant, but there are obviously a few extenuating circumstances for any comparative study of French and US leadership styles. First, France and much of the rest of the EU are socialized healthcare systems, driven less by what the health delivery, pharmaceutical, managed care, and reimbursement markets will support than by what the government will. As we never tire of reminding ourselves, most real innovation behind current AD therapies and the next generation of disease-modifying drugs has been driven by US corporate leadership, not a government health system.
Because of this market driven reality, much of the organizational infrastructure that France now rallies to develop has existed here in some form for a while.
We already have NIH-coordinated research, for instance, and some efforts are underway to dovetail the best of it with that going on across the Atlantic and elsewhere. Our information technology industries like Microsoft have already begun to support globalization of data in ways that may better support research and caregiving. The FDA is already working with industry and the AD community to address regulatory roadblocks to better treatments, in some limited respects collaborating with the EU's EMEA in the process. (It is worth noting, though, that Dr. Ménard and a growing part of the international AD community argue that greater coordination is needed between governments and regulatory bodies, including Japan and Australia.)
Meanwhile, there are already some efforts within the US non-governmental sector to integrate a scientific, political and caregiving national plan against AD. And it could even be argued that we have already come to see the need for greater caregiving support, as the French are now addressing. We talk that talk, at least. In short, many of the pieces of an integrated plan are already to be found in the US. They are just not in place yet.
But the most significant issue differentiating France and the US is probably what we started with: the overwhelming cost of revamping our mismanaged healthcare system to accommodate a disease like AD at a time of historic economic crisis. Alzheimer's Disease International estimates that by 2010 there will be 864,000 people in France affected by all forms of dementia, with a subset of that representing the total French AD population by the end of the decade.17 This compares with an estimated five million AD cases in the US today.18 So ours is a significantly larger public health challenge, especially as our healthcare expenditures continue to skyrocket at a rate that Victor R. Fuchs, Ph.D. professor emeritus of economics at Stanford University, recently estimated could “absorb 30% of the gross domestic product — a proportion that exceeds that of current government spending for all purposes combined” in 30 years.19
This system-wide financial pressure makes it perhaps more difficult than ever before to fund an ongoing effort to fight AD, especially since we fight yearly incremental budgeting by the legislature that makes the kind of long-term package-deal budget behind the French Plan impossible here. Without doubt, funding of an American Alzheimer's Plan is uniquely challenging.
The French and Europeans also admit that the global economic crisis will inject a degree of uncertainty into their AD plan. But even before the crisis had defined itself, Sarkozy had taken the extraordinary measure of instituting healthcare levies against French workers, who previously enjoyed strictly state-funded healthcare. With blunt common sense, Sarkozy justified the unparalleled move up front, even as he announced the AD plan in February:
If anyone doesn't want these levies, then they should come and tell the French population how we're going to pay the extra expense. The debate cannot be ignored. I didn't want to leave families alone to face this drama. I didn't want to say to research: “do what you can with the resources you have”, because you know full well that that isn't possible.
I want and have to get out of this “always more” logic. A Plan is not about “always more”. I want the Alzheimer's plan to make what already exists more efficient, I want it to promote what has been achieved. The extra resources will only be enough – 1 billion 600 million euros – if they are used coherently. 20
The price tag may be much larger here in the US, but the need to fight what will become the most costly disease of the next generation is exactly the same. As we focus on our own fiscal reality, with billions and even trillions tossed around every day, we would do well to learn from the French resolve.
As the leaders of two very different nations meet for the first French/American tete-a-tete this year, the AD community must insist that President Obama be mindful not only of the more straightforward matters of trans-Atlantic collaborations such as shared clinical trial data, drug patent extensions, and truly global studies on the impact of AD. Likewise, we must insist that he bring plans for something more than reimbursement. As our new leader, it falls to him to rediscover an American duty to care in the face of the epidemic that will define a generation. President Sarkozy has much to say on that matter and it behooves us all to learn a bit of French.
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Metabolic Acidosis in AIDS Patients
Metabolic Acidosis in AIDS Patients
Elizabeth F. Dahera, 
, 
, Lia C. Cezara, Geraldo B. Silva Juniora, , Rafael S. Limaa, Lisandra S. Damascenob, Ericka B. Lopesa, Fernanda R. Nunesa, Rosa S. Motac and Alexandre B. Libórioa
aDepartment of Internal Medicine, Division of Nephrology, Faculdade de Medicina, Hospital Universitário Walter Cantídio, Universidade Federal do Ceará, Fortaleza, Ceará, Brazil
bHospital Sáo José de Doenças Infecciosas, Fortaleza, Ceará, Brazil
cDepartment of Statistics, Universidade Federal do Ceará, Fortaleza, Ceará, Brazil
Received 3 August 2008;
Background and Aims
Metabolic acidosis (MA) is a frequent and serious complication in HIV-infected patients. The aim of the study is to compare patients with and without MA associated with HIV.
Methods
Patients were retrospectively studied involving all HIV-infected patients with blood gas analysis performed during hospital stay admitted to a single hospital between April 2004 and July 2006. Statistical analysis was performed using SPSS 10.0 for Windows.
Results
Included in the study were 159 HIV patients, 72 cases (45.3%) with MA and 87 cases (54.7%) without. The comparison of both groups showed a mean arterial pH of 7.24 ± 0.08 vs. 7.44 ± 0.05, HCO3 12 ± 5.7 vs. 21 ± 5.1 mEq/L, serum urea 81 ± 68 mg/dL vs. 39 ± 46 mg/dL and serum creatinine 2.7 ± 2.6 mg/dL vs. 1.2 ± 1.9 mg/dL in MA-HIV and non-MA-HIV, respectively (p <0.05).>p = 0.57). There was no association between the use of ART and MA. Mortality was higher in patients with acidosis (52.7 vs. 17.2%, p <0.0001).
Conclusions
In the present study, MA was associated with acute kidney injury and increased mortality. There was no association between the use of ART and MA.
Key Words: Metabolic acidosis; HIV; AIDS; Renal dysfunction; Antiretroviral therapy
Article Outline
Introduction
Metabolic acidosis (MA) has been described in human immunodeficiency virus (HIV) patients and is associated with antiretroviral therapy (ART). The majority of cases reported in the medical literature are due to lactic acidosis (LA) secondary to ART. There are several studies to investigate which factors are associated with LA in HIV-infected patients (1) and (2), but few studies investigated the factors associated with MA in general and its prognostic implication.In the last few years, ART has shown a dramatic improvement in the prognosis of HIV disease. As a result, other medical problems are assuming increasing relevance in the follow-up of HIV-infected patients (3). Among these medical problems are metabolic disturbances such as dyslipidemias, lipodystrophy, glucose intolerance and increased lactic acid, generally caused by ART drugs (3) and (4). Nucleoside reverse transcriptase inhibitors (NRTIs) induce mitochondrial toxicity by inhibiting polymerase, which lead to mitochondrial DNA depletion and respiratory chain dysfunction. Accumulation of lactate in the cytoplasm results in severe MA (5), (6), (7), (8), (9) and (10). The prevalence of hyperlactatemia in outpatients on ART is 
9–16% (11) and (12). Among untreated patients, prevalence is 2% (13). It is important to consider mitochondrial abnormalities due to ART in the differential diagnosis of MA in HIV-infected patients (14). However, other causes of MA must be considered in this population, especially in hospitalized patients.
Some studies show a prevalence of MA at 20% in HIV (2). There are multiple factors that could lead to MA in HIV including opportunistic infections, comorbidities such as diabetes, hepatitis, renal diseases, alcoholism and ART.
The aim of this study is to describe the clinical and laboratory features of HIV-associated MA, identifying its risk factors and prognostic implications.
Materials and Methods
The study was conducted at the Hospital São José de Doenças Infecciosas in Fortaleza in the northeastern region of Brazil. Clinical files of all HIV patients admitted from April 2004 to July 2006 were reviewed, and patients with blood gas analyses performed during their hospital stay were included.
Clinical and laboratory data at admission and during the hospital stay were analyzed. Clinical data evaluated were gender, age, signs and symptoms presented at admission, comorbidities, drugs and duration of ART and length of hospital stay. Laboratory data evaluated were hemoglobin, hematocrit, white blood count, lymphocytes, platelets, serum sodium, potassium, lactate dehydrogenase levels (LDH), alkaline phosphatase, aspartate amino transaminase, alanine amino transaminase, CD4 and viral loading and blood gas analysis. Renal function was analyzed by serum urea and creatinine and acute kidney injury (AKI) was classified according to RIFLE (risk, injury, failure, loss, and end stage renal disease) criteria (15).
MA was defined as arterial pH <7.35>
The study was approved by the Ethical Committee of the Institution.
Statistical Analysis
Statistical analysis of clinical and laboratory data was performed using SPSS v. 10.0 (SPSS Inc., Chicago, IL) and Epi Info, 6.04b, 2001 (Centers for Disease Control and Prevention, Atlanta, GA). Between-group comparison were done using Student's t-test, Mann-Whitney test and Fisher's exact test. Results were expressed using tables and summary measures (mean ± SD) in the cases of quantitative variables. A logistic regression model was used for quantitative variables. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. The factors included in the multivariate model were those that showed a significance level <20%>2 test); values of p <0.05>
Results
Included in the study were 159 HIV patients with a mean age of 36 ± 10 years. There were 110 (69.1%) male patients. MA was found in 72 cases (45.2%). No difference in age or gender was observed between MA and non-MA groups. Hospital stay was longer among patients without MA (p <0.0001).>Pneumocystis jiroveci pneumonia (6.9%), neurotoxoplasmosis (6.9%), bacterial pneumonia (5.0%), and others (gastrointestinal infections, visceral leishmaniasis, herpes zoster, varicella, candidiasis). There was no association of any particular disease with mortality. Clinical characteristics of patients with and without MA are summarized in Table 1.
Clinical characteristics of HIV patients with and without MA
| MA-HIV (n = 72) | Non-MA-HIV (n = 87) | p | |
|---|---|---|---|
| Age (years) | 37 ± 8.4 | 36 ± 12 | 0.21 |
| Gender | |||
| Male, n (%) | 49 (68.1%) | 61 (70.1%) | |
| Female, n (%) | 23 (31.9%) | 26 (29.9%) | 0.86 |
| Length of hospital stay (days) | 18 ± 16 | 24 ± 22 | <0.0001 |
| Signs/symptoms | |||
| Fever | 49 (68.1%) | 55 (63.2%) | 0.61 |
| Chills | 9 (12.5%) | 16 (18.4%) | 0.38 |
| Cough | 35 (48.6%) | 53 (60.9%) | 0.14 |
| Dyspnea | 27(37.5%) | 27 (31%) | 0.40 |
| Diarrhea | 47 (65.3%) | 44 (50.6%) | 0.07 |
| Vomiting | 38 (52.8%) | 29 (33.3%) | 0.01 |
| Weight loss | 25 (34.7%) | 40 (46%) | 0.19 |
| Oliguria | 2 (2.8%) | 3 (3.4%) | 1.0 |
| Convulsions | 3 (4.2%) | 3 (3.4%) | 1.0 |
| Headache | 13 (18.1%) | 13 (14.9%) | 0.66 |
| Thoracic pain | 3 (4.2%) | 10 (11.5%) | 0.14 |
| Abdominal pain | 20 (27.8%) | 14 (16.3%) | 0.08 |
| ART use | 38 (52.8%) | 45 (51.7%) | 1.0 |
| ART administration | |||
| <1> | 12 (30.8%) | 6 (40%) | |
| 1–5 years | 20 (51.3%) | 8 (53.3%) | |
| >5 years | 7 (17.9%) | 1 (6.7%) | 0.52 |
| ART use (years) | 2.6 ± 1.1 | 2.7 ± 1.2 | 0.25 |
| Death | 38 (52.7%) | 15 (17.2%) | <0.0001 |
MA, metabolic acidosis; MA-HIV, HIV patients with MA; non-MA-HIV, HIV patients without MA; ART, antiretroviral therapy.
Fisher's exact test and Student's t-test. Values expressed as mean ± SD and %.
p <0.05>
Serum urea and creatinine were significantly higher in MA-HIV than in non-MA-HIV groups (p <0.05).>p = 0.09). Viral load was significantly higher in MA-HIV than non-MA-HIV group (p = 0.02). A comparison of laboratory data is shown in Table 2.
Laboratory data in HIV patients with and without MA
| MA-HIV (n = 72) | Non-MA-HIV (n = 87) | p | |
|---|---|---|---|
| Arterial pH | 7.24 ± 0.08 | 7.44 ± 0.05 | <0.001 |
| pCO2 (mm Hg) | 28 ± 15 | 31 ± 7.8 | 0.007 |
| HCO3 (mEq/L) | 12 ± 5.7 | 21 ± 5.1 | <0.001 |
| pO2 (mm Hg) | 111 ± 51 | 93 ± 42 | 0.02 |
| O2 saturation (%) | 93 ± 7.2 | 95 ± 6.8 | 0.16 |
| Base excess (mEq/L) | −13 ± 5.4 | −1.5 ± 4.7 | <0.001 |
| Serum sodium (mEq/L) | 133 ± 8.9 | 130 ± 6.1 | 0.03 |
| Serum potassium (mEq/L) | 3.8 ± 1.1 | 3.7 ± 0.7 | 0.67 |
| Hemoglobin (g/dL) | 10 ± 2.5 | 9.9 ± 2.7 | 0.35 |
| Hematocrit (%) | 30 ± 7.3 | 28 ± 8.7 | 0.16 |
| White blood count (mm3) | 7140 ± 5407 | 5478 ± 3279 | 0.15 |
| Lymphocytes (mm3) | 1165 ± 140 | 566 ± 132 | <0.0001 |
| Platelets (×103/mm3) | 172 ± 129 | 204 ± 128 | 0.10 |
| LDH (U/L) | 614 ± 709 | 881 ± 1381 | 0.45 |
| Urea (mg/dL) | 81 ± 68 | 38 ± 45 | <0.0001 |
| Creatinine (mg/dL) | 2.7 ± 2.6 | 1.2 ± 1.9 | <0.0001 |
| AP (U/L) | 281 ± 354 | 377 ± 292 | 0.40 |
| AST (IU/L) | 162 ± 171 | 132 ± 263 | 0.16 |
| ALT (IU/L) | 106 ± 165 | 107 ± 318 | 0.21 |
| CD4 (cells/mm3) | 228 ± 239 | 185 ± 283 | 0.09 |
| Viral loading (copies/mm3) | 147,313 ± 32,106 | 60,651 ± 39,107 | 0.02 |
MA-HIV, HIV patients with MA; non-MA-HIV, HIV patients without MA; AP, alkaline phosphatase; AST, aspartate amino transaminase; ALT, alanine amino transaminase; LDH, lactate dehydrogenase.
Fisher exact test, Student t-test and Mann-Whitney test. Values expressed as mean ± SD. Significant at p <0.05.
ART was administered in 83 patients (52.2%), 38 in MA-HIV and 45 in non-MA-HIV (p = 0.57). The mean time of ART use was 2.7 ± 1.2 years. There was no difference in the mean time of ART between MA-HIV and non-MA-HIV groups (p = 0.25; Table 1). There was no association between the use of ART and MA.
AKI was found in 53 patients (33.3%). The majority of patients with AKI had MA (66%). Patients were classified according to Risk (26.5%), Injury (24.5%) and Failure (49%) according to RIFLE classification. Failure was significantly high in MA-HIV group (p <0.0001) name="btbl3">Table 3). Death occurred in 53 cases (33.3%). Mortality was higher in patients with MA (52.7% vs. 17.2%, p <0.0001).
Classification of HIV patients with and without MA-associated AKI according to RIFLE
| MA-HIV (n = 35) | Non-MA-HIV (n = 18) | p | |
|---|---|---|---|
| “Risk”, n = 14 (26.5%) | 8 (57.1%) | 6 (42.9%) | 0.44 |
| “Injury”, n = 13 (24.5%) | 7 (53.8%) | 6 (46.2%) | 0.69 |
| “Failure”, n = 26 (49%) | 20 (76.9%) | 6 (23.1%) | 0.0001 |
AKI, acute kidney injury.
MA-HIV, HIV patients with MA; non-MA-HIV, HIV patients without MA;
Fischer exact test. Significant at p <0.05.
Univariate logistic regression showed that the predictors for death were high serum level of potassium and urea and low level of bicarbonate and platelets. These data are shown in Table 4. Multivariate regression model was built with the variables that showed a significance level <20%>3, hyperkalemia, hemoglobin level, platelet count and urea at admission). The independent risk factors for death were MA, hyperkalemia and low CD4 count (Table 5).
Risk factors for death in patients in HIV with and without MA by univariate logistic regression
| OR | 95% CI | p | |
|---|---|---|---|
| HCO3− | 0.95 | 0.903–0.999 | 0.046 |
| High urea | 1.008 | 1.002–1.015 | 0.013 |
| Platelets | 0.999 | 0.998–0.999 | <0.001 |
| Hyperkalemia | 1.54 | 1.025–2.321 | 0.038 |
| CD4 level | 0.998 | 0.996–1.001 | 0.208 |
OR, odds ratio; CI, confidence interval.
Discussion
In our data we identified that MA in HIV-infected patients is prevalent in patients with AKI, especially in those with its severe form (failure in RIFLE classification). Moreover, it was independently associated with a higher mortality in HIV hospitalized patients.
Clinical manifestations related to MA are nonspecific, such as gastrointestinal symptoms present in >50% of cases (16). Dyspnea and tachypnea classically associated with MA are seen in 41% of cases in the same review (16). In the present study, the most frequent clinical manifestations found in patients with MA were diarrhea, vomiting, weight loss and dyspnea. The only manifestation that was statistically different between the two groups was vomiting, although it was classically associated with metabolic alkalosis. This symptom can be more a consequence of acidosis than its etiology.
Several studies showed an association between MA and the use of ART, mainly the NRTIs (3), (17), (18), (19), (20), (21), (22), (23), (24), (25) and (26). In the present study we were unable to determine any relationship between any ART drug and MA. In a population study, this suggests LA is not as frequent as other causes of MA. Otherwise, renal dysfunction was more frequent in patients with acidosis, especially in its severe form, suggesting this is greatly responsible for MA in this population causing MA directly due non-measurable anion accumulation or through higher serum levels of ART drugs. Lactate levels were unavailable because lactase measurement was not performed by the hospital where the study was performed. In the absence of lactate monitoring, periodic aminotransferase measurements are recommended (27) and (28).
RIFLE classification is an improvement in predicting outcome of patients with AKI (29) and (30). AKI classified as “failure” was significantly high in MA-HIV group. This finding strongly supports the hypothesis that MA is mainly due to renal dysfunction. Because the number of patients in each group according to RIFLE criteria is small, association with mortality may be significant if the sample was larger.
In our study, average hospital stay was higher among patients without MA. These data corroborate with severe clinical conditions of those patients with MA-HIV. Therefore, mortality was higher in patients with MA (52%). Our study is similar to previous reviews that have reported fatality ratio associated with LA in 33–60% (16), (26) and (31).
Independent risk factors for death were MA, hyperkalemia and low CD4. There are few studies to investigate the factors associated with mortality in HIV patients. Peak venous lactate level was the best predictor of mortality in HIV patients. Zidovudine is associated with higher lactate levels and higher mortality than stavudine and lamivudine (32). The presence of hypokalemia, MA, and renal failure are significantly associated with mortality in AIDS (2).
This study has some limitations: 1) it is a retrospective study, being difficult to define a cause-effect relationship; 2) we do not have chloride values to perform anion gap analyses; 3) lactate levels were not measured, making it impossible to evaluate the exact importance of its accumulation in MA.
In summary, MA is an important complication observed in HIV patients, which per se increases mortality. It was not directly associated with ART in the present study, although the lack of association is possible due to its low incidence compared with other causes of MA. There was a significant association between MA and AKI. It is possible that renal dysfunction plays an important role in the pathogenesis of HIV-associated MA. It is important to search for the occurrence of MA in all hospitalized HIV patients, investigate its causes and promptly correct it. Further studies, including a randomized controlled trial, are required to better establish the etiology of MA in HIV.
Acknowledgments
We are very grateful to the team of physicians, residents, medical students and nurses of the Hospital São José de Doenças Infecciosas for the assistance provided to the patients. This research was financially supported by the Brazilian Research Council (Conselho Nacional de Desenvolvimento Científico e Tecnológico-CNPq, Brazil).
References
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