Adrenal and Renal Physiology, and Medical Renal Disease

ADRENAL AND RENAL PHYSIOLOGY, AND MEDICAL RENAL DISEASE

ADRENAL AND RENAL PHYSIOLOGY, AND MEDICAL RENAL DISEASE Ketorolac, Diclofenac, and Ketoprofen are Equally Safe for Pain Relief After Major Surgery J. B. FORREST, F. CAMU, I. A. GREER, H. KEHLET, M. ABDALLA, F. BONNET, S. EBRAHIM, G. ESCOLAR, J. JAGE, S. POCOCK, G. VELO, M. J. S. LANGMAN, G. B. PORRO, M. M. SAMAMA AND E. HEITLINGER FOR THE POINT INVESTIGATORS, Departments of Anaesthesia, McMaster University, Hamilton, Ontario, Canada, and Vrije Universiteit, Brussels, Belgium, Department of Obstetrics and Gynaecology, University of Glasgow, Glasgow, Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London, Departments of Primary Care and Population Sciences, and Social Medicine, University of Bristol, Bristol and Department of Medicine, Birmingham University, Birmingham, United Kingdom, Department of Surgical Gastroenterology, University of Copenhagen, Hvidovre, Denmark, Department of Anaesthesia, Hoˆ pital Tenon and Department of Haematology, Hoˆ pital-Dieu de Paris, Paris, France, Department of Haematology, University of Barcelona, Barcelona, Spain, Department of Anaesthesia, Universita¨ t Mainz, Mainz, Germany, Department of Pharmacology, University of Verona, Verona and Department of Gastroenterology, L. Sacco University Hospital, Milan, Italy, and Ckdt Communications Ltd, Allschwil, Switzerland Br J Anaesth, 88: 227–233, 2002 Background. Ketorolac is approved for the relief of postoperative pain but concerns have been raised over a possible risk of serious adverse effects and death. Two regulatory reviews in Europe on the safety of ketorolac found the data were inconclusive and lacked comparison with other non-steroidal antiinflammatory drugs. The aim of this study was to compare the risk of serious adverse effects with ketorolac vs diclofenac or ketoprofen in adult patients after elective major surgery. Methods. This prospective, randomized multicentre trial evaluated the risks of death, increased surgical site bleeding, gastrointestinal bleeding, acute renal failure, and allergic reactions, with ketorolac vs diclofenac or ketoprofen administered according to their approved parenteral and oral dose and duration of treatment. Patients were followed for 30 days after surgery. Results. A total of 11 245 patients completed the trial at 49 European hospitals. Of these, 5634 patients received ketorolac and 5611 patients received one of the comparators. 155 patients (1.38%) had a serious adverse outcome, with 19 deaths (0.17%), 117 patients with surgical site bleeding (1.04%), 12 patients with allergic reactions (0.12%), 10 patients with acute renal failure (0.09%), and four patients with gastrointestinal bleeding (0.04%). There were no differences between ketorolac and ketoprofen or diclofenac. Postoperative anticoagulants increased the risk of surgical site bleeding equally with ketorolac (odds ratio ⫽ 2.65, 95% CI ⫽ 1.51– 4.67) and the comparators (odds ratio ⫽ 3.58, 95% CI ⫽ 1.93– 6.70). Other risk factors for serious adverse outcomes were age, ASA score, and some types of surgery (plastic/ear, nose and throat, gynaecology, and urology). Conclusion. We conclude that ketorolac is as safe as ketoprofen and diclofenac for the treatment of pain after major surgery. Editorial Comment: This is a nice study in which more than 11,000 patients participated to determine the untoward effects of ketorolac, diclofenac and ketoprofen. There were no differences in death rates, gastrointestinal bleeding, postoperative surgical site bleeding or adverse renal events. Of interest was the fact that the use of these drugs in urological surgery increased the risk of bleeding at the surgical site by 2.5 times. This study shows that there does not appear to be any particular reason to use any of these drugs over the other in an attempt to avoid complications. W. Scott McDougal, M.D.

Clinical Impact of Differential Renal Function to Indicate and Assess Pyeloplasty and the Significance of Coexisting Vesicoureteral Reflux T. SCHUSTER, M. STEHR, B. ROß MÜLLER, H. G. DIETZ AND K. HAHN, Kinderchirurgische Klinik im Dr. v. Haunerschen Kinderspital, Klinik and Poliklink fu¨ r Nuklearmedizin, and Klinikurn der Ludwig Maximillens Universita¨ t Mu¨ nchen, Innenstadt, Mu¨ nchan, Germany Clin Nucl Med, 26: 923–929, 2001 Purpose: In patients with ureteropelvic junction obstruction (JPJO) who are conservatively treated, 5% to 10% of them show a deterioration of renal function without recovery after delayed pyeloplasty. Should surgery be indicated based on observed deterioration of differential renal function (DRF)? Can we expect improvement of the DRF after pyeloplasty? What other influencing parameters may affect DRF? Materials and Methods: In this study, the authors examined 85 ureterorenal junctions that had undergone the Anderson-Hynes technique for surgical correction of UPJO. Based on the values obtained from the preoperative DRF (Tc-99m mercaptoacetyltriglycine), the cases were separated into three categories: group I had poor DRF (less than 11% of total renal function [TRF]), group II had moderate DRF (11% to 33% of

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TRF), and group III had adequate DRF (more than 33% of TRF). Twelve months after surgery, renal function was reassessed. The results were correlated with age at surgery, symptoms, coexisting vesicoureteral reflux, and drainage. Results: Seven ureterorenal junctions (8%) comprised group I, 15 (18%) comprised group II, and 63 (74%) comprised group III. After UPJO repair, 13% showed marked improvement in DRF, 86% remained stable, and 1% exhibited diminished function. In 50% of the renal cases with preoperative DRF less than 33%, postoperative improvement was seen. In follow-up renal scans, 30 cases (35%) revealed nonobstructive drainage, whereas the remaining 53 junctions (62%) showed moderate delayed drainage. Both the moderate delayed group (57%) and the nonobstructive group (50%) showed similar DRF improvement. Sixty-six percent of the patients with impaired DRF improved after pyeloplasty performed within the first 3 months of life, compared with 42.8% of patients in whom surgery was performed after 5 years of age. Vesicoureteral reflux was evident in 27.2% of the patients with preoperative impaired DRF compared with 11% with normal DRF. Forty-five percent of the patients with impaired DRF and no improvement after surgery had coexisting vesicoureteral reflux, compared with 9% of those with postoperative improvement. Conclusions: Sustained renal impairment after pycloplasty is likely as a result of preexisting renal dysplasia with vesicoureteral reflux. Moderate delayed drainage after surgery does not affect DRF. Surgery for UPJO should be indicated independent of a DRF follow-up (except very low DRF) or the age at the time of diagnosis. Editorial Comment: The authors studied 80 children and categorized them, according to differential renal function of the involved kidney, into those with renal function less than 11%, 11% to 33% and greater than 33%. They compared the time of repair in the 3 groups and noted that patients with reflux and presumable preexisting renal dysplasia had sustained renal impairment after pyeloplasty. There was an improvement in renal function following pyeloplasty irrespective of the preoperative split renal function. If the split function was less than one-third, there was no significant difference regarding when the repair was done, as many of the patients who underwent repair were older than 5 years. This study once again indicates the inadequacy of renal scans and provides no new information that might help the clinician resolve the controversy of when a ureteropelvic junction obstruction should be repaired. Unfortunately studies such as this do not adequately address the issue, and present results and suggest conclusions that are not justified by the data. In this case many explanations for the observed results are possible and, therefore, evidence as to who should undergo repair and when is not provided. W. Scott McDougal, M.D.

Increased Expression of Cyclooxygenase-2 in Malignant Pheochromocytomas K. SALMENKIVI, C. HAGLUND, A. RISTIMÄKI, J. AROLA AND P. HEIKKILÄ, Department of Pathology, Haartman Institute, University of Helsinki and HUCH Laboratory Diagnostics, and Department of Surgery, Helsinki University Central Hospital, and Molecular and Cancer Biology Program, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland J Clin Endocrinol Metab, 86: 5615–5619, 2001 Pheochromocytomas are rare tumors of the adrenal medulla or the paraganglion system. There are no histological or chemical markers available that define the malignant behavior of these tumors, so far only the discovery of metastases reveals malignancy. Cyclooxygenase (Cox) is the key enzyme in conversion of arachidonic acid to PGs, and two isoforms, Cox-1 and Cox-2, have been identified. Cox-2 has been associated with carcinogenesis, and it is overexpressed in many human malignancies. We have now investigated the expression of Cox-2 in normal adrenal gland, in 92 primary pheochromocytomas and in six metastases using immunohistochemistry and Northern blot and Western blot analyses. Cox-2 protein was expressed in the adrenal cortex, whereas the medulla was negative as detected by immunohistochemistry. Interestingly, all malignant pheochromocytomas (n ⫽ 8), regardless of the primary location of the tumor, showed moderate or strong Cox-2 immunoreactivity, whereas 75% of the benign adrenal tumors (n ⫽ 36) showed no or only weak immunopositivity. The staining was negative or weak in 79% of the adrenal tumors that showed histologically suspicious features (n ⫽ 24), but had not metastasized. Most of the pheochromocytoma samples studied also expressed low levels of Cox-2 mRNA. Our data show that normal adrenal medulla does not express Cox-2 immunohistochemically. However, strong Cox-2 protein expression was found in malignant pheochromocytomas, whereas most benign tumors expressed Cox-2 only weakly. To our knowledge, this is the first report on Cox-2 expression in pheochromocytomas and enhanced expression in malignant pheochromocytomas. These findings suggest that negative or weak Cox-2 expression in pheochromocytomas favors benign diagnosis. Editorial Comment: There have been many attempts to define which adrenal masses, particularly those of the medulla, have malignant potential. Although about 10% of pheochromocyto-

ADRENAL AND RENAL PHYSIOLOGY, AND MEDICAL RENAL DISEASE

mas are malignant, often it is extremely difficult by histological criteria alone to define which have the potential for metastasis. Therefore, the authors examined Cox-2 expression and noted that in all 8 patients with malignant (metastatic) pheochromocytoma Cox-2 was over expressed, whereas in 75% of patients with benign tumors it was not expressed. Cox-2 protein is in fact normally expressed in the adrenal cortex, whereas in the medulla it is not. Unfortunately the sensitivity of this test is not sufficient to be useful in selecting patients for adjuvant therapy, since 25% of individuals would be treated for no reason. Obviously there is a need for specific genetic markers to indicate which tumors have the potential for metastasis and which are benign. Unfortunately such a test is not available at this time. W. Scott McDougal, M.D.

Contrast Media as Markers of GFR B. FRENNBY AND G. STERNER, Department of Diagnostic Radiology and Division of Nephrology, Malmo¨ University Hospital, Malmo¨ , Sweden Eur Radiol, 12: 475– 484, 2002 Determination of the glomerular filtration rate (GFR) is generally considered as the most important parameter of quantifying renal function. The GFR is determined as renal or plasma clearance of an ideal filtration marker which is freely filtered by the kidney, does not undergo metabolism, tubular secretion or absorption. Markers that fulfil these demands are inulin, 51Cr-EDTA, 99mTc-DTPA, labelled or unlabelled contrast media. The renal clearance of inulin is the classic reference method for estimation of the GFR. This method is however not practical for routine clinical purposes. Radionucleids have therefore been used as alternative filtration markers since the 60s. Drawbacks related to radiation exposure especially in children and pregnant women and the safety in handling radiolabelled markers have led to an increasing interest in using non-radioactive markers. The development of simple and reliable methods to determine the concentration of contrast media in plasma and urine, such as high-performance liquid chromatography (HPLC) and X-ray fluorescence analysis have made this possible. The non-ionic low osmolar contrast medium io-hexol has become the most commonly used contrast medium for GFR measurements in Europe. However, other contrast media with similar pharmacokinetics may be equally suitable as GFR markers. Editorial Comment: We were all taught that an excretory urogram is a poor marker of renal function. This in fact is true if one assesses renal function by visual inspection of the excretory urogram. The authors review the use of various substances, including inulin, chromium ethylenediaminetetraacetic acid and 99m technetium diethylenetriaminepentaacetic acid as markers for determining glomerular filtration rate. If one analyzes radio contrast in the serum by high performance liquid chromatography or x-ray fluorescence, thus, objectively quantifying it, one can in fact use the contrast material (iohexol) to determine glomerular filtration rate. Although accurate determination is somewhat problematic with a single injection, due to the assumption of a 1 compartment model, for clinical purposes if the radiology department is set up to measure glomerular filtration rate, it seems as though it would give the clinician a reasonable assessment of total renal function. Unfortunately its use does not allow for the determination of split function. W. Scott McDougal, M.D.

Natural History of Chronic Renal Insufficiency After Partial and Radical Nephrectomy J. MCKIERNAN, R. SIMMONS, J. KATZ AND P. RUSSO, Department of Urology, Memorial Sloan-Kettering Cancer Center, New York, New York Urology, 59: 816 – 820, 2002 Objectives. To compare the incidence of newly developed chronic renal insufficiency after partial nephrectomy (PN) and radical nephrectomy (RN). Elective PN for renal tumors is intended to preserve renal function; however, studies of transplant donors suggest normal renal function is also maintained after unilateral nephrectomy. Methods. We retrospectively compared all patients undergoing PN or RN for renal tumors 4 cm or less in the presence of a normal contralateral kidney from 1989 to 2000. Creatinine failure was defined as a serum creatinine value greater than 2.0 mg/dL. Risk factors for renal insufficiency, including diabetes, hypertension, American Society of Anesthesiologists score, age, preoperative creatinine, and history of smoking tobacco, were compared between the two groups. We compared the two groups using the chi-square and Mann-Whitney U tests and the creatinine failure rates using the Kaplan-Meier method. Results. One hundred seventy-three patients met the criteria for analysis after RN and 117 did so after

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PN (median follow-up 25 months). The 5-year freedom from recurrence rate was 96.4% and 98.6% for PN and RN, respectively (P ⬎0.05). The mean preoperative serum creatinine was 1.0 mg/dL (range 0.4 to 1.4) and 0.98 (range 0.6 to 1.5) for RN and PN, respectively (P ⫽ 0.4, not significant). The incidence of risk factors for renal insufficiency did not differ between the two groups. The mean postoperative serum creatinine in the RN and PN groups was 1.5 mg/dL (range 0.8 to 3.8) and 1.0 mg/dL (range 0.5 to 1.9), respectively (P ⬍0.001). The chance of creatinine failure over time was significantly greater in the RN group (P ⫽ 0.008). Conclusions. When controlled for preoperative risk factors for renal insufficiency, patients undergoing RN are at a greater risk of chronic renal insufficiency than a similar cohort of patients undergoing PN. Editorial Comment: This is a retrospective analysis of patients who underwent either partial nephrectomy or radical nephrectomy for tumors smaller than 4 cm. The recurrence rate during a 5-year period was extremely low, ranging from 1.5% to 3.5% with no significant difference between the 2 groups. The conclusion of the study, when a creatinine of 2 mg./dl. is chosen as a definition of renal insufficiency, is that this outcome occurred to a lesser degree in patients undergoing partial nephrectomy. Unfortunately there was a significant difference in age between the 2 groups, with the total nephrectomy group having a higher average age. Followup was significantly longer in the total nephrectomy group as well. Those facts aside, it is not unlikely that during the long term patients who have a greater nephron mass remaining will in fact have a lesser degree of creatinine increase. What this article does not address is whether any of these patients were disadvantaged from a renal function perspective during their life span. Longer followup studies will be necessary to answer this important question. W. Scott McDougal, M.D.

A Comparative Study of Metastatic Renal Cell Carcinoma With Correlation to Subtype and Primary Tumor K. T. MAI, D. C. LANDRY, S. J. ROBERTSON, A. S. COMMONS, B. F. BURNS, A. THIJSSEN AND J. COLLINS, Division of Anatomical Pathology, Department of Laboratory Medicine and Division of Urology, Department of Surgery, Ottawa Hospital, and Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, Ontario, Canada Pathol Res Pract, 197: 671– 675, 2001 Clear cell (CRCC), papillary (PRCC) and chromophobe (CHRC) renal cell carcinoma (RCC) are the three most frequent subtypes of RCC. The rate and distribution of their metastatic lesions have not been well documented. We compared metastatic RCC according to subtype and primary tumor characteristics to better understand their behavior and to aid in the diagnosis of metastatic RCC. Pathology reports and clinical charts related to 283 CRCC, 48 PRCC and 13 CHRCC, including their respective sarcomatoid variants, were reviewed. A hundred and thirty seven CRCC, 5 PRCC and 1 CHRCC with metastases were identified. CRCC and non CRCC (PRCC and CHRCC) had different patterns of metastasis and primary tumor growth. CRCC metastases were predominantly distributed in lungs, bone, brain, lymph nodes, and adrenal glands. The associated primary CRCC measured 1.5 to 15 cm., were of all grades and stages, and were often associated with invasion of small or large veins. Three PRCC had regional lymph node metastases, 1 PRCC had both regional and mediastinal lymph node metastases. Bone metastasis was present in 1 case each of PRCC and CHRCC. One PRCC with metastasis solely to regional nodes measured 4 cm. The other 4 cases of PRCC with regional lymph node and/or distant metastases as well as the CHRCC with distant metastases were greater than 8 cm in diameter. In metastasizing and non-metastasizing non-CRCC, invasion of small veins was rare and invasion of renal veins was not seen. We cannot comment with any certainty on the metastatic behavior of CHRCC. In our experience, PRCC tend to loco-regional invasion with lymph node spread. They have a low potential for vascular invasion and distant metastases that likely occur only at late stages of the disease. CRCC has a propensity for vascular invasion and may be associated with distant metastasis at an early stage. Therefore, metastatic RCC at a distant location are most likely to be of CRCC origin than PRCC origin. Editorial Comment: This is an interesting study that reviewed the natural history of 283 patients with clear cell, 48 with papillary and 13 with chromophobe carcinoma. It is noteworthy that the patients with clear cell carcinoma had tumors ranging from 1.5 to 15 cm., thus, once again confirming the metastatic potential for tumors smaller than 2 cm. All papillary tumors that were metastatic except for 1 were greater than 8 cm. The regions of spread for clear cell carcinoma were distant, including lung, bone and brain, whereas papillary carcinoma tended toward local regional spread with lymph node involvement. There were too few chromophobe carcinomas to comment on. Five-year survival for papillary renal cell carcinoma was approxi-

VOIDING FUNCTION, BLADDER PHYSIOLOGY AND PHARMACOLOGY, AND FEMALE UROLOGY

mately 80%, whereas that of clear cell carcinoma was 50%. This report is helpful in defining the differences between these types of renal cell carcinomas. W. Scott McDougal, M.D.

VOIDING FUNCTION AND DYSFUNCTION, BLADDER PHYSIOLOGY AND PHARMACOLOGY, AND FEMALE UROLOGY Clinical Options for Imipramine in the Management of Urinary Incontinence J. M. HUNSBALLE AND J. C. DJURHUUS, International Enuresis Research Centre, Institute of Experimental Clinical Research, University of Aarhus and Skejby University Hospital, and Department of Neurology, Aarhus University Hospital, Aarhus, Denmark Urol Res, 29: 118 –125, 2001 Urinary incontinence is a common disorder in both childhood and adulthood. Proper treatment depends on insight into the pathophysiology and pharmacology of the lower urinary tract. This article reviews the mechanism of action of an old but commonly used drug, the tricyclic antidepressant agent imipramine, in nocturnal enuresis and stress and urge incontinence with reference to neuropharmacology and the relevant pathophysiology. Editorial Comment: The authors review the theoretical bases for the use of imipramine in overactive bladder, stress incontinence and nocturnal enuresis. They review and cite articles relating to the potential for a central effect at the level of the spinal cord secondary to inhibition of postsynaptic amine neurotransmitter re-uptake of serotonin and norepinephrine; a peripheral effect secondary to the inhibition of norepinephrine re-uptake, which theoretically would cause a ␤-blocker or relaxant effect in the bladder body and an ␣-blocker or contractile effect in the bladder base and proximal urethra; and an antidiuretic effect, attributable to an antidiuretic hormone independent renal mechanism, which conserves fluid by decreasing solute excretion. They then review clinical evidence for the use of imipramine and conclude, “. . . small poorly conducted human experiments suggest it can be applied in the management of stress and urge incontinence . . . yet only limited clinical data are available to support the use of imipramine in these micturitional disorders and recommendations must await future more reliable validation of the effect . . . in contrast, numerous trials have documented achievement from imipramine in nocturnal enuresis . . . however, side effects associated with imipramine therapy are frequent and moreover, imipramine is extremely toxic . . . the use of trycyclic antidepressants in the management of a nocturnal enuresis today is restricted and cannot generally be recommended as a primary choice.” Alan J. Wein, M.D. Urinary Symptoms and Incontinence in an Urban Community: Prevalence and Associated Factors in Older Men and Women D. J. MUSCATELLO, C. RISSEL AND G. SZONYI, New South Wales Health Department, North Sydney, Health Promotion Unit, Central Sydney Area Health Service, Department of Geriatric Medicine, Royal Prince Alfred Hospital and Balmain Hospital, Sydney, New South Wales, Australia Intern Med J, 31: 151–160, 2001 Background: There is increasing recognition of the importance of a wide range of urinary symptoms in both men and women and that these symptoms are undertreated. Aims: To determine the prevalence of and factors associated with urinary symptoms, including nocturia, urgency, urge and stress incontinence and, in men, urinary stream difficulties; and the prevalence of being bothered by the symptoms and ever seeking treatment for them. Method: Household survey by computer-assisted telephone interviews of people aged 41 years and over and living in inner metropolitan Sydney. Results: Fifty-three per cent (95% confidence interval (CI) 46 – 60) of men and 61% (95% CI 55– 67) of women reported one or more symptoms in the previous month. In men, the most frequently reported symptoms were urgency (30%, 95% CI 24 –36) and nocturia (25%, 95% CI 19 –31). In women, stress incontinence (35%, 95% CI 29 – 41) and urgency (33%, 95% CI 27–39) were the most common symptoms reported. In men, the significant factors associated with reporting one or more symptoms, after adjustment for other variables, were age 60 years or more, no private medical insurance, obesity and fair or poor self-rated health. For women, the significant associations were age 50 –59 years, age 70 years or more, no private health insurance, high psychological distress and fair or poor self-rated health. Conclusions: Urinary symptoms are experienced by more than half of men and women aged over 40 in the

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