Role of tolvaptan in the management of hyponatremia in patients with lung and other cancers: current data and future perspectives.

Hyponatremia is the most frequently observed electrolyte abnormality in clinical practice, and its frequency is almost double in hospitalized cancer patients. As a subset of cancer, hyponatremia is quite common in lung cancer patients, and it is often coupled with the diagnosis of syndrome of inappropriate antidiuretic hormone secretion. The presence of hyponatremia is consequential in that its presence adversely affects cancer patients' prognosis and outcomes. Limited data suggest that correcting hyponatremia in lung cancer patients can increase response to anticancer treatment, may help reduce length of hospital stay and cost, and reduce morbidity and mortality. The type of treatment for hyponatremia depends on several factors; the key factors are the duration and severity of neurological symptoms of hyponatremia and the status of extracellular volume. When hyponatremia is caused by syndrome of inappropriate antidiuretic hormone, hypertonic saline is indicated for acute symptomatic cases, whereas fluid restriction is recommended in chronic asymptomatic hyponatremia. The latter allows a slower rate of correction, thus avoiding the dreaded complication of osmotic demyelination syndrome. Fluid restriction is, however, insufficient or impractical, and often the use of pharmacological therapy such as antidiuretic hormone receptor antagonists becomes necessary. Availability of these antagonists as an effective treatment in the management of hyponatremia has been a major breakthrough, and furthermore, its clinical or investigational use in cancer-related hyponatremia may offer a potential opportunity to gain further insights into the prognostic impact of hyponatremia correction on cancer patients' outcomes. Tolvaptan is a prototype of ADH receptor antagonists that acts at renal tubular levels to increase free water excretion without inducing major systemic electrolyte abnormalities such as hypokalemia or alkalosis. The aim of this paper is to provide a brief review while focusing on cancer hyponatremia; (1) of the epidemiology of hyponatremia and its pathophysiology and diagnostic approaches and (2) of the pharmacokinetics of tolvaptan and its clinical efficacy, safety, and compliance.

Improvement in Gemcitabine-Induced Thrombotic Microangiopathy with Rituximab in a Patient with Ovarian Cancer: Mechanistic Considerations.

Gemcitabine is a potent and widely used anticancer drug. We report a case of gemcitabine-induced thrombotic microangiopathy (GCI-TMA), a known but not widely recognized complication of gemcitabine use, and our experience of treating GCI-TMA with rituximab. A 74-year-old woman was referred to our clinic for an evaluation of worsening renal function. She has recently been treated for ovarian cancer (diagnosed in 2011) with surgery (tumor debulking and bilateral salpingo-oophorectomy) along with cisplatin chemotherapy in 2012, followed by carboplatin/doxorubicin in 2013 and recent therapy for resistant disease with gemcitabine. Laboratory tests showed anemia, normal platelets and elevated lactate dehydrogenase. A peripheral smear revealed numerous schistocytes, and a kidney biopsy showed acute as well as chronic TMA. The patient continued on gemcitabine therapy, and treatment with plasma exchange was started. Since there was no response to treatment even after 5 sessions of plasma exchange, one dose of rituximab was given, which was associated with a drop in the creatinine level to 2 mg/dl. The pathogenesis of renal injury could be the effect of direct injury to the endothelium mediated by cytokines. Usual treatment includes withdrawing the drug and initiation of treatment with plasmapheresis with or without steroids. In cases resistant to plasmapheresis, treatment with rituximab can be tried. The mechanism of action of rituximab might be due to the reduced production of B-cell-dependent cytokines that drive endothelial dysfunction by depleting B cells. Patients receiving gemcitabine chemotherapy should be monitored for the development of TMA, and early treatment with plasma exchange along with rituximab might benefit these patients who already have a bad prognosis.

Tolvaptan in hospitalized cancer patients with hyponatremia: a double-blind, randomized, placebo-controlled clinical trial on efficacy and safety.

BACKGROUND: The rate of hyponatremia is higher in hospitalized cancer patients than in hospitalized patients without cancer and is associated with poor clinical outcomes. The availability of V2 receptor antagonists has been a major breakthrough in the management of hyponatremia, but its efficacy and safety in treating hyponatremia in patients with cancer is not known. METHODS: Adult patients with cancer who were admitted to The University of Texas MD Anderson Cancer Center with nonhypovolemic hyponatremia (125-130 mmol/L) were randomized to receive either tolvaptan or placebo in a double-blind, placebo-controlled, adaptive, randomized trial. Both groups received the standard of care for hyponatremia, except that patients were allowed to drink to thirst. RESULTS: A preplanned Data Safety Monitoring Board analysis of 30 of 48 randomized patients who completed the study revealed that the primary endpoint of hyponatremia correction was met by 16 of 17 patients who received tolvaptan and by 1 of 13 patients who received placebo (94% vs 8%; P < .001), which met the study stopping rule for superiority. The secondary endpoints between the tolvaptan and placebo groups (mean ± standard deviation) for length of stay (21 ± 15 days vs 26 ± 15 days, respectively) and change in the Mini-Mental State Examination score (-0.35 ± 1.66 vs 0.31 ± 2.42, respectively) were not significantly different. No overcorrection of serum sodium (>12 mmol/L per day) was noted in the tolvaptan group, and the main adverse events noted were dry mouth, polydipsia, and polyuria, leading to 13% study withdrawal. CONCLUSIONS: Although tolvaptan was effective for correcting hyponatremia in patients with cancer, studies with a larger sample size will be required to confirm the current findings, including the outcomes of secondary endpoints.

The frequency, cost, and clinical outcomes of hypernatremia in patients hospitalized to a comprehensive cancer center.

PURPOSE: To study the frequency of hypernatremia in hospitalized cancer patients and its impact on clinical outcomes and healthcare cost. METHODS: Cross-sectional analysis of data obtained from patients admitted to the University of Texas M. D. Anderson Cancer Center over a 3-month period in 2006. The clinical outcomes and hospital costs were compared among hypernatremics, eunatremics, and hyponatremics (serum sodium values include >147, 135-147, and <135 mEq/L, respectively). RESULTS: Of 3,446 patients with at least one serum sodium value, 51.4 % were eunatremic, 46.0 % hyponatremic, and 2.6 % hypernatremic with most of the hypernatremia (90 %) acquired during hospital stay. The multivariate hazard ratio (HR) for mortality in hypernatremic was 5-fold higher than eunatremic (HR for 90 days-5.09 (95 % CI, 3.32-7.81); p < 0·01) and over 2-fold higher than hyponatremic (HR for 90 days-2.79 (95 % CI, 1.91-4.11), p < 0.01). The length of hospital stay in hypernatremic was 2-fold higher than in hyponatremic and 4-fold higher than in eunatremic (e.g., 27 ± 22 days in hypernatremic vs. 6 ± 5 days in eunatremic; mean ± SD, p < 0.01). The hospital bill was higher for hypernatremic compared with the rest of the groups (46 % over eunatremic and 37 % over hyponatremic, p < 0.01 for both). CONCLUSIONS: Although hypernatremia was far less frequent than hyponatremia in the hospitalized cancer patients, most hypernatremia were acquired in the hospital and had substantially higher mortality, hospital stay, and hospital bills than eunatremic or even hyponatremic patients. Studies are warranted to determine whether avoidance of hypernatremia or its prompt and sustained correction improves clinical outcomes.

Urinary tubular protein-based biomarkers in the rodent model of cisplatin nephrotoxicity: a comparative analysis of serum creatinine, renal histology, and urinary KIM-1, NGAL, and NAG in the initiation, maintenance, and recovery phases of acute kidney injury.

BACKGROUND: Several biomarkers are becoming available for the early detection of acute kidney injury (AKI), but few have been directly compared. OBJECTIVE: To compare urinary kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), and N-acetyl glucosaminidase (NAG) against serum creatinine and renal histological score in the initiation, maintenance, and recovery phases of cisplatin (CP)-induced AKI. METHODS: Sprague-Dawley rats (300-350 g) were injected once through their tail veins with CP (CP group) at 5.5 mg/kg or with same volume of normal saline vehicle (Control group). Rats were euthanized at 2, 4, 6, 12, and 24 hours, and on days 2, 3, 6, and 10 (n = 12 in the CP group and n = 6 in the Control group at each time point), and urine, blood, and kidney samples were analyzed. RESULTS: A significant increase in serum creatinine was noted by day 3 in the CP group versus Control group [1.46 (0.12) vs 0.28 (0.03) mg/dL; mean (SE); P < 0.05]. The renal histology scores for brush border loss and tubular necrosis were significantly higher at 12 and 24 hours, respectively, in the CP group. Urinary kidney injury molecule-1 levels were significantly higher at 24 hours in the CP group than in the Control group [48.26 (13.13) vs 8.21 (3.31) pg/mg creatinine; P < 0.05] and remained elevated through day 10. Both urine NAG and NGAL levels were significantly higher by day 2 in the CP than in the Control group [NAG, 8.19 (0.82) vs 3.48 (0.40) pg/mg creatinine, P G 0.05; NGAL, 2911.80 (368.10) vs 1412.60 (250.20) pg/mg creatinine, P < 0.05]. Urinary NAG remained elevated for 6 days and NGAL for 3 days. CONCLUSIONS: Our study suggests a temporal hierarchy in the ability of certain urinary protein-based biomarkers to detect AKI after a well-defined tubular injury. Comparative analyses of urinary biomarkers are warranted in clinical settings such as patients receiving CP to discern the time course and pattern of expression.

Incidence rate, clinical correlates, and outcomes of AKI in patients admitted to a comprehensive cancer center.

BACKGROUND AND OBJECTIVES: Incidence of AKI in hospitalized patients with cancer is increasing, but reports are scant. The objective of this study was to determine incidence rate, clinical correlates, and outcomes of AKI in patients admitted to a cancer center. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Cross-sectional analysis of prospectively collected data on 3558 patients admitted to the University of Texas M.D. Anderson Cancer Center over 3 months in 2006. RESULTS: Using modified RIFLE (Risk, Injury, Failure, Loss, ESRD) criteria, 12% of patients admitted to the hospital had AKI, with severity in the Risk, Injury, and Failure categories of 68%, 21%, and 11%, respectively. AKI occurred in 45% of patients during the first 2 days and in 55% thereafter. Dialysis was required in 4% of patients and nephrology consultation in 10%. In the multivariate model, the odds ratio (OR) for developing AKI was significantly higher for diabetes (OR, 1.89; 95% confidence interval [CI], 1.51-2.36), chemotherapy (OR, 1.61; 95% CI, 1.26-2.05), intravenous contrast (OR, 4.55; 95% CI, 3.51-5.89), hyponatremia (OR, 1.97; 95% CI, 1.57-2.47), and antibiotics (OR, 1.52; 95% CI, 1.15-2.02). In patients with AKI, length of stay (100%), cost (106%), and odds for mortality (4.7-fold) were significantly greater. CONCLUSION: The rate of AKI in patients admitted to a comprehensive cancer center was higher than the rate in most noncancer settings; was correlated significantly with diabetes, hyponatremia, intravenous contrast, chemotherapy, and antibiotics; and was associated with poorer clinical outcomes. AKI developed in many patients after admission. Studies are warranted to determine whether proactive measures may limit AKI and improve outcomes.

Onconephrology: the latest frontier in the war against kidney disease.

Renal diseases in patients with cancer have many unique features, and often these diseases require specialized approaches. Newer cancer therapy has increased cancer cure rate and survival time, but such benefit is not fully realized, partly because of therapy-associated toxicities. Fluid and electrolyte abnormalities are very common in patients with cancer, as are acute and chronic kidney injury. With the evolving complexities of newer cancer therapies, a comprehensive team approach is becoming necessary. It is essential for nephrologists to be informed and involved in cancer care. Many nephrologists caring for patients with cancer in the United States have recently met and formed a focus group, the OncoNephrology Forum, under the American Society of Nephrology. This update addresses what is clinically unique about onconephrology, the objectives and functions of the newly formed forum, and the potential of onconephrology becoming a subspecialty in nephrology.

Hyponatremia in hospitalized cancer patients and its impact on clinical outcomes.

BACKGROUND: Hyponatremia is the most common electrolyte abnormality in clinical practice, yet little is known about its frequency in patients with cancer or its impact on their clinical outcomes. STUDY DESIGN: Retrospective analysis of prospectively collected data. SETTING & PARTICIPANTS: Patients with cancer admitted to the University of Texas M.D. Anderson Cancer Center in 2006 for 3 months. PREDICTOR: Serum sodium levels categorized as eunatremia (serum sodium, 135-147 mEq/L) and mild (134-130 mEq/L), moderate (129-120 mEq/L), and severe (<120 mEq/L) hyponatremia. OUTCOMES: (1) Length of hospital stay and (2) 90-day mortality. RESULTS: In 4,702 admissions in 3,357 patients with cancer, hyponatremia (serum sodium <135 mEq/L) was noted in 47% of admissions. It was mild in 36%, moderate in 10%, and severe in 1%. Hyponatremia was acquired during the hospital stay in 24%. Using the first admission data, mean length of stay was 5.6 ± 5.0 days for patients with eunatremia and 9.9 ± 9.2, 13.0 ± 14.1, and 11.5 ± 12.6 days for those with mild, moderate, and severe hyponatremia, respectively. The respective HRs in the multivariate Cox model for longer hospital stay, using patients with eunatremia as reference, were 1.92 (95% CI, 1.75-2.13; P < 0.01), 2.94 (95% CI, 2.56-3.45; P < 0.01), and 2.32 (95% CI, 1.32-4.00; P = 0.01). 283 (8.4%) deaths occurred during 90 days, and in the multivariate model, the respective HRs for 90-day mortality for mild, moderate, and severe hyponatremia were 2.04 (95% CI, 1.42-2.91; P < 0.01); 4.74 (95% CI, 3.21-7.01; P < 0.01), and 3.46 (95% CI, 1.05-11.44; P = 0.04). These findings were consistent when analyses were repeated with sodium levels in tertiles. LIMITATIONS: Observational study, retrospective, inability to adjust for all comorbid conditions. CONCLUSION: Hyponatremia in patients with cancer is associated with longer hospital stay and higher mortality. Whether long-term correction of hyponatremia would improve these outcomes remains to be determined.

Nonerythropoietic properties of erythropoietin: implication for tissue protection.

Erythropoietin (EPO) is used at present in clinical practice to stimulate red cell production. However, a number of reports have emerged suggesting the presence of nonerythropoietic properties for EPO. Chief among them is its ability to confer protection against acute tissue injury. In this report, we briefly review the role of EPO in tissue protection and provide examples of tissue protection using cisplatin-induced kidney injury model. Also provided is a brief description of potential pathways through which EPO may be mediating this effect.

Costs and outcomes of acute kidney injury in critically ill patients with cancer.

BACKGROUND: Acute kidney injury (AKI) is a common complication in critically ill patients with cancer. The RIFLE criteria define three levels of AKI based on the percent increase in serum creatinine (Scr) from baseline: risk (> or = 50%), injury (> or = 100%), and failure (> or = 200% or requiring dialysis). The utility of the RIFLE criteria in critically ill patients with cancer is not known. OBJECTIVE: To examine the incidence, outcomes, and costs associated with AKI in critically ill patients with cancer. METHODS: We retrospectively analyzed all patients admitted to a single-center ICU over a 13-month period with a baseline Scr < or = 1.5 mg/dL (n = 2,398). Kaplan-Meier estimates for survival by RIFLE category were calculated. Logistic regression was used to determine the association of AKI on 60-day mortality. A log-linear regression model was used for economic analysis. Costs were assessed by hospital charges from the provider's perspective. RESULTS: For the risk, injury, and failure categories of AKI, incidence rates were 6%, 2.8%, and 3.7%; 60-day survival estimates were 62%, 45%, and 14%; and adjusted odds ratios for 60-day mortality were 2.3, 3, and 14.3, respectively (P < or = 0.001 compared to patients without AKI). Hematologic malignancy and hematopoietic cell transplant were not associated with mortality in the adjusted analysis. Hospital cost increased by 0.16% per 1% increase in creatinine and by 21% for patients requiring dialysis. LIMITATIONS: Retrospective analysis. Single-center study. No adjustment by cost-to-charge ratios. CONCLUSIONS: AKI is associated with higher mortality and costs in critically ill patients with cancer.

Fenoldopam preconditioning: role of heme oxygenase-1 in protecting human tubular cells and rodent kidneys against cold-hypoxic injury.

BACKGROUND: Kidneys from brain-dead donors are cold preserved until transplanted. However, prolonged cold storage can contribute to allograft failure. Studies suggest that donor preconditioning with dopaminergics may reduce cold-ischemic transplant injury, but whether heme oxygenase (HO)-1 induction is an underlying mechanism is not known. OBJECTIVE: To test whether preconditioning with fenoldopam (FD) induce HO-1 and protect kidneys against cold storage injury and whether HO-1 plays a role in protection. METHOD: We used human renal proximal tubular epithelial cells, rat kidney transplants, and HO-1 null mice kidneys. RESULTS: FD preconditioning of cells for 4 hr significantly protected against cell death from 24-hr cold hypoxia and was associated with a dose-dependent increase in HO-1 expression. In a syngeneic rat kidney transplant model, FD preconditioning for 18 hr markedly increased kidney HO-1 expression and protected kidneys against 24-hr cold-ischemic transplant injury. To test the role of HO-1, renal proximal tubular epithelial cells were treated with HO-1 small interfering RNA, followed by FD-preconditioning. Small interfering RNA inhibited the HO-1 messenger RNA expression and reversed the FD protection. Suspension of kidneys of HO-1 null and wild-type mice preconditioned with FD or saline were subjected to 24- and 48-hr cold storage. N-acetyl glucosaminidase, a specific tubular injury marker, was significantly lower in FD-preconditioned wild-type kidneys, but not in HO-1 null kidneys, suggesting a role for HO-1 in FD's preconditioning. CONCLUSION: Our data suggest HO-1 induction as an underlying mechanism for FD preconditioning and support the idea of testing FD preconditioning in the clinical setting. Studies are required to determine the optimum FD-preconditioning protocol.

Predictors and outcome of acute kidney injury in patients with acute myelogenous leukemia or high-risk myelodysplastic syndrome.

BACKGROUND: : Acute kidney injury (AKIis a common complication in the treatment of patients with acute myelogenous leukemia (AML) or high-risk myelodysplastic syndrome (HR-MDS), but, to the authors' knowledge, its clinical relevance has not been detailed to date. The objective of the current study was to identify the incidence, predictors, and outcome for AKI in patients with AML and HR-MDS. METHODS: : Data were analyzed from 537 patients with AML or HR-MDS undergoing induction chemotherapy from 1999 to 2007. Predictors for AKI were identified by logistic regression. Eight-week mortality of patients was estimated by the Kaplan-Meier method stratified by the RIFLE criteria, a novel multilevel classification system for AKI based on the percent rise in serum creatinine from baseline (Risk, >50%; Injury, >100%; and Failure, >200% or requiring dialysis). RESULTS: : A total of 187 patients (36%) developed AKI. Significant independent risk factors for AKI included the following: age >/=55 years (odds ratio [OR], 1.8), mechanical ventilation (OR, 16), use of vancomycin (OR, 2.3), diuretics (OR, 3.0), amphotericin B lipid formulation (OR, 2.7), vasopressors (OR, 4.9), leukopenia (OR, 1.9), hypoalbuminemia (OR, 1.4), and use of non-fludarabine-based chemotherapy (OR, 2.7). The 8-week mortality rates were 3.8%, 13.6%, 19.6%, and 61.7% for the non-RIFLE, Risk, Injury, and Failure categories, respectively. Patients requiring dialysis (8%) had a median survival of 33 days. Survival of patients who achieved complete remission was favorable, regardless of degree of AKI. CONCLUSIONS: : The RIFLE classification for AKI appears to have prognostic utility in predicting mortality in patients with AML or HR-MDS. Relatively mild elevations in creatinine are associated with higher mortality. Strategies to avoid nephrotoxic drugs or fluid overload may be of benefit. Cancer 2010. (c) 2010 American Cancer Society.

Sustained low efficiency dialysis in the continuous mode (C-SLED): dialysis efficacy, clinical outcomes, and survival predictors in critically ill cancer patients.

BACKGROUND AND OBJECTIVES: Oliguric, hypotensive patients who require large amounts of fluids may benefit from sustained low-efficiency dialysis performed continuously (C-SLED). C-SLED through higher clearance may improve survival, or through greater nutritional loss may worsen survival. No studies have assessed survival on C-SLED. The objective was to examine patient outcomes and survival predictors on C-SLED. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The data of 199 consecutive cancer patients treated with C-SLED were analyzed. The median duration of C-SLED was 50 h. With 48 h of C-SLED, the blood urea nitrogen (BUN) and serum creatinine levels had decreased by 80% and 73%, respectively. The mean arterial pressure (MAP) was maintained despite higher ultrafiltration and reduced vasopressor use. The 30-d mortality rate was 65%. Despite excellent dialysis, the sequential organ failure assessment (SOFA) score remained predictive of mortality. In the univariate model, higher SOFA scores and lower values for MAP, blood pH, and serum albumin and creatinine levels were associated with higher mortality. Administration of total parenteral nutrition (TPN) was, however, associated with lower mortality. RESULTS: In the multivariate model, the higher SOFA score and lower blood pH, MAP and C-SLED duration were associated with higher mortality. In a subset analysis of 129 patients who received C-SLED for at least 48 h, those with higher BUN levels, which were associated with higher TPN infusion, had a lower mortality risk. CONCLUSION: This first detailed report on C-SLED indicates that C-SLED can be effective and suggests a link between nutrition and survival.

Antiapoptotic properties of erythropoiesis-stimulating proteins in models of cisplatin-induced acute kidney injury.

Erythropoietin (Epo) induces erythrocytosis by suppressing erythroid progenitor cell apoptosis through the Janus-activated kinase-signal transducers and activators of transcription (JAK-STAT) pathway. Since apoptosis contributes to cisplatin (CP)-induced nephrotoxicity and Epo receptors (EpoR) are expressed in the kidney, we examined the role of antiapoptosis in recombinant human erythropoietin (rHuEpo)-mediated renal protection. In human renal proximal tubular epithelial (RPTE) cells in culture, rHuEpo, but not inactive rHuEpo (I-rHuEpo), the receptor-binding sites of which are mutated, caused a significant reduction in CP-induced apoptosis at > or = 100 U/ml. rHuEpo, but not I-rHuEpo, increased STAT5 and Akt/PKB phosphorylation, demonstrating functional EpoR expression on RPTE cells. Furthermore, the JAK2 inhibitor tyrphostin AG-490 attenuated rHuEpo protection, suggesting a role of the JAK-STAT pathway in rHuEpo-mediated antiapoptosis. In rats, intravenous administration of 5,000 U/kg rHuEpo, but not an equivalent peptide mass of I-rHuEpo, before a single 5.5 mg/kg iv injection of CP, significantly increased hematocrit (Hct) and reduced the CP-induced increase in serum creatinine. Serum creatinine on day 4 was 3.4 +/- 0.3, 1.9 +/- 0.3, and 3.5 +/- 0.4 mg/dl in the CP, CP + rHuEpo, and CP + I-rHuEpo groups, respectively. Similarly, darbepoietin-alpha (DA), a hyperglycosylated analog of rHuEpo with prolonged in vivo activity when injected at 25 microg/kg iv before CP, significantly increased Hct and reduced serum creatinine. Renal clearance studies based on glomerular filtration rate and renal blood flow confirmed the significant renal protection by DA against CP. Tubular apoptosis and necrosis were significantly reduced in the kidneys of the CP + DA vs. the CP + saline group. Moreover, the equalization of Hct by venesection did not abrogate the DA-mediated renal protection. Administration of DA 48 h after CP injection also conferred significant renal protection. Thus our experiments confirm a role for erythropoiesis-stimulating proteins, including the new analog DA, in limiting CP-induced nephrotoxicity and suggest that antiapoptosis via the Epo-EpoR interaction is an important mechanism for renal protection.

Obesity-survival paradox-still a controversy?

Since the original description of the obesity-survival paradox in 1999, which suggested a survival advantage for overweight and obese patients undergoing hemodialysis, a large body of evidence supporting the paradox has accumulated. The reason for the paradox has yet to be defined. Better nutrition may be a partial explanation, or it may be that in uremic milieu, excessive fat and surplus calories might confer some survival advantage. The "surplus calorie theory" as a potential mechanism for the paradox is of great interest. If proven to be correct, it might explain why peritoneal dialysis patients who receive excessive calories through dialysis do not exhibit the paradox and, secondly and more importantly, therapy could be directed to enhance a greater caloric intake by renal failure patients to engender a better survival outcome. Finally, other clinical settings, for example, congestive heart failure, have their own obesity-survival paradox. Thus, the paradox appears to be a wider phenomenon and might merely be the external expression of a larger principle yet to be uncovered.

Carbon monoxide (CO) protects renal tubular epithelial cells against cold-rewarm apoptosis.

Recent studies have suggested that carbon monoxide (CO) inhalation can reduce ischemia-reperfusion injury of kidneys. The purpose of the present study was to determine whether the direct application of CO using tricarbonylchloro (glycinato) ruthenium II (CORM3) would reduce cold-rewarm-associated apoptosis in renal tubular epithelial (RPTE) cells. RPTE cells were subjected to 48 hours of cold followed by 24 hours of rewarming with increasing concentrations (0-500 microM) of CORM3. CORM3 (100 microM) reduced apoptosis as determined by the TUNEL method from 21.6 +/- 5.2 to 5.8 +/- 1.1 % (untreated vs. treated, n = 5; p < 0.001). We subsequently observed that the incubation of RPTE cells with CORM3 induced heme oxygenase (HO)-1 gene expression. As HO-1 itself can confer protection against cold rewarm injury, we investigated the role of HO-1 in the protective actions of CORM3 using siRNA oligonucleotides directed against HO-1. CORM3 treatment of RPTE cells caused a 4.9- fold increase in HO-1 gene expression as determined by real time PCR. Prior treatment of RPTE cells with siRNAs against HO-1 was able to completely abolish the CORM3 mediated induction of HO-1 mRNA and protein. The abolition of HO-induction with siRNAs did reduce CORM3-mediated protection against cold rewarm-induced apoptosis; however, CORM3 was able to significantly protect RPTE cells against cold-rewarm injury: apoptosis was 33.7 +/- 0.9% vs. 15.4 +/- 0.5% vs. 62.8 +/- 1.5% vs. 23.5 +/- 3.4 in control cold-rewarm vs. cold-rewarm + CORM3 (100 microM) vs. cold-rewarm + HO-1 siRNA vs. cold-rewarm + CORM3 (100 microM) + HO-1 siRNA (n = 4). These results suggest that increased levels of CO alone can protect against cold-rewarm-induced apoptosis.

Survival advantages of obesity in dialysis patients.

In the general population, a high body mass index (BMI; in kg/m(2)) is associated with increased cardiovascular disease and all-cause mortality. However, the effect of overweight (BMI: 25-30) or obesity (BMI: >30) in patients with chronic kidney disease (CKD) undergoing maintenance hemodialysis (MHD) is paradoxically in the opposite direction; ie, a high BMI is associated with improved survival. Although this "reverse epidemiology" of obesity or dialysis-risk-paradox is relatively consistent in MHD patients, studies in CKD patients undergoing peritoneal dialysis have yielded mixed results. Growing confusion has developed among physicians, some of whom are no longer confident about whether to treat obesity in CKD patients. A similar reverse epidemiology of obesity has been described in geriatric populations and in patients with chronic heart failure (CHF). Possible causes of the reverse epidemiology of obesity include a more stable hemodynamic status, alterations in circulating cytokines, unique neurohormonal constellations, endotoxin-lipoprotein interaction, reverse causation, survival bias, time discrepancies among competitive risk factors, and malnutrition-inflammation complex syndrome. Reverse epidemiology may have significant clinical implications in the management of dialysis, CHF, and geriatric patients, ie, populations with extraordinarily high mortality. Exploring the causes and consequences of the reverse epidemiology of obesity in dialysis patients can enhance our insights into similar paradoxes observed for other conventional risk factors, such as blood pressure and serum cholesterol and homocysteine concentrations, and in other populations such as those with CHF, advanced age, cancer, or AIDS. Weight-gaining interventional studies in dialysis patients are urgently needed to ascertain whether they can improve survival and quality of life.