Chronic kidney disease and risk of kidney or urothelial malignancy: systematic review and meta-analysis.

BACKGROUND: Chronic kidney disease (CKD) is highly prevalent, affecting approximately 11% of U.S. adults. Multiple studies have evaluated a potential association between CKD and urinary tract malignancies. Summary estimates of urinary tract malignancy risk in CKD patients with and without common co-existing conditions may guide clinical practice recommendations. METHODS: Four electronic databases were searched for original cohort studies evaluating the association between CKD and urinary tract cancers (kidney cancer and urothelial carcinoma) through May 25, 2023, in persons with at least moderate CKD and no dialysis or kidney transplantation. Quality assessment was performed for studies meeting inclusion criteria using the Newcastle-Ottawa Scale. Meta-analysis with a random-effects model was performed for unadjusted incidence rate ratios (IRR) as well as adjusted hazard ratios (aHR) for confounding conditions (diabetes, hypertension, and/or tobacco use), shown to have association with kidney cancer and urothelial carcinoma. Sub-analysis was conducted for estimates associated with CKD stages separately. RESULTS: Six cohort studies with 8 617 563 persons were included. Overall, methodological quality of the studies was good. CKD was associated with both higher unadjusted incidence and adjusted hazard of kidney cancer (IRR, 3.36; 95% confidence interval [CI], 2.32-4.88; aHR, 2.04; 95% CI, 1.77-2.36) and urothelial cancer (IRR, 3.96; 95% CI, 2.44-6.40; aHR, 1.40; 95% CI, 1.22-1.68) compared with persons without CKD. Examining incident urinary tract cancers by CKD severity, risks were elevated in stage 3 CKD (kidney aHR, 1.89; 95% CI, 1.56-2.30; urothelial carcinoma aHR, 1.40; 95% CI, 1.18-1.65) as well as in stages 4/5 CKD (kidney cancer aHR, 2.30; 95% CI, 2.00-2.66, UC aHR, 1.24; 95% CI, 1.04-1.49). CONCLUSIONS: Even moderate CKD is associated with elevated risk of kidney cancer and UC. Providers should consider these elevated risks when managing individuals with CKD, particularly when considering evaluation for the presence and etiology of hematuria.

International practice patterns of dyslipidemia management in patients with chronic kidney disease under nephrology care: is it time to review guideline recommendations?

BACKGROUND: In contrast to guidelines related to lipid therapy in other areas, 2012 Kidney Disease Improving Global Outcomes (KDIGO) guidelines recommend conducting a lipid profile upon diagnosis of chronic kidney disease (CKD) and treating all patients older than 50 years without defining a target for lipid levels. We evaluated multinational practice patterns for lipid management in patients with advanced CKD under nephrology care. METHODS: We analyzed lipid-lowering therapy (LLT), LDL- cholesterol (LDL-C) levels, and nephrologist-specified LDL-C goal upper limits in adult patients with eGFR < 60 ml/min from nephrology clinics in Brazil, France, Germany, and the United States (2014-2019). Models were adjusted for CKD stage, country, cardiovascular risk indicators, sex, and age. RESULTS: LLT treatment differed significantly by country, from 51% in Germany to 61% in the US and France (p = 0.002) for statin monotherapy. For ezetimibe with or without statins, the prevalence was 0.3% in Brazil to 9% in France (< 0.001). Compared with patients not taking lipid-lowering therapy, LDL-C was lower among treated patients (p < 0.0001) and differed significantly by country (p < 0.0001). At the patient level, the LDL-C levels and statin prescription did not vary significantly by CKD stage (p = 0.09 LDL-C and p = 0.24 statin use). Between 7-23% of untreated patients in each country had LDL-C ≥ 160 mg/dL. Only 7-17% of nephrologists believed that LDL-C should be < 70 mg/dL. CONCLUSION: There is substantial variation in practice patterns regarding LLT across countries but not across CKD stages. Treated patients appear to benefit from LDL-C lowering, yet a significant proportion of hyperlipidemia patients under nephrologist care are not receiving treatment.

A Pilot Randomized Controlled Trial of Integrated Palliative Care and Nephrology Care.

Background: There has been a call by both patients and health professionals for the integration of palliative care with nephrology care, yet there is little evidence describing the effect of this approach. The objective of this paper is to report the feasibility and acceptability of a pilot randomized controlled trial testing the efficacy of integrated palliative and nephrology care. Methods: English speaking patients with CKD stage 5 were randomized to monthly palliative care visits for 3 months in addition to their usual care, as compared with usual nephrology care. Feasibility of recruitment, retention, completion of intervention processes, and feedback on participation was measured. Other outcomes included differences in symptom burden change, measured by the Integrated Palliative Outcome Scale-Renal, and change in quality of life, measured by the Kidney Disease Quality of Life questionnaire and completion of advance care planning documents. Results: Of the 67 patients approached, 45 (67%) provided informed consent. Of these, 27 patients completed the study (60%), and 14 (74%) of those in the intervention group completed all visits. We found small improvements in overall symptom burden (-2.92 versus 1.57) and physical symptom burden scores (-1.92 versus 1.79) in the intervention group. We did not see improvements in the quality-of-life scores, with the exception of the physical component score. The intervention group completed more advance care planning documents than controls (five health care proxy forms completed versus one, nine Medical Orders for Life Sustaining Treatment forms versus none). Conclusions: We found that pilot testing through a randomized controlled trial of an ambulatory integrated palliative and nephrology care clinical program was feasible and acceptable to participants. This intervention has the potential to improve the disease experience for those with nondialysis CKD and should be tested in other CKD populations with longer follow-up. Clinical Trials registry name and registration number: Pilot Randomized-controlled Trial of Integrated Palliative and Nephrology Care Versus Usual Nephrology Care, NCT04520984.

Platelet Activity and Cardiovascular Risk in CKD and Peripheral Artery Disease.

Introduction: Platelet dysfunction and cardiovascular risk are well-recognized features of chronic kidney disease (CKD). Platelets drive the development and progression of cardiovascular disease (CVD). The relationships between kidney function, platelet activity, and cardiovascular risk are poorly defined. Methods: We compared platelet activity and incident cardiovascular events by CKD status (estimated glomerular filtration rate [eGFR] < 60 ml/min per 1.73 m2) using data from the Platelet Activity and Cardiovascular Events study, a prospective cohort study that enrolled adults with peripheral artery disease (PAD) undergoing lower extremity revascularization. Platelet activity was measured using light transmission aggregometry (LTA) in response to submaximal dose agonist stimulation, and the subjects were followed for incident adverse cardiovascular events for a median of 18 months. Results: Overall, 113 of 285 (40%) subjects had CKD. Subjects with, versus without, CKD had higher platelet aggregation in response to stimulation with adenosine diphosphate (ADP), serotonin, epinephrine, and arachidonic acid (AA) + ex vivo aspirin (P < 0.05 for each). Following multivariable adjustment, subjects with CKD had elevated risk for myocardial infarction (MI) (adjusted hazard ratio 2.2, 95% confidence interval [1.02-4.9]) and major adverse cardiovascular events (MACE) (1.9 [1.2-3.3]) compared to those without CKD. Platelet aggregation in response to submaximal dose agonist stimulation mediated 7% to 26% of the excess risk for cardiovascular events associated with CKD. Conclusion: Among subjects with PAD undergoing lower extremity revascularization, CKD is associated with increased platelet activity that mediates, in part, elevated cardiovascular risk.

Guideline-Directed Medical Therapy Attainment and Outcomes in Dialysis-Requiring Versus Nondialysis Chronic Kidney Disease in the ISCHEMIA-CKD Trial.

BACKGROUND: Patients with chronic kidney disease (CKD) on dialysis (CKD G5D) have worse cardiovascular outcomes than patients with advanced nondialysis CKD (CKD G4-5: estimated glomerular filtration rate <30 mL/[min·1.73m2]). Our objective was to evaluate the relationship between achievement of cardiovascular guideline-directed medical therapy (GDMT) goals and clinical outcomes for CKD G5D versus CKD G4-5. METHODS: This was a subgroup analysis of ISCHEMIA-CKD (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches-Chronic Kidney Disease) participants with CKD G4-5 or CKD G5D and moderate-to-severe myocardial ischemia on stress testing. Exposures included dialysis requirement at randomization and GDMT goal achievement during follow-up. The composite outcome was all-cause mortality or nonfatal myocardial infarction. Individual GDMT goal (smoking cessation, systolic blood pressure <140 mm Hg, low-density lipoprotein cholesterol <70 mg/dL, statin use, aspirin use) trajectory was modeled. Percentage point difference was estimated for each GDMT goal at 24 months between CKD G5D and CKD G4-5, and for association with key predictors. Probability of survival free from all-cause mortality or nonfatal myocardial infarction by GDMT goal achieved was assessed for CKD G5D versus CKD G4-5. RESULTS: A total of 415 CKD G5D and 362 CKD G4-5 participants were randomized. Participants with CKD G5D were less likely to receive statin (-6.9% [95% CI, -10.3% to -3.7%]) and aspirin therapy (-3.0% [95% CI, -5.6% to -0.6%]), with no difference in other GDMT goal attainment. Cumulative exposure to GDMT achieved during follow-up was associated with reduction in all-cause mortality or nonfatal myocardial infarction (hazard ratio, 0.88 [95% CI, 0.87-0.90]; per each GDMT goal attained over 60 days), irrespective of dialysis status. CONCLUSIONS: CKD G5D participants received statin or aspirin therapy less often. Cumulative exposure to GDMT goals achieved was associated with lower incidence of all-cause mortality or nonfatal myocardial infarction in participants with advanced CKD and chronic coronary disease, regardless of dialysis status. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01985360.

BNT162b2 vaccine effectiveness in chronic kidney disease patients-an observational study.

Background: Chronic kidney disease (CKD) is a risk factor for severe coronavirus disease 2019 (COVID-19). We aimed to evaluate the real-life effectiveness of the BNT162b2 messenger RNA vaccine for a range of outcomes in patients with CKD compared with matched controls. Methods: Data from Israel's largest healthcare organization were retrospectively used. Vaccinated CKD [estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2] and maintenance dialysis patients were matched to vaccinated controls without CKD (eGFR ≥60 ml/min/1.73 m2) according to demographic and clinical characteristics. Study outcomes included documented infection with severe acute respiratory syndrome coronavirus 2, symptomatic infection, COVID-19-related hospitalization, severe disease and death. Vaccine effectiveness was estimated as the risk ratio (RR) at days 7-28 following the second vaccine dose, using the Kaplan-Meier estimator. Effectiveness measures were also evaluated separately for various stages of CKD. Results: There were 67 861 CKD patients not treated with dialysis, 2606 hemodialysis (HD) patients and 70 467 matched controls. The risk of severe disease {RR 1.84 [95% confidence interval (CI) 0.95-2.67]} and death [RR 2.00 (95% CI 0.99-5.20)] was increased in nondialysis CKD patients compared with controls without CKD following vaccination. For the subgroup of patients with eGFR <30 ml/min/1.73 m2, the risk of severe disease and death was increased compared with controls [RR 6.42 (95% CI 1.85-17.51) and RR 8.81 (95% CI 1.63-13.81), respectively]. The risks for all study outcomes were increased in HD patients compared with controls. Conclusion: Two doses of the BNT162b2 vaccine were found to be less efficient for patients with eGFR <30 ml/min/1.73 m2. Risk in HD patients is increased for all outcomes. These results suggest prioritizing patients with eGFR <30 ml/min/1.73 m2 for booster shots, pre- and post-exposure prophylaxis and early COVID-19 therapy.

A randomized controlled pilot trial of anakinra for hemodialysis inflammation.

Chronic inflammation is highly prevalent among patients receiving maintenance hemodialysis and is associated with morbidity and mortality. Inhibiting inflammation with anti-cytokine therapy has been proposed but not well studied in this population. Therefore, we conducted the ACTION trial, a pilot, multicenter, randomized, placebo-controlled trial of an IL-1 receptor antagonist, anakinra, to evaluate safety, tolerability, and feasibility, and explore efficacy. Eighty hemodialysis patients with plasma concentrations of high sensitivity C-reactive protein (hsCRP) 2 mg/L and above were randomized 1:1 to placebo or anakinra 100 mg, three times per week via the hemodialysis circuit for 24 weeks, with an additional 24 weeks of post-treatment safety monitoring. Efficacy outcomes included changes in hsCRP (primary), cytokines, and patient-reported outcomes. Rates of serious adverse events and deaths were similar with anakinra and placebo (serious adverse events: 2.71 vs 2.74 events/patient-year; deaths: 0.12 vs 0.22 events/patient-year). The rate of adverse events of interest (including infections and cytopenias) was significantly lower with anakinra than placebo (0.48 vs 1.40 events/patient-year). Feasibility was demonstrated by attaining the enrollment target, a retention rate of 80%, and administration of 72% of doses. The median decrease in hsCRP from baseline to Week 24 was 41% in the anakinra group and 6% in the placebo group, a between-group difference that was not statistically significant. For IL-6, the median decreases were significant: 25% and 0% in the anakinra and placebo groups, respectively. An effect of anakinra on patient-reported outcomes was not evident. Thus, anakinra was well tolerated and did not increase infections or cytopenias. The promising safety data and potential efficacy on CRP and IL-6 provide support for conducting definitive trials of IL-1 inhibition to improve outcomes in hemodialysis patients.

Outcomes with revascularization and medical therapy in patients with coronary disease and chronic kidney disease: A meta-analysis.

BACKGROUND AND AIMS: Chronic kidney disease (CKD) confers a high risk for poor cardiovascular outcomes. We conducted a systematic review and meta-analysis to estimate the effects of revascularization as the initial management strategy compared with medical therapy among patients with CKD and coronary artery disease. METHODS: A Medline/PubMed literature research was conducted to identify randomized studies comparing early coronary revascularization with optimal medical therapy or medical therapy alone in patients with CKD (estimated glomerular filtration rate <60 mL/min/1.73 m2 or maintenance dialysis). The primary outcome was myocardial infarction. The secondary outcomes were all-cause mortality or progression to kidney failure. The risk ratio (RR) was estimated using a random-effects model. RESULTS: Eleven randomized trials were included (3422 patients). Revascularization was associated with lower incidence of myocardial infarction compared with medical therapy in patients with CKD: RR 0.71 (95% confidence interval [CI] 0.54-0.94; p=0.02). This result was mainly driven from a significantly lower incidence of myocardial infarction with early revascularization among patients with stable coronary artery disease: RR 0.59; 95% CI 0.37-0.93. A similar incidence of all-cause mortality was observed with both treatment strategies: RR 0.88 (95% CI 0.72-1.08; p=0.22). A trend towards lower incidence of all-cause mortality was observed with revascularization in the subgroup of patients presenting with NSTE-ACS: RR 0.73 (95% CI 0.51-1.04; p=0.08) but not among patients with stable coronary disease. There was no difference in progression to kidney failure between the two strategies. CONCLUSIONS: Coronary revascularization may be superior to medical therapy among patients with CKD and coronary disease.

Utilization of Palliative Care for Patients with COVID-19 and Acute Kidney Injury during a COVID-19 Surge.

BACKGROUND AND OBJECTIVES: AKI is a common complication of coronavirus disease 2019 (COVID-19) and is associated with high mortality. Palliative care, a specialty that supports patients with serious illness, is valuable for these patients but is historically underutilized in AKI. The objectives of this paper are to describe the use of palliative care in patients with AKI and COVID-19 and their subsequent health care utilization. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted a retrospective analysis of New York University Langone Health electronic health data of COVID-19 hospitalizations between March 2, 2020 and August 25, 2020. Regression models were used to examine characteristics associated with receiving a palliative care consult. RESULTS: Among patients with COVID-19 (n=4276; 40%), those with AKI (n=1310; 31%) were more likely than those without AKI (n=2966; 69%) to receive palliative care (AKI without KRT: adjusted odds ratio, 1.81; 95% confidence interval, 1.40 to 2.33; P<0.001; AKI with KRT: adjusted odds ratio, 2.45; 95% confidence interval, 1.52 to 3.97; P<0.001), even after controlling for markers of critical illness (admission to intensive care units, mechanical ventilation, or modified sequential organ failure assessment score); however, consults came significantly later (10 days from admission versus 5 days; P<0.001). Similarly, 66% of patients initiated on KRT received palliative care versus 37% (P<0.001) of those with AKI not receiving KRT, and timing was also later (12 days from admission versus 9 days; P=0.002). Despite greater use of palliative care, patients with AKI had a significantly longer length of stay, more intensive care unit admissions, and more use of mechanical ventilation. Those with AKI did have a higher frequency of discharges to inpatient hospice (6% versus 3%) and change in code status (34% versus 7%) than those without AKI. CONCLUSIONS: Palliative care was utilized more frequently for patients with AKI and COVID-19 than historically reported in AKI. Despite high mortality, consultation occurred late in the hospital course and was not associated with reduced initiation of life-sustaining interventions. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2022_02_24_CJN11030821.mp3.

Serum Biomarkers of Iron Stores Are Associated with Increased Risk of All-Cause Mortality and Cardiovascular Events in Nondialysis CKD Patients, with or without Anemia.

BACKGROUND: Approximately 30%-45% of patients with nondialysis CKD have iron deficiency. Iron therapy in CKD has focused primarily on supporting erythropoiesis. In patients with or without anemia, there has not been a comprehensive approach to estimating the association between serum biomarkers of iron stores, and mortality and cardiovascular event risks. METHODS: The study included 5145 patients from Brazil, France, the United States, and Germany enrolled in the Chronic Kidney Disease Outcomes and Practice Patterns Study, with first available transferrin saturation (TSAT) and ferritin levels as exposure variables. We used Cox models to estimate hazard ratios (HRs) for all-cause mortality and major adverse cardiovascular events (MACE), with progressive adjustment for potentially confounding variables. We also used linear spline models to further evaluate functional forms of the exposure-outcome associations. RESULTS: Compared with patients with a TSAT of 26%-35%, those with a TSAT ≤15% had the highest adjusted risks for all-cause mortality and MACE. Spline analysis found the lowest risk at TSAT 40% for all-cause mortality and MACE. Risk of all-cause mortality, but not MACE, was also elevated at TSAT ≥46%. Effect estimates were similar after adjustment for hemoglobin. For ferritin, no directional associations were apparent, except for elevated all-cause mortality at ferritin ≥300 ng/ml. CONCLUSIONS: Iron deficiency, as captured by TSAT, is associated with higher risk of all-cause mortality and MACE in patients with nondialysis CKD, with or without anemia. Interventional studies evaluating the effect on clinical outcomes of iron supplementation and therapies for alternative targets are needed to better inform strategies for administering exogenous iron.

Cost-Effectiveness of Coronary Artery Bypass Grafting and Percutaneous Coronary Intervention in Patients With Chronic Kidney Disease and Acute Coronary Syndromes in the US Medicare Program.

Background Coronary revascularization provides important long-term clinical benefits to patients with high-risk presentations of coronary artery disease, including those with chronic kidney disease. The cost-effectiveness of coronary interventions in this setting is not known. Methods and Results We developed a Markov cohort simulation model to assess the cost-effectiveness of percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) in patients with chronic kidney disease who were hospitalized with acute myocardial infarction or unstable angina. Model inputs were primarily drawn from a sample of 14 300 patients identified using the Medicare 20% sample. Survival, quality-adjusted life-years, costs, and cost-effectiveness were projected over a 20-year time horizon. Multivariable models indicated higher 30-day mortality and end-stage renal disease with both PCI and CABG, and higher stroke with CABG, relative to medical therapy. However, the model projected long-term gains of 0.72 quality-adjusted life-years (0.97 life-years) for PCI compared with medical therapy, and 0.93 quality-adjusted life-years (1.32 life-years) for CABG compared with PCI. Incorporation of long-term costs resulted in incremental cost-effectiveness ratios of $65 326 per quality-adjusted life-year gained for PCI versus medical therapy, and $101 565 for CABG versus PCI. Results were robust to changes in input parameters but strongly influenced by the background costs of the population, and the time horizon. Conclusions For patients with chronic kidney disease and high-risk coronary artery disease presentations, PCI and CABG were both associated with markedly increased costs as well as gains in quality-adjusted life expectancy, with incremental cost-effectiveness ratios indicating intermediate value in health economic terms.

An Exploratory Qualitative Study of Patient and Caregiver Perspectives of Ambulatory Kidney Palliative Care.

OBJECTIVES: The ideal clinical model to deliver palliative care to patients with advanced kidney disease is currently unknown. Internationally, ambulatory kidney palliative care clinics have emerged with positive outcomes, yet there is limited data from the United States (US). In this exploratory study we report perceptions of a US-based ambulatory kidney palliative care clinic from the perspective of patient and caregiver attendees. The objective of this study was to inform further improvement of our clinical program. METHODS: Semi-structured interviews were conducted to elicit the patient and caregiver experience. Eleven interviews (8 patients with chronic kidney disease stage IV or V and 3 caregivers) were analyzed using qualitative description design. RESULTS: We identified 2 themes: "Communication addressing the emotional and physical aspects of disease" and "Filling gaps in care"; Subthemes include perceived value in symptom management, assistance with coping with disease, engagement in advance care planning, program satisfaction and patient activation. SIGNIFICANCE OF RESULTS: Qualitative analysis showed that attendees of an ambulatory kidney palliative care clinic found the clinic enhanced the management of their kidney disease and provided services that filled current gaps in their care. Shared experiences highlight the significant challenges of life with kidney disease and the possible benefits of palliative care for this population. Further study to determine the optimal model of care for kidney palliative care is needed. Inclusion of the patient and caregiver perspective will be essential in this development.

Cardiovascular Issues Among Homeless People: An Issue that Needs Attention.

Cardiovascular disease is one of the most common causes of death with social factors increasingly recognized as determinants of cardiovascular prognosis. Homelessness, transient or chronic, may be one of the factors which predict treatment access and eventual outcomes as socially and economically disadvantaged group has high prevalence of cardiovascular risk factors such as smoking, and delayed diagnosis and poor control of other risk factors such as diabetes and hypertension. This perspective article aims to discuss the issues associated with cardiovascular disease treatment, outcomes and future directions for homeless patients.

Acute Peritoneal Dialysis During the COVID-19 Pandemic at Bellevue Hospital in New York City.

Background: The COVID-19 pandemic strained hospital resources in New York City, including those for providing dialysis. New York University Medical Center and affiliations, including New York City Health and Hospitals/Bellevue, developed a plan to offset the increased needs for KRT. We established acute peritoneal dialysis (PD) capability, as usual dialysis modalities were overwhelmed by COVID-19 AKI. Methods: Observational study of patients requiring KRT admitted to Bellevue Hospital during the COVID surge. Bellevue Hospital is one of the largest public hospitals in the United States, providing medical care to an underserved population. There were substantial staff, supplies, and equipment shortages. Adult patients admitted with AKI who required KRT were considered for PD. We rapidly established an acute PD program. A surgery team placed catheters at the bedside in the intensive care unit; a nephrology team delivered treatment. We provided an alternative to hemodialysis and continuous venovenous hemofiltration for treating patients in the intensive-care unit, demonstrating efficacy with outcomes comparable to standard care. Results: From April 8, 2020 to May 8, 2020, 39 catheters were placed into ten women and 29 men. By June 10, 39% of the patients started on PD recovered kidney function (average ages 56 years for men and 59.5 years for women); men and women who expired were an average 71.8 and 66.2 years old. No episodes of peritonitis were observed; there were nine incidents of minor leaking. Some patients were treated while ventilated in the prone position. Conclusions: Demand compelled us to utilize acute PD during the COVID-19 pandemic. Our experience is one of the largest recently reported in the United States of which we are aware. Acute PD provided lifesaving care to acutely ill patients when expanding current resources was impossible. Our experience may help other programs to avoid rationing dialysis treatments in health crises.

Long-term outcomes of patients with stable coronary disease and chronic kidney dysfunction: 10-year follow-up of the Medicine, Angioplasty, or Surgery Study II Trial.

BACKGROUND: Chronic kidney disease (CKD) is associated with a worse prognosis in patients with stable coronary artery disease (CAD); however, there is limited randomized data on long-term outcomes of CAD therapies in these patients. We evaluated long-term outcomes of CKD patients with CAD who underwent randomized therapy with medical treatment (MT) alone, percutaneous coronary intervention (PCI) or coronary artery bypass graft surgery (CABG). METHODS: Baseline estimated glomerular filtration rate (eGFR) was obtained in 611 patients randomized to one of three therapeutic strategies in the Medicine, Angioplasty, or Surgery Study II trial. Patients were categorized in preserved renal function and mild or moderate CKD groups depending on their eGFR (≥90, 89-60 and 59-30 mL/min/1.73 m2, respectively). The primary clinical endpoint, a composite of overall death and myocardial infarction, and its individual components were analyzed using proportional hazards regression (Clinical Trial registration information: http://www.controlled-trials.com. Registration number: ISRCTN66068876). RESULTS: Of 611 patients, 112 (18%) had preserved eGFR, 349 (57%) mild dysfunction and 150 (25%) moderate dysfunction. The primary endpoint occurred in 29.5, 32.4 and 44.7% (P = 0.02) for preserved eGFR, mild CKD and moderate CKD, respectively. Overall mortality incidence was 18.7, 23.8 and 39.3% for preserved eGFR, mild CKD and moderate CKD, respectively (P = 0.001). For preserved eGFR, there was no significant difference in outcomes between therapies. For mild CKD, the primary event rate was 29.4% for PCI, 29.1% for CABG and 41.1% for MT (P = 0.006) [adjusted hazard ratio (HR) = 0.26, 95% confidence interval (CI) 0.07-0.88; P = 0.03 for PCI versus MT; and adjusted HR = 0.48; 95% CI 0.31-0.76; P = 0.002 for CABG versus MT]. We also observed higher mortality rates in the MT group (28.6%) compared with PCI (24.1%) and CABG (19.0%) groups (P = 0.015) among mild CKD subjects (adjusted HR = 0.44, 95% CI 0.25-0.76; P = 0.003 for CABG versus MT; adjusted HR = 0.56, 95% CI 0.07-4.28; P = 0.58 for PCI versus MT). Results were similar with moderate CKD group but did not achieve significance. CONCLUSIONS: Coronary interventional therapy, both PCI and CABG, is associated with lower rates of events compared with MT in mild CKD patients >10 years of follow-up. More study is needed to confirm these benefits in moderate CKD.

The axis of local cardiac endogenous Klotho-TGF-ß1-Wnt signaling mediates cardiac fibrosis in human.

BACKGROUND: Cardiovascular fibrosis is a major contributor to cardiovascular disease, the primary cause of death in patients with chronic kidney disease (CKD). We previously reported expression of endogenous Klotho in human arteries, and that CKD is a state of Klotho deficiency, resulting in vascular calcification, but myocardial expression of Klotho is poorly understood. This study aimed to further clarify endogenous Klotho's functional roles in cardiac fibrosis in patients with underlying CKD. METHODS AND RESULTS: Human atrial appendage specimens were collected during cardiac surgery from individuals with or without CKD. Cardiac fibrosis was quantified using trichrome staining. For endogenous Klotho functional studies, primary human cardiomyocytes (HCMs) were treated with uremic serum from CKD patients or recombinant human TGF-ß1. The effects of endogenous Klotho in HCMs were studied using Klotho-siRNA and Klotho-plasmid transfection. Both gene and protein expression of endogenous Klotho are found in human heart, but decreased Klotho expression is clearly associated with the degree of cardiac fibrosis in CKD patients. Moreover, we show that endogenous Klotho is expressed by HCMs and cardiac fibroblasts (HCFs) but that HCM expression is suppressed by uremic serum or TGF-ß1. Klotho knockdown or overexpression aggravates or mitigates TGF-ß1-induced fibrosis and canonical Wnt signaling in HCMs, respectively. Furthermore, co-culture of HCMs with HCFs increases TGF-ß1-induced fibrogenic proteins in HCFs, but overexpression of endogenous Klotho in HCMs mitigates this effect, suggesting functional crosstalk between HCMs and HCFs. CONCLUSIONS: Our data from analysis of human hearts as well as functional in vitro studies strongly suggests that the loss of cardiac endogenous Klotho in CKD patients, specifically in cardiomyocytes, facilitates intensified TGF-ß1 signaling which enables more vigorous cardiac fibrosis through upregulated Wnt signaling. Upregulation of endogenous Klotho inhibits pathogenic Wnt/ß-catenin signaling and may offer a novel strategy for prevention and treatment of cardiac fibrosis in CKD patients.

Chronic kidney disease and valvular heart disease: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference.

Chronic kidney disease (CKD) is a major risk factor for valvular heart disease (VHD). Mitral annular and aortic valve calcifications are highly prevalent in CKD patients and commonly lead to valvular stenosis and regurgitation, as well as complications including conduction system abnormalities and endocarditis. VHD, especially mitral regurgitation and aortic stenosis, is associated with significantly reduced survival among CKD patients. Knowledge related to VHD in the general population is not always applicable to CKD patients because the pathophysiology may be different, and CKD patients have a high prevalence of comorbid conditions and elevated risk for periprocedural complications and mortality. This Kidney Disease: Improving Global Outcomes (KDIGO) review of CKD and VHD seeks to improve understanding of the epidemiology, pathophysiology, diagnosis, and treatment of VHD in CKD by summarizing knowledge gaps, areas of controversy, and priorities for research.

Safety and cardiovascular efficacy of spironolactone in dialysis-dependent ESRD (SPin-D): a randomized, placebo-controlled, multiple dosage trial.

The safety and efficacy of spironolactone is uncertain in end-stage renal disease. We randomized 129 maintenance hemodialysis patients to placebo (n=51) or spironolactone 12.5 mg (n=27), 25 mg (n=26), or 50 mg (n=25) daily for 36 weeks in a double-blind, placebo-controlled, multiple dosage trial to assess safety, tolerability and feasibility and to explore cardiovascular efficacy. The primary safety endpoints were hyperkalemia (potassium > 6.5 mEq/L) and hypotension requiring emergency department visit or hospitalization. Diastolic function was assessed by Doppler echocardiography. 125 participants (97%) completed dose escalation, with no significant difference in permanent study drug discontinuation between the groups (27.5% in placebo versus 16.7% in the combined spironolactone groups and 28% in the 50 mg group). Hyperkalemia frequency was similar between spironolactone and placebo (0.49 versus 0.50 events per patient-year) but demonstrated a significant linear trend due primarily to an increased event rate at the 50 mg dose (0.89 events per patient-year). The primary hypotension outcome was infrequent and similar with spironolactone and placebo (0.11 versus 0 events per patient-year). Gynecomastia was rare and did not differ significantly between groups. Change in diastolic function was similar with spironolactone and placebo. Spironolactone appears safe in carefully monitored maintenance hemodialysis patients, but did not affect cardiovascular parameters in this small study. Hyperkalemia occurs more frequently as dosage increases to 50 mg daily.

Relation of Serum and Urine Renal Biomarkers to Cardiovascular Risk in Patients with Type 2 Diabetes Mellitus and Recent Acute Coronary Syndromes (From the EXAMINE Trial).

A deeper understanding of the interplay between the renal axis and cardiovascular (CV) disease is needed in type 2 diabetes mellitus (T2DM). We aimed to explore the prognostic value of a comprehensive panel of renal biomarkers in patients with T2DM at high CV risk. We evaluated the prognostic performance of both serum (Cystatin C) and urine renal biomarkers (neutrophil gelatinase-associated lipocalin, kidney injury molecule-1 protein, and indices of urinary protein excretion) in 5,380 patients with T2DM and recent acute coronary syndromes in the EXAMINE trial. Patients requiring dialysis within 14 days were excluded. Single- and multimarker covariate-adjusted Cox proportional hazards models were developed to predict times to events. Primary endpoint was composite nonfatal myocardial infarction, nonfatal stroke, or CV death. Median age was 61 years, 68% were men, and mean baseline estimated glomerular filtration rate (eGFR) was 74 mL/min/1.73 m2. During median follow-up of 18 months, 621 (11.5%) experienced the primary endpoint and 326 (6.1%) patients had died. All renal biomarkers were robustly associated with adverse CV events in step-wise fashion, independent of baseline eGFR. However, in the multimarker prediction model, only Cystatin C (per 1 SD) was associated with the primary endpoint (hazard ratio [HR] 1.28 [1.14 to 1.45]; p ≤ 0.001), death (HR 1.51 [1.30 to 1.74]; p ≤ 0.001), and heart failure hospitalization (HR 1.20 [0.96 to 1.49]; p = 0.11). Association between Cystatin C and the primary endpoint was similar in baseline eGFR above and below 60 mL/min/1.73 m2 (Pinteraction > 0.05). In conclusion, serum and urine renal biomarkers, when tested alone, independently predict long-term adverse CV events in high-risk patients with T2DM. In an integrative panel of renal biomarkers, only serum Cystatin C remained independently associated with subsequent CV risk. Renal biomarkers informing various aspects of kidney function may further our understanding of the complex interplay between diabetic kidney disease and CV disease.

Extracorporeal Stromal Cell Therapy for Subjects With Dialysis-Dependent Acute Kidney Injury.

INTRODUCTION: The pathophysiology of acute kidney injury (AKI) involves damage to renal epithelial cells, podocytes, and vascular beds that manifests into a deranged, self-perpetuating immune response and peripheral organ dysfunction. Such an injury pattern requires a multifaceted therapeutic to alter the wound healing response systemically. Mesenchymal stromal cells (MSCs) are a unique source of secreted factors that can modulate an inflammatory response to acute organ injury and enhance the repair of injured tissue at the parenchymal and endothelial levels. This phase Ib/IIa clinical trial evaluates SBI-101, a combination product that administers MSCs extracorporeally to overcome pharmacokinetic barriers of MSC transplantation. SBI-101 contains allogeneic human MSCs inoculated into a hollow-fiber hemofilter for the treatment of patients with severe AKI who are receiving continuous renal replacement therapy (CRRT). SBI-101 therapy is designed to reprogram the molecular and cellular components of blood in patients with severe organ injury. METHODS: This study is a prospective, multicenter, randomized, double-blind, sham-controlled, study of subjects with a clinical diagnosis of AKI who are receiving CRRT. Up to 32 subjects may be enrolled to provide 24 evaluable subjects (as a per protocol population). Subjects will receive CRRT in tandem with a sham control (0 MSCs), or the low- (250 × 106 MSCs) or high-dose (750 × 106 MSCs) SBI-101 therapeutic. RESULTS: The study will measure dose-dependent safety, renal efficacy, and exploratory biomarkers to characterize the pharmacokinetics and pharmacodynamics of SBI-101 in treated subjects. CONCLUSION: This first-in-human clinical trial will evaluate the safety and tolerability of SBI-101 in patients with AKI who require CRRT.