In The Name Of God
The Books That Authored And Translated by
4 A different method of evaluation of the ERSPC trial confirms that prostate-specific antigen testing has a significant impact on prostate cancer mortality Full Text European Urology, September 2, 2014
7 A multinational, multi-institutional study comparing positive surgical margin rates among 22393 open, laparoscopic, and robot-assisted radical prostatectomy patients Full Text European Urology, September 2, 2014
15 Comparison of radiation dose from conventional and triple-bolus computed tomography urography protocols in the diagnosis and management of patients with renal cortical neoplasms Urology, September 2, 2014
Renal cell carcinoma is a type of kidney cancer that starts in the lining of very small tubes (tubules) in the kidney.
Renal cancer; Kidney cancer; Hypernephroma; Adenocarcinoma of renal cells; Cancer - kidney
Renal cell carcinoma is the most common type of kidney cancer in adults. It occurs most often in men ages 50 to 70.
The exact cause is unknown.
The following may increase your risk of kidney cancer:
- Dialysis treatment
- Family history of the disease
- High blood pressure
- Horseshoe kidney
- Polycystic kidney disease
- Von Hippel-Lindau disease (a hereditary disease that affects blood vessels in the brain, eyes, and other body parts)
- Abdominal pain and swelling
- Back pain
- Blood in the urine
- Swelling of the veins around a testicle (varicocele)
- Flank pain
- Weight loss
Other symptoms that can occur with this disease:
Exams and Tests
The health care provider will perform a physical exam. This may reveal:
- Mass or swelling of the abdomen
- A varicocele in the male scrotum
- Abdominal CT scan
- Blood chemistry
- Complete blood count (CBC)
- Intravenous pyelogram (IVP)
- Liver function tests
- Renal arteriography
- Ultrasound of the abdomen and kidney
- Urine tests
The following tests may be done to see if the cancer has spread:
Surgery to remove of all or part of the kidney (nephrectomy) is recommended. This may include removing the bladder, surrounding tissues, or lymph nodes. A cure is unlikely unless all of the cancer is removed with surgery. But even if some cancer is left behind, patients can still benefit from surgery.
Hormone treatments may make the tumor smaller in some cases.
Chemotherapy is generally not effective for treating kidney cancer. The immune system medicine interleukin-2 (IL-2) may help some patients. Medicines that target the development of blood vessels that feed the tumor may be used to treat kidney cancer. Your doctor can tell you more.
Radiation therapy usually does not work for kidney cancer.
You can ease the stress of illness by joining a support group whose members share common experiences and problems.
Sometimes, both kidneys are involved. The cancer spreads easily, most often to the lungs and other organs. In about one-third of patients, the cancer has already spread (metastasized) at the time of diagnosis.
How well a patient does depends on how much the cancer has spread and how well treatment works. The survival rate is highest if the tumor is in the early stages and has not spread outside the kidney. If it has spread to the lymph nodes or to other organs, the survival rate is much lower.
- High blood pressure (hypertension)
- Too much calcium in the blood
- High red blood cell count
- Liver problems
- Spread of the cancer
When to Contact a Medical Professional
Call your health care provider any time you see blood in the urine. Also call if you have any other symptoms of this disorder.
Stop smoking. Follow your health care provider's recommendations in the treatment of kidney disorders, especially those that may require dialysis.
National Cancer Institute: PDQ Renal Cell Cancer Treatment. Bethesda, Md: National Cancer Institute. Date last modified: Feb. 21, 2014. Available at: http://cancer.gov/cancertopics/pdq/treatment/renalcell/HealthProfessional. Accessed: March 23, 2014.
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Kidney cancer. Version 2.2014. Available at: http: //www.nccn.org/professionals/physician_gls/pdf/kidney.pdf. Accessed: March 23, 2014.
Pili R, Kauffman E, Rodriguez R. Cancer of the kidney. In: Niederhuber JE, Armitage JO, Doroshow JH, et al., eds. Abeloff's Clinical Oncology. 5th ed. Philadelphia, Pa: Elsevier Churchill Livingstone; 2013:chap 82.
Review Date: 3/23/2014
Urology news Sep.02,2014
Aug. 27, 2014 – Men who are physically active are at lower risk of nocturia (waking up at night to urinate), according to a study led by a Loyola University Chicago Stritch School of Medicine researcher.
The study, by Kate Wolin, ScD, and colleagues, is published online ahead of the print edition in Medicine & Science in Sports & Exercise, the official journal of the American College of Sports Medicine.
Nocturia is the most common and bothersome lower urinary tract symptom in men. It can be due to an enlarged prostate known as benign prostatic hyperplasia (BPH) in which the enlarged prostate squeezes down on the urethra. Other causes include overproduction of urine, low bladder capacity and sleep disturbances. Nocturia increases with age and is estimated to occur in more than 50 percent of men 45 and older.
Wolin and colleagues analyzed data from a large, ongoing clinical trial called the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO). Men ages 55 to 74 were eligible for the trial. The study included questions on BPH-related outcomes, including enlarged prostate, elevated PSA levels and nocturia. PLCO also asked men about physical activity and other lifestyle factors.
Wolin’s analysis included 28,404 men in the PLCO trial who had BPH outcomes before enrolling in the study (prevalent group) and 4,710 men who had newly developed BPH (incident group).
Among men in the incident group, those who were physically active one or more hours per week were 13 percent less likely to report nocturia and 34 percent less likely to report severe nocturia than men who reported no physical activity. (Nocturia was defined as waking two or more times during the night to urinate; severe nocturia was defined as waking three or more times to urinate.)
“Combined with other management strategies, physical activity may provide a strategy for the management of BPH-related outcomes, particularly nocturia,” Wolin and colleagues wrote.
There are several possible mechanisms by which physical activity can protect against nocturia, including reducing body size, improving sleep, decreasing sympathetic nervous system activity and lowering levels of systemic inflammation.
Future studies should explore physical activity as a potential symptom-management strategy, “with particular attention to the dose of physical activity necessary and the mechanisms that might underlie the association,” Wolin and colleagues wrote.
Wolin is an epidemiologist whose research focuses on the role of lifestyle in reducing the risk of cancer and other chronic diseases, and on improving outcomes. She is an associate professor in the departments of Surgery and Public Health Sciences of Loyola University Chicago Stritch School of Medicine.
Co-authors of the study are Robert Grubb III, Ratna Pakpahan, Gerald Andriole and Siobhan Sutcliffe of Washington University in St. Louis; and Lawrence Ragard and Jerome Mabie, who work in private industry.The study is titled “Physical Activity and Benign Prostatic Hyperplasia-Related Outcomes and Nocturia.” It was supported by a grant from the National Institute of Diabetes and Digestive and Kidney Diseases.
Urology news Sep.01,2014
Sakthivel MuniyanxSakthivel Muniyan
Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, US
Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan, ROC
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
- Department of Chemistry, Clark Atlanta University, Atlanta, GA, USA
July 3, 2014; Published Online: July 19, 2014
- •The imidazopyridine family is a promising class of compounds to combat CR PCa.
- •Members of this family can have differential effects on PCa vs. normal epithelia.
- •These compounds decrease cancer cell proliferation and tumorigenicity.
- •The inhibitory activity was in part due to the induction of apoptosis.
- •Imidazopyridine compounds inhibit both AR and PI3K/Akt signaling pathways.
Metastatic prostate cancer (mPCa) relapses after a short period of androgen deprivation therapy and becomes the castration-resistant prostate cancer (CR PCa); to which the treatment is limited.
Hence, it is imperative to identify novel therapeutic agents towards this patient population. In the present study, antiproliferative activities of novel imidazopyridines were compared. Among three derivatives, PHE, AMD and AMN, examined, AMD showed the highest inhibitory activity on LNCaP C-81 cell proliferation, following dose- and time-dependent manner. Additionally, AMD exhibited significant antiproliferative effect against a panel of PCa cells, but not normal prostate epithelial cells.
Further, when compared to AMD, its derivative DME showed higher inhibitory activities on PCa cell proliferation, clonogenic potential and in vitro tumorigenicity. The inhibitory activity was apparently in part due to the induction of apoptosis. Mechanistic studies indicate that AMD and DME treatments inhibited both AR and PI3K/Akt signaling. The results suggest that better understanding of inhibitory mechanisms of AMD and DME could help design novel therapeutic agents for improving the treatment of CR PCa.
ADT (androgen deprivation therapy), AI (androgen-independent), AR (androgen receptor), AS (androgen-sensitive), CR PCa (castration-resistant prostate cancer), DHT (dihyrotestosterone), ECL (enhanced chemiluminescence), FBS (fetal bovine serum), PCa (prostate cancer), PI3K (phosphatidylinositol-3 kinase), PSA (prostate-specific antigen), p66Shc (a 66kDa Src homologous-collagen homologue), SR (steroid-reduced).
Source: Cancer Letters
Volume 353, Issue 1, Pages 59–67, October 10, 2014
The pelvic mass workup Sep.01,2014
APR 01, 2014
Workup for a pelvic mass begins with a careful history and physical examination. Although ovarian cancer has long been considered an asymptomatic “silent killer,” recent studies have shown that certain symptoms may help diagnose ovarian cancer. These include symptoms of bloating, increased abdominal size, pelvic or abdominal pain, difficulty eating, and early satiety, which have a sensitivity of 80% in detecting advanced-stage ovarian cancer and 57% in detecting early-stage disease.8 Other symptoms that are concerning for less common ovarian tumors are abnormal uterine bleeding, breast tenderness, and precocious puberty, which can be seen in granulosa cell tumors or thecomas, and hirsutism, deepening of the voice, and other symptoms of excess testosterone, which can be suggestive of a Sertoli-Leydig tumor. Fever and vaginal discharge can suggest a tubo-ovarian abscess, while dysmenorrhea, dyspareunia, and dyschezia suggest endometriosis or an endometrioma.
Physical examination includes a general assessment, including assessment for signs of cachexia, virilization, or hyperestrogenism. A lymphatic survey should be performed, including palpation of supraclavicular, axillary, and inguinal lymph nodes. An abdominal examination should be done to assess for pain, palpable masses, omental caking, and possible fluid wave suggestive of ascites. The pelvic examination should begin with a speculum examination to assess for recent bleeding and for position of the cervix, as it may be displaced by a large pelvic mass. If a mass is palpable on pelvic examination, it should be characterized in terms of contour, firmness, size, location, and mobility.
Lastly, rectovaginal examination should be done to palpate the uterosacral ligaments and cul-de-sac to assess for the presence of metastatic disease, nodularity, or obliteration of the cul-de-sac. As a general rule, physicians tend to underestimate the size of a mass palpated on pelvic examination. Pelvic examination has a sensitivity of only 45% in the detection of pelvic masses.9 This underscores the need for physicians to be aware of the limitations of pelvic examination, especially in obese patients.
Consideration of ovarian cancer risk factors
The symptoms of ovarian cancer are often vague, but risk factors may be useful in determining a patient’s risk of malignancy. Age is the most important risk factor in the general population. The incidence of ovarian cancer increases after menopause, and the median age at diagnosis is 63 years.10
Family history of breast or ovarian cancer increases the lifetime risk of ovarian cancer. Women who have BRCA1 mutations have a 40% lifetime risk and those with BRCA2 mutations have a 20% lifetime risk of developing ovarian cancer.2 Women with hereditary nonpolyposis colorectal cancer (Lynch syndrome) have a 13-fold increased risk of ovarian cancer compared to the general population.7
Other risk factors for ovarian cancer include nulliparity, primary infertility, endometriosis, early menarche, late menopause, white race, and residence in North America, Northern Europe, or any industrialized Western country.
Several factors have been associated with a reduced risk of developing ovarian cancer, including tubal ligation, hysterectomy, multiparity, and use of oral contraceptives (OCs). Large studies have found up to a 40% reduction in ovarian cancer risk in women who used OCs at any point in their lives for any amount of time. A 90% reduction in risk was seen in women who used OCs for longer than 15 years.7
Imaging for pelvic masses typically begins with TVS. Sonography has the advantages of being widely available, well tolerated by patients, and cost-effective. The major limitation is its lack of specificity for diagnosing cancer. Mass characteristics that should be assessed include size, blood flow, location, locularity, and echogenicity.11,12 Findings suggestive of malignancy include excrescences, ascites, complex or solid components, bilateral tumors, mass larger than 10 cm in diameter, and mural nodules.11
Various scoring systems have been established to distinguish benign from malignant masses on sonography. DePriest and colleagues developed a system that used 3 criteria (tumor volume, cyst wall structure, and septa structure) and assigned a score to each criterion based on measurements.13 High intraobserver variation was found in utilization of the scoring system, particularly in assigning scores for cyst wall structure and septa structure.
Color Doppler sonography is used to evaluate pelvic masses because hypoxic tissue in tumors will often undergo angiogenesis and, therefore, a “chaotic” vascular architecture correlating with malignancy may be seen.14 If the malignant potential of a pelvic mass is indeterminate on sonography, magnetic resonance imaging can be used to further characterize the mass. Computed tomography scan is recommended when there is high suspicion of malignancy to aid in preoperative staging and determining disease resectability.
American Congress of Obstetricians and Gynecologists Sep.01,2014
Updated Guidelines, New Safety Data Make Stronger Argument for Vaccination
August 19, 2014
New data show the continued critical need for all pregnant women, regardless of trimester, to receive the influenza vaccination, according to an updated Committee Opinion released by the American College of Obstetricians and Gynecologists (the College). Several studies released in recent years have increasingly demonstrated the safety and efficacy of influenza vaccine during pregnancy.
The College emphasizes that preventing the flu is an essential element of preconception, prenatal, and postpartum care. Moreover, physicians, healthcare organizations, and public health officials should improve their efforts to increase immunization rates among pregnant women, according to the Committee Opinion.
Prior to the H1N1 pandemic in 2009, influenza immunization rates for pregnant women were at only 15%. This rate increased to 50% in the 2009-2010 flu season and has been sustained or slightly increased every flu season since due to strong efforts by the College, the CDC and others. However, there is still room for significant improvement to increase influenza immunization rates for all pregnant women beyond 50%.
Flu vaccination is crucial for all pregnant women because the immune system changes during pregnancy, which puts women at increased risk of serious illness and complications if they get the flu. In addition, flu vaccination performs double duty by protecting both pregnant women and their fetuses; babies cannot be vaccinated against the flu until they are six months old, but they receive antibodies from their vaccinated mother, helping to protect them until they can be vaccinated directly.
“The flu virus is highly infectious and can be particularly dangerous to pregnant women, as it can cause pneumonia, premature labor, and other complications, “ said Laura Riley, MD, chair of the College’s Immunization Expert Work Group, which developed the Committee Opinion in conjunction with the College’s Committee on Obstetric Practice. “Vaccination every year, early in the season and regardless of the stage of pregnancy, is the best line of defense.”
Vaccination early in the flu season is optimal, regardless of the stage of pregnancy, but it can be done at any time during the season, which is October through May. The College advises that all women who are or who become pregnant during the annual flu season get the inactivated flu vaccine. Women can also receive the flu vaccine postpartum and while they are breastfeeding. The live attenuated version of the flu vaccine (the nasal mist) should not be given to pregnant women.
August is National Immunization Awareness Month. For more information see The College’s hub on immunization for women: http://www.immunizationforwomen.org/
Committee Opinion #608, "Influenza Vaccination During Pregnancy," will be published in the September issue of Obstetrics & Gynecology.
Urology news Sep. 01,2014
Mainwaring, P.; Yu, Evan Y; Londhe, A.; Van Poppel, H.; Rathkopf, D. E.; Smith, M. R.; Souza, P.; Griffin, T. W.; Ryan, C. J.; Investigators, Study COU-AA-302 Bju International, Volume 113, p.21-21 (2014)2014, Clinical Research Division, Clinical Research Division May 2014 2014Q2 CCSG, May 2014
Introduction: Prognostic models have been developed for men with mCRPC. In this analysis we undertook a pragmatic approach to focus on commonly obtained markers. Baseline alkaline phosphatase (ALP) and normalization of elevated ALP post-docetaxel have prognostic value for overall survival (OS).
We examined the association between ALP and prostate specific antigen (PSA) elevation at baseline and after 4 cycles of therapy (C5D1), when both markers were assessed, with longterm clinical outcomes in COU-AA-302, a randomized phase 3 study of abiraterone acetate (AA) in chemotherapy-naïve mCRPC patients. Patients and Methods: 1088 patients were randomized 1:1 to AA (1 g) + prednisone (P) (5 mg BID) or placebo + P. Radiographic progression-free survival (rPFS) and OS were co-primary end points.
The study design, as well as primary and secondary end point results obtained at the time of a prespecified interim analysis at 55% OS events, have been described in detail previously. The effect of elevated ALP (above upper limit of normal) and PSA (above 106.2 μ g/mL, baseline third quartile) status on rPFS and OS was assessed retrospectively using a stratified Cox regression model that included treatment and baseline factors log (lactate dehydrogenase), hemoglobin, whether patient had only bone metastasis, and age.
Results: Elevated status of ALP and PSA were independent significant predictors of increased risk for outcomes at baseline as well as after 4 cycles of therapy (Table). Conclusions: These post hoc analyses of data from COU-AA-302 suggest that elevated ALP and PSA at baseline and during treatment confers individual and additive risk for adverse clinical outcomes in chemotherapy-naïve mCRPC.
T M Reynolds1/1Clinical Chemistry Department, Queen’s Hospital, Burton-on-Trent, UKProfessor TM Reynolds, Clinical Chemistry Department, Queen’s Hospital, Belvedere Road, Burton-on-Trent, Staffordshire DE13 0RB, UK. E-mail: Tim.Reynolds@BurtonFT.NHS.UK/Journal of Human Hypertension (2014) 28, 519–520; doi:10.1038/jhh.2013.147; published online 16 January 2014
Which came first, the chicken or the egg? This is a difficult question to answer because defining when the precursor to the chicken became a chicken is impossible, so we can never be sure in which geological strata we should look for fossils. To an extent the same applies to hypertension. At what point does blood pressure become too high and in need of reduction? All definitions we have are artificial numerical thresholds based on a value judgement because they have to cater to entire populations and not individuals.
What is too high for one person may be just fine for another. This is important because if we could identify those people whose blood pressure would increase excessively, it may be possible to treat them early and avoid the need to treat others who may not develop any problems. Thus, attempts to identify causal links between other parameters and development of hypertension are important because it may mean that we can target individuals who will develop problems earlier in life while avoiding treatment in people who will never develop any problems.
Uric acid has long been considered a potential culprit. Many studies have found significant correlations between urate and blood pressure. The Normative Aging Study showed that baseline urate concentration is a durable marker for the risk of development of hypertension.1 Framingham data also show that urate is a prognostic indicator for the development of hypertension.2 Takase et al.3 have shown that in a Japanese population baseline urate is significantly correlated with onset of hypertension in both males and females, and that baseline urate is significantly correlated with future blood pressure.
In addition to demonstrating that urate was associated with the development of hypertension, other hazards with positive correlation included age, body mass index, baseline blood pressure and impaired glucose tolerance. Some of these correlations are only to be expected: clearly, patients who start with a higher blood pressure are more likely to progress to a diagnosis of hypertension than someone who starts with a low blood pressure because the change required to move from one category to another is less. Others may simply appear logical, such as the link between body mass index and blood pressure.
It is perhaps significant that body mass, blood pressure, blood glucose and uric acid are all linked by the metabolic syndrome, although urate is only an unofficial member of the club: the standard definition includes increased fasting glucose (insulin resistance), increased triglycerides, decreased HDL-cholesterol, central obesity and hypertension. It has been proposed that urate should be recognised as part of the syndrome.4 Correlations between Metabolic syndrome and urate are significant—in the Turkish population a 1 standard deviation increase in urate is associated with a 35% increase in metabolic syndrome.5 Urate is also correlated with triglycerides and HDL-cholesterol.4 It is therefore entirely unsurprising that there is a correlation between urate and hypertension.
However, it is well known that correlation does not prove causation. It could be that the association between urate and hypertension is simply a mathematical artefact of the correlation with the other parameters that are correlated with hypertension. Therefore, it is necessary to consider what mechanisms that have been tested in animals might link uric acid to the development of hypertension and review whether these might be relevant in humans.
This is where the question of chickens and eggs becomes very relevant. Humans have an inactive gene for the enzyme urate oxidase as a result of several mutations.6 The first mutation is believed to have occurred in the Miocene period, ~18–22 million years ago at the evolutionary branch point where the higher primate (Pongo (orang-utan)/Gorilla/Pan (chimpanzee)/Homo (human)) line divided from other apes.
Gibbons and siamangs, for example, do not have mutated uricase. The second and third mutations occurred after the Pongo line separated. This means that humans are genetically predestined to have a ‘high’ uric acid level in their blood. Simulation of this condition can be achieved by treating rats with oxonic acid.7 If these rats are then given a low-sodium diet their blood pressure increases in comparison to control rats whose blood pressure stays constant or decreases slowly. Reducing the rats’ hyperuricaemia by inhibiting xanthine oxidase with allopurinol or increasing urate excretion with a uricosuric agent such as benziodarone prevents the hypertension from developing. This has been shown to be partially regulated by the renin–angiotensin system, which has a key role in maintaining blood pressure, glomerular filtration and sodium balance in low-salt dietary conditions.
In addition to hypertension, the rats develop renal microvascular disease particularly affecting the afferent arteriole and mild interstitial inflammation and tubular damage, both of which can be prevented with allopurinol treatment.8, 9
There are many studies demonstrating the link between urate and hypertension, of which Takase et al.3 is but one of many. Even though there are many studies this does not prove a causal link: it is well known that association alone is not evidence of causation and therefore in the absence of the rat evidence, all we could say is that there is a link between the two factors but that this may not be causal, because there may be some other factor that drives both phenomena. The rat data strongly suggest that there is a causal link and the genetic data suggest how that link may have come into being.
In the field of cardiovascular medicine relating to hyperlipidemia, the concept of primary and secondary prevention is well established. In primary prevention the aim is to provide treatment before there is any evidence of damage. Perhaps, a similar trial needs to be conceived for hypertension, that is, a placebo study where people with normal blood pressure should be given allopurinol to see whether it can prevent the development of hypertension.
- Perlstein TS, Gumieniak O, Williams GH, Sparrow D, Vokonas PS, Gaziano M et al. Uric acid and the development of hypertension: the normative aging study. Hypertension 2006; 48: 1031–1036. | Article | PubMed | ISI | CAS |
- Sundstrom J, Sullivan L, D’Agostino RB, Levy D, Kannel WB, Vasan RS. Relations of serum uric acid to longitudinal blood pressure tracking and hypertension incidence. Hypertension 2005; 45: 28–33. | Article | PubMed | ISI |
- Takase H, Kimura G, Dohi Y. Uric acid levels predict future blood pressure and new onset hypertension in the general Japanese population. J Hum Hypertens 2014; 28: 529–534. | Article |
- Tsouli SG, Liberopoulos EN, Mikhaildis DP, Athyros VG, Elisaf ME. Elevated serum uric acid levels in metabolic syndrome: an active component or an innocent bystander. Metab Clin Exp 2006; 55: 1293–12301. | Article | PubMed |
- Onat A, Uyarel H, Hergenc G, Karabulat A, Albayrak S, Sari I et al. Serum uric acid is a determinant of metabolic syndrome n a population-based study. Am J Hypertens 2006; 19: 1055–1062. | Article | PubMed | ISI | CAS |
- Watanabe S, Kang D-H, Feng I, Nakagawa T, Kanellis J, Lan H et al. Uric acid, hominid evolution, and the pathogenesis of salt sensitivity. Hypertension 2002; 40: 355–360. | Article | PubMed | ISI | CAS |
- Watanabe S, Kang D-H, Feng L, Nakagawa T, Kanellis J, Lan H et al. Uric acid, hominid evolution, and the pathogenesis of salt sensitivity. Hypertension 2002; 40: 355–360. | Article | PubMed | ISI | CAS |
- Mazzali M, Hughes J, Kim YG, Jefferson JA, Kang DH, Lan HY. t al. Elevated uric acid increases blood pressure in the rat by a novel crystal independent mechanism. Hypertension 2001; 38: 1101–1106. | Article | PubMed | ISI | CAS |
- Mazzali M, Kanellis J, Han L, Feng L, Xia Y-Y, Chen Q et al. Hyperuricemia induces a primary arteriopathy in rats by a blood pressure-independent mechanism. Am J Physiol Renal Physiol 2002; 6: F991–F997.