Combination Treatment with Sodium Nitrite and Isoquercetin on Endothelial Dysfunction among Patients with CKD: A Randomized Phase 2 Pilot Trial.

BACKGROUND AND OBJECTIVES: Endothelial dysfunction is common among patients with CKD. We tested the efficacy and safety of combination treatment with sodium nitrite and isoquercetin on biomarkers of endothelial dysfunction in patients with CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This randomized, double-blind, placebo-controlled phase 2 pilot trial enrolled 70 patients with predialysis CKD. Thirty-five were randomly assigned to combination treatment with sodium nitrite (40 mg twice daily) and isoquercetin (225 mg once daily) for 12 weeks, and 35 were randomly assigned to placebo. The primary outcome was mean change in flow-mediated vasodilation over the 12-week intervention. Secondary and safety outcomes included biomarkers of endothelial dysfunction, inflammation, and oxidative stress as well as kidney function, methemoglobin, and adverse events. Intention-to-treat analysis was conducted. RESULTS: Baseline characteristics, including age, sex, race, cigarette smoking, history of hypertension and diabetes, use of renin-angiotensin system blockers, BP, fasting glucose, lipid profile, kidney function, urine albumin-creatinine ratio, and endothelial biomarkers, were comparable between groups. Over the 12-week intervention, flow-mediated vasodilation increased 1.1% (95% confidence interval, -0.1 to 2.3) in the treatment group and 0.3% (95% confidence interval, -0.9 to 1.5) in the placebo group, and net change was 0.8% (95% confidence interval, -0.9 to 2.5). In addition, changes in biomarkers of endothelial dysfunction (vascular adhesion molecule-1, intercellular adhesion molecule-1, E-selectin, vWf, endostatin, and asymmetric dimethylarginine), inflammation (TNF-α, IL-6, C-reactive protein, IL-1 receptor antagonist, and monocyte chemoattractant protein-1), and oxidative stress (oxidized LDL and nitrotyrosines) were not significantly different between the two groups. Furthermore, changes in eGFR, urine albumin-creatinine ratio, methemoglobin, and adverse events were not significantly different between groups. CONCLUSIONS: This randomized phase 2 pilot trial suggests that combination treatment with sodium nitrite and isoquercetin did not significantly improve flow-mediated vasodilation or other endothelial function biomarkers but also did not increase adverse events compared with placebo among patients with CKD. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Nitrite, Isoquercetin, and Endothelial Dysfunction (NICE), NCT02552888.

The association of angiogenic factors and chronic kidney disease.

BACKGROUND: There are limited data on the associations of circulating angiogenic factors with chronic kidney disease (CKD). We investigate the associations of circulating vascular endothelial growth factor (VEGF)-A, angiopoietin-1, angiopoietin-1/VEGF-A ratio, VEGF receptor 1 (VEGFR-1), VEGFR-2, and pentraxin-3 with CKD. METHODS: We recruited 201 patients with CKD and 201 community controls without CKD from the greater New Orleans area. CKD was defined as estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 or presence of albuminuria. Multivariable quantile and logistic regression models were used to examine the relationship between angiogenesis-related factors and CKD adjusting for confounding factors. RESULTS: After adjusting for covariables including traditional cardiovascular disease (CVD) risk factors, C-reactive protein, and history of CVD, the medians (interquartile range) were 133.08 (90.39, 204.15) in patients with CKD vs. 114.17 (72.45, 170.32) pg/mL in controls without CKD (p = 0.002 for group difference) for VEGF-A; 3951.2 (2471.9, 6656.6) vs. 4270.5 (2763.7, 6537.2) pg/mL (p = 0.70) for angiopoietin-1; 25.87 (18.09, 47.90) vs. 36.55 (25.71, 61.10) (p = 0.0001) for angiopoietin-1/VEGF-A ratio; 147.81 (122.94, 168.79) vs. 144.16 (123.74, 168.05) ng/mL (p = 0.25) for VEGFR-1; 26.20 (22.67, 29.92) vs. 26.28 (23.10, 29.69) ng/mL (p = 0.31) for VEGFR-2; and 1.01 (0.79, 1.49)vs. 0.89 (0.58, 1.18) ng/mL (p = 0.01) for pentraxin-3, respectively. In addition, an elevated VEGF-A level and decreased angiopoietin-1/VEGF-A ratio were associated with increased odds of CKD. CONCLUSIONS: These data indicate that plasma VEGF-A and pentraxin-3 levels were increased and the angiopoietin-1/VEGF-A ratio was decreased in patients with CKD. Future prospective studies are warranted to examine whether angiogenic factors play a role in progression of CKD.

Interrelationship of Multiple Endothelial Dysfunction Biomarkers with Chronic Kidney Disease.

The interrelationship of multiple endothelial biomarkers and chronic kidney disease (CKD) has not been well studied. We measured asymmetric dimethylarginine (ADMA), L-arginine, soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular adhesion molecule-1 (sVCAM-1), soluble E-selectin (sE-selectin), von Willebrand factor (vWF), flow-mediated dilation (FMD), and nitroglycerin-induced dilation (NID) in 201 patients with CKD and 201 community-based controls without CKD. Multivariable analyses were used to examine the interrelationship of endothelial biomarkers with CKD. The multivariable-adjusted medians (interquartile ranges) were 0.54 (0.40, 0.75) in patients with CKD vs. 0.25 (0.22, 0.27) µmol /L in controls without CKD (p<0.0001 for group difference) for ADMA; 67.0 (49.6, 86.7) vs. 31.0 (27.7, 34.2) µmol/L (p<0.0001) for L-arginine; 230.0 (171.6, 278.6) vs. 223.9 (178.0, 270.6) ng/mL (p=0.55) for sICAM-1; 981.7 (782.6, 1216.8) vs. 633.2 (507.8, 764.3) ng/mL (p<0.0001) for sVCAM-1; 47.9 (35.0, 62.5) vs. 37.0 (28.9, 48.0) ng/mL (p=0.01) for sE-selectin; 1320 (1044, 1664) vs. 1083 (756, 1359) mU/mL (p=0.008) for vWF; 5.74 (3.29, 8.72) vs. 8.80 (6.50, 11.39)% (p=0.01) for FMD; and 15.2 (13.5, 16.9) vs. 19.1 (17.2, 21.0)% (p=0.0002) for NID, respectively. In addition, the severity of CKD was positively associated with ADMA, L-arginine, sVCAM-1, sE-selectin, and vWF and inversely associated with FMD and NID. Furthermore, FMD and NID were significantly and inversely correlated with ADMA, L-arginine, sVCAM-1, sE-selectin, and vWF. In conclusion, these data indicate that multiple dysfunctions of the endothelium were present among patients with CKD. Interventional studies are warranted to test the effects of treatment of endothelial dysfunction on CKD.

Circulating adipocytokines and chronic kidney disease.

BACKGROUND: Adipokines have been associated with atherosclerotic heart disease, which shares many common risk factors with chronic kidney disease (CKD), but their relationship with CKD has not been well characterized. METHODS: We investigated the association of plasma leptin, resistin and adiponectin with CKD in 201 patients with CKD and 201 controls without. CKD was defined as estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m(2) or presence of albuminuria. Quantile regression and logistic regression models were used to examine the association between adipokines and CKD adjusting for multiple confounding factors. RESULTS: Compared to controls, adjusted median leptin (38.2 vs. 17.2 ng/mL, p<0.0001) and adjusted mean resistin (16.2 vs 9.0 ng/mL, p<0.0001) were significantly higher in CKD cases. The multiple-adjusted odds ratio (95% confidence interval) of CKD comparing the highest tertile to the lower two tertiles was 2.3 (1.1, 4.9) for leptin and 12.7 (6.5, 24.6) for resistin. Median adiponectin was not significantly different in cases and controls, but the odds ratio comparing the highest tertile to the lower two tertiles was significant (1.9; 95% CI, 1.1, 3.6). In addition, higher leptin, resistin, and adiponectin were independently associated with lower eGFR and higher urinary albumin levels. CONCLUSIONS: These findings suggest that adipocytokines are independently and significantly associated with the risk and severity of CKD. Longitudinal studies are warranted to evaluate the prospective relationship of adipocytokines to the development and progression of CKD.

The association of plasma fluorescent oxidation products and chronic kidney disease: a case-control study.

BACKGROUND/AIMS: Plasma fluorescent oxidation products (FLOP) constitute a stable and easily measured biomarker of cumulative oxidative stress. However, their association with chronic kidney disease (CKD) has not been studied. METHODS: We examined the association of FLOP and CKD in 201 CKD patients and 201 controls without CKD from the community. CKD was defined as an estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m(2) or the presence of albuminuria. RESULTS: Adjusted median (interquartile range) FLOP levels were significantly higher in patients with CKD than in controls [FLOP1 (lipid oxidation products): 215.2 (181.3-268.7) vs. 156.6 (139.6-177.3) fluorescent intensity units/ml, p < 0.0001; FLOP2 (DNA oxidation products): 534.8 (379.3-842.4) vs. 269.9 (232.4-410.5) fluorescent intensity units/ml, p < 0.0001; FLOP3 (protein and phospholipid oxidation products): 51.4 (44.4-66.0) vs. 45.2 (38.3-51.7) fluorescent intensity units/ml, p = 0.002]. Compared with those with a FLOP level below the 75th percentile, participants with a FLOP level above the 75th percentile had increased odds of CKD after adjustment for covariables (FLOP1: odds ratio 13.1, 95% confidence interval 6.2-27.6; FLOP2: odds ratio 5.7, 95% confidence interval 2.9-11.1; FLOP3: odds ratio 2.4, 95% confidence interval 1.2-4.7). Levels of FLOP1, FLOP2 and FLOP3 were related to eGFR (p < 0.0001 for all) and log-transformed urine albumin (p < 0.005 for all) in multivariable-adjusted linear regression models. CONCLUSION: These data indicate that an elevated FLOP level is associated with CKD status and severity. Future studies are warranted to elucidate its role in the development and progression of CKD.

Elevated plasma levels of endostatin are associated with chronic kidney disease.

BACKGROUND/AIMS: Angiogenesis may play an important role in the renal repair process after injury. We investigated the association between plasma endostatin, an endothelial-specific antiangiogenic factor, and chronic kidney disease (CKD). METHODS: We compared plasma endostatin levels in 201 CKD patients and 201 controls. CKD was defined as estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m(2) or presence of albuminuria (≥30 mg/24 h). RESULTS: After adjustment for established CKD risk factors, the median (interquartile range) of plasma endostatin was 276.7 ng/dl (199.3-357.5) in patients with CKD and 119.4 ng/dl (103.7-134.6) in controls without CKD (p < 0.0001 for group difference). log-transformed plasma endostatin was significantly and inversely correlated with eGFR (r = -0.83, p < 0.0001) and positively correlated with log-transformed urine albumin (r = 0.66, p < 0.0001) in the study participants. In addition, one standard deviation increase in log-transformed plasma endostatin (0.55 ng/dl) was associated with a decline in eGFR of -26.2 ml/min and an increase in urine albumin of 3.26 mg/ 24 h after adjusting for multiple covariables. Furthermore, the multivariable-adjusted odds ratio for CKD comparing the highest tertile (≥131.4 ng/dl) to the two lower tertiles of plasma endostatin was 21.6 (95% CI: 10.2-45.5; p < 0.0001). CONCLUSION: These data indicate that elevated plasma endostatin is strongly and independently associated with CKD. Prospective cohort studies and clinical trials are warranted to further examine the causal relationship between endostatin and risk of CKD and to develop novel interventions targeting circulating endostatin aimed at reducing CKD risk.

Network 13 partnership to improve the influenza, pneumococcal pneumonia, and hepatitis B vaccination rates among dialysis patients.

Vaccinations are available for primary prevention of many infections in adults. Morbidity and mortality from invasive diseases such as influenza and Streptococcus pneumoniae (pneumococcus) remain high and may be largely preventable by vaccination of high-risk adults, including dialysis patients. The current 23-valent vaccine-efficacious, with a low adverse event profile-is widely available. Revaccination is also recommended in patients with immunocompromising conditions, including chronic kidney disease. Despite having many opportunities to be vaccinated, adult hemodialysis and peritoneal dialysis patients are often missed During the recent H1N1 influenza outbreak, we conducted a performance improvement project to increase the vaccination rates for pneumococcal pneumonia, hepatitis B, and influenza, with a special focus on prevention. The project included an education phase, baseline assessment of vaccination rates, intervention, and a follow-up assessment of vaccination rates. The geographic jurisdiction of ESRD Network 13 encompasses the states of Arkansas, Louisiana, and Oklahoma. At the beginning of the network-wide project, the documented state-specific rates for influenza immunization were below the average influenza immunization rates for adults reported by Centers for Disease Control and Prevention and far below its target for adults. Our improvement project incorporated educational interventions to improve patient acceptance of vaccinations, educational interventions to improve staff participation in quality improvement activities, and improved techniques of quality improvement data collection and analysis by participants. During this project, the immunization rates for hepatitis B and pneumococcal pneumonia were also reviewed. At project's conclusion, improvement was demonstrated in all three focus areas, with statistically significant improvements noted in both influenza and pneumococcus vaccination rates. The use of educational interventions to improve staff participation in quality improvement, and the collection and analysis of quality improvement data can be replicated in many practice settings to improve immunization rates for dialysis patients and other patients with chronic illnesses.

An arteriovenous fistula (AVF) functionality quality improvement tracking tool--developed and implemented to improve newly placed AVF utilization rates and patient outcomes.

The authors developed a reporting tool to assist hemodialysis clinicians to track new arteriovenous fistulas (AVFs), their maturation, and use. The tool identifies impediments to timely use (6 weeks/42 days) of AVFs. The use of this tool in nine dialysis units with high gaps between AVF placement and usage reduced the gap from 19.5% to 13.5% and reflected a reduction in the percentage of AVFs in place but not in use from 31.4% to 23.2%.

Disaster preparedness of dialysis patients for Hurricanes Gustav and Ike 2008.

Hurricanes Katrina and Rita resulted in massive devastation of the Gulf Coast at Mississippi, Louisiana, and Texas during 2005. Because of those disasters, dialysis providers, nephrologists, and dialysis patients used disaster planning activities to work to mitigate the morbidity and mortality associated with the 2005 hurricane season for future events affecting dialysis patients. As Hurricane Gustav approached, anniversary events for Hurricane Katrina were postponed because of evacuation orders for nearly the entire Louisiana Gulf Coast. As part of the hurricane preparation, dialysis units reviewed the disaster plans of patients, and patients made preparation for evacuation. Upon evacuation, many patients returned to the dialysis units that had provided services during their exile from Hurricane Katrina; other patients went to other locations as part of their evacuation plan. Patients uniformly reported positive experiences with dialysis providers in their temporary evacuation communities, provided that those communities did not experience the effects of Hurricane Gustav. With the exception of evacuees to Baton Rouge, patients continued to receive their treatments uninterrupted. Because of extensive damage in the Baton Rouge area, resulting in widespread power losses and delayed restoration of power to hospitals and other health care facilities, some patients missed one treatment. However, as a result of compliance with disaster fluid and dietary recommendations, no adverse outcomes occurred. In most instances, patients were able to return to their home dialysis unit or a nearby unit to continue dialysis treatments within 4 - 5 days of Hurricane Gustav. Hurricane Ike struck the Texas Gulf Coast near Galveston, resulting in devastation of that area similar to the devastation seen in New Orleans after Katrina. The storm surge along the Louisiana Gulf Coast resulted in flooding that temporarily closed coastal dialysis units. Patients were prepared and experienced minimal interruption of dialysis services. Early planning and evacuation in the face of hurricane landfall--lessons learned from Hurricane Katrina in 2005--prevented disruption of treatment.

Shifts in dialysis patients from natural disasters in 2005.

Hurricanes Katrina and Rita alerted the world to North America's Gulf Coast's vulnerability to natural disasters. This vulnerability was most evident in poor, minority and elderly populations, and patients with chronic diseases requiring treatment such as dialysis. These hurricanes resulted in massive devastation of the healthcare infrastructure, including dialysis units, across the Gulf Coast region, and often resulted in temporary or permanent closure of dialysis units, predominantly in the New Orleans metropolitan area; however, Hurricane Rita primarily affected Lake Charles. Most notable was the population shift of dialysis patients in Louisiana due to hurricanes Katrina and Rita. Before the 2005 hurricane season, there were 2011 and 362 dialysis patients residing in the parishes (the Louisiana equivalent to counties) most affected by hurricanes Katrina and Rita, respectively. Each of these parishes had experienced increases in dialysis patient populations over the past 5 years. However, following the storms, there were 1014 and 316 dialysis patients residing in the affected parishes. Reasons for the population shifts were multifactorial in nature and included individual, provider, and healthcare system factors. As patients and physicians return to these affected areas, dialysis services will need to be reallocated based on new demographics and distribution of services in Louisiana communities. In planning for future dialysis services, adaptations will need to occur to prevent future interruption of services and loss of patient access to dialysis services.

End-stage renal disease use in hurricane-prone areas: should nephrologists increase the utilization of peritoneal dialysis?

Hurricane Katrina resulted in massive destruction of the gulf coast of the United States in 2005. In the immediate aftermath, displaced dialysis patients required urgent hemodialysis or additional peritoneal dialysis (PD) supplies. Massive damage to the health care infrastructure in these communities disrupted dialysis services for several months. As a result of this event and subsequent storms during the 2005 Atlantic hurricane season, many decisions regarding future services to dialysis patients in hurricane prone communities (HPCs) need to occur. Nephrologists, dialysis nurses, dialysis providers, and patients need to discuss the ramifications of and types of continued dialysis services in HPC. Nephrologists should encourage PD, and efforts to educate on other renal replacement therapies including PD and transplant should occur. With the potential for interruption of electrical, sewerage, and water services, more patients should consider PD. Recovery from future events begins with appropriate disaster planning. Many questions are considered and need answering in planning for dialysis services in HPC and other communities subject to natural disasters. This summary provides the basis to begin discussions when planning for dialysis services in communities prone to natural disasters.

Dialysis services in the hurricane-affected areas in 2005: lessons learned.

BACKGROUND: Hurricane Katrina resulted in partial or complete devastation of dialysis services throughout the Gulf Coast, including the New Orleans metropolitan area. In the immediate aftermath, dialysis had to be provided to patients by surrounding communities in Louisiana, and ultimately by dialysis programs throughout the nation. Peritoneal dialysis patients, though typically more independent, also endured challenges in continuing dialysis following Hurricane Katrina. Hurricane Rita caused similar damage to the western Gulf Coast at Lake Charles, Louisiana and Beaumont, Texas and further delayed recovery of dialysis services in the New Orleans metropolitan area. SETTING: A review of the problems created by the disaster provided many opportunities to improve healthcare delivery and to prepare for recovery from the event. Understanding what happened to the delivery of dialysis and chronic kidney disease services allows the opportunity to develop better systems to support this particularly vulnerable population of patients. CONCLUSION: Many lessons can be learned from these events to minimize future interruption of dialysis services in the face of natural disasters such as hurricanes.

The Massachusetts health insurance law: providing health insurance to all.

There have been increasing rates of uninsured patients in the United States over the past few decades. Despite this growing problem, little progress has been made to decrease the rate of growth of uninsured patients or to provide affordable insurance coverage to those who are unable to maintain insurance coverage throughout the year. The legislature in the Commonwealth of Massachusetts has enacted legislation that requires health insurance for all in the same manner that automobile insurance is required in many states. This bold comprehensive legislation augments current Medicaid and state child health insurance program coverage and expands coverage options for part-time workers, those employed by small companies or those employed at lower-income jobs.

Management of hypertension and dyslipidemia.

Cardiovascular disease, the leading cause of death in the United States and other developed societies, can be managed with intensive risk factor modification, including treatment of hypertension and dyslipidemia. Evidence for reduction of cardiovascular morbidity and mortality is summarized in evidence-based guidelines, primarily for hypertension in the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure and for dyslipidemia in the Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Many medications exist for treatment of hypertension and a limited number for dyslipidemia; the cornerstone of therapy for both remains lifestyle modification, including dietary interventions. Despite guidelines, control rates of concomitant hypertension and dyslipidemia remain low. Patient adherence may affect achievement of recommended goals of therapy for dyslipidemia and hypertension. Effective education and communication may improve overall achievement of treatment goals.

Perioperative management of peritoneal dialysis patients: review of abdominal surgery.

On abdominal computed tomography scan for evaluation of hematuria, the index patient, a 23-year-old male, was found to have multiple renal cysts bilaterally. He had been on peritoneal dialysis for 6 years, complicated by intermittent episodes of exit-site infection and peritonitis. Over time, he developed recurrent urinary tract infection and nephrolithiasis with intermittent hematuria. His maintenance dose of recombinant erythropoietin was discontinued, and he maintained a normal hemoglobin level. Annual surveillance of the bilateral renal cysts with magnetic resonance imaging revealed development of a complex cystic mass that warranted further investigation. Following a urology consultation, laparoscopic nephrectomy was performed without complications and with minimal interruption of PD. Pathology evaluation revealed renal cell carcinoma within the renal parenchyma and multiple cystic structures consistent with acquired cystic kidney disease. No clear recommendations exist in the literature regarding continuation or interruption of PD in the perioperative period for planned nephrectomy, tumor resection, or other uncomplicated abdominal or retroperitoneal procedures. A perioperative management strategy for PD patients requiring abdominal or retroperitoneal surgery is outlined here. If these recommendations are followed, patients may continue PD with minimal interruption, preservation of the peritoneal membrane, and few complications.