The latest medical research on Nephrology

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IL-1 Inhibition and Function of the HDL-Containing Fraction of Plasma in Patients with Stages 3 to 5 CKD.

Clinical Journal of the American

Systemic inflammation modulates cardiovascular disease risk and functionality of HDL in the setting of CKD. Whether interventions that modify systemic inflammation can improve HDL function in CKD is unknown.

We conducted a post hoc analysis of two randomized, clinical trials, IL-1 trap in participants with GFR 15-59 ml/min per 1.73 m2 (study A) and IL-1 receptor antagonist in participants on maintenance hemodialysis (study B), to evaluate if IL-1 blockade had improved the anti-inflammatory activity (IL-6, TNF-α, and Nod-like receptor protein 3), antioxidant function (superoxide production), and net cholesterol efflux capacity of HDL. HDL function was measured using LPS-stimulated THP-1 macrophages or peritoneal macrophages of apoE-deficient mice exposed to the apoB-depleted, HDL-containing fraction obtained from the plasma of the study participants, collected before and after the interventions to block IL-1 effects. Analysis of covariance was used for between group comparisons.

The mean age of the participants was 60±13 years, 72% (n=33) were men, and 39% (n=18) were black. There were 32 CKD (16 IL-1 trap and 16 placebo) and 14 maintenance hemodialysis (7 IL-1 receptor antagonist and 7 placebo) participants. Compared with placebo, IL-1 inhibition, in study A and B reduced cellular expression of TNF-α by 15% (P=0.05) and 64% (P=0.02), IL-6 by 38% (P=0.004) and 56% (P=0.08), and Nod-like receptor protein 3 by 16% (P=0.01) and 25% (P=0.02), respectively. The intervention blunted superoxide production in the treated arm compared with placebo, with the values being higher by 17% in the placebo arm in study A (P<0.001) and 12% in the placebo arm in study B (P=0.004). Net cholesterol efflux capacity was not affected by either intervention.

IL-1 blockade improves the anti-inflammatory and antioxidative properties of the HDL-containing fraction of plasma in patients with stages 3-5 CKD, including those on maintenance hemodialysis.

Duration of Dual Antiplatelet Therapy in Patients with CKD and Drug-Eluting Stents: A Meta-Analysis.

Clinical Journal of the American

Whether prolonged dual antiplatelet therapy (DAPT) is more protective in patients with CKD and drug-eluting stents compared with shorter DAPT is uncertain. The purpose of this meta-analysis was to examine whether shorter DAPT in patients with drug-eluting stents and CKD is associated with lower mortality or major adverse cardiovascular event rates compared with longer DAPT.

A Medline literature research was conducted to identify randomized trials in patients with drug-eluting stents comparing different DAPT duration strategies. Inclusion of patients with CKD was also required. The primary outcome was a composite of all-cause mortality, myocardial infarction, stroke, or stent thrombosis (definite or probable). Major bleeding was the secondary outcome. The risk ratio (RR) was estimated using a random-effects model.

Five randomized trials were included (1902 patients with CKD). Short DAPT (≤6 months) was associated with a similar incidence of the primary outcome, compared with 12-month DAPT among patients with CKD (48 versus 50 events; RR, 0.93; 95% confidence interval [95% CI], 0.64 to 1.36; P=0.72). Twelve-month DAPT was also associated with a similar incidence of the primary outcome compared with extended DAPT (≥30 months) in the CKD subgroup (35 versus 35 events; RR, 1.04; 95% CI, 0.67 to 1.62; P=0.87). Numerically lower major bleeding event rates were detected with shorter versus 12-month DAPT (9 versus 13 events; RR, 0.69; 95% CI, 0.30 to 1.60; P=0.39) and 12-month versus extended DAPT (9 versus 12 events; RR, 0.83; 95% CI, 0.35 to 1.93; P=0.66) in patients with CKD.

Short DAPT does not appear to be inferior to longer DAPT in patients with CKD and drug-eluting stents. Because of imprecision in estimates (few events and wide confidence intervals), no definite conclusions can be drawn with respect to stent thrombosis.

Serum and Urine Albumin and Response to Loop Diuretics in Heart Failure.

Clinical Journal of the American

Diuretic resistance can limit successful decongestion of patients with heart failure. Because loop diuretics tightly bind albumin, low serum albumin and high urine albumin can theoretically limit diuretic delivery to the site of action. However, it is unknown if this represents a clinically relevant mechanism of diuretic resistance in human heart failure.

In total, 208 outpatients with heart failure at the Yale Transitional Care Center undergoing diuretic treatment were studied. Blood and urine chemistries were collected at baseline and 1.5 hours postdiuretic administration. Urine diuretic levels were normalized to urine creatinine and adjusted for diuretic dose administered, and diuretic efficiency was calculated as sodium output per doubling of the loop diuretic dose. Findings were validated in an inpatient heart failure cohort (n=60).

Serum albumin levels in the outpatient cohort ranged from 2.4 to 4.9 g/dl, with a median of 3.7 g/dl (interquartile range, 3.5-4.1). Serum albumin had no association with urinary diuretic delivery (r=-0.05; P=0.52), but higher levels weakly correlated with better diuretic efficiency (r=0.17; P=0.02). However, serum albumin inversely correlated with systemic inflammation as assessed by plasma IL-6 (r=-0.35; P<0.001), and controlling for IL-6 eliminated the diuretic efficiency-serum albumin association (r=0.12; P=0.12). In the inpatient cohort, there was no association between serum albumin and urinary diuretic excretion (r=0.15; P=0.32) or diuretic efficiency (r=-0.16; P=0.25). In the outpatient cohort, 39% of patients had microalbuminuria, and 18% had macroalbuminuria. There was no correlation between albuminuria and diuretic efficiency after adjusting for kidney function (r=-0.02; P=0.89). Results were similar in the inpatient cohort.

Serum albumin levels were not associated with urinary diuretic excretion, and urinary albumin levels were not associated with diuretic efficiency.

Autologous Hematopoietic Stem Cell Transplantation for Refractory Lupus Nephritis.

Clinical Journal of the American

Our study evaluated the efficiency and safety of autologous hematopoietic stem cell transplantation treatment for patients with refractory lupus nephritis.

From July 2011 to January 2015, a total of 22 patients with refractory lupus nephritis were enrolled in this study. Peripheral blood stem cells were mobilized with cyclophosphamide and granulocyte colony stimulating factor and reinfused after treatment with cyclophosphamide and antithymocyte globulin. The primary end point was the rate of remission, and secondary end points included the survival and relapse rates, changes in proteinuria, kidney function, and serology immunologic test. All complications were recorded for safety assessment.

Twenty-two patients were enrolled and underwent stem cell mobilization. There were nine men and 13 women, with a median lupus nephritis duration of 46 (33-71) months. The mean number of CD34+ cells was (7.3±3.8)×106/kg. All patients had successful engraftment, and the median times of granulocyte and platelet engraftment were 8 (7-9) and 9 (6-10) days, respectively. The major complications of stem cell transplantation were fever and gastrointestinal tract symptoms. The treatment-related mortality was 5% (one of 22). After a median follow-up of 72 (60-80) months, 18 (82%) patients achieved completed remission, one (5%) patient achieved partial remission, and one patient had no response and received peritoneal dialysis at 12 months after transplantation. The 5-year overall survival and disease-free survival rates were 91% and 53%, respectively. Six patients experienced relapse during the follow-up, and the relapse rate was 27%.

Autologous hematopoietic stem cell transplant could be used as a treatment option for refractory lupus nephritis, because it was relatively safe and associated with good outcomes.

Safety of Dynamic Intravenous Iron Administration Strategies in Hemodialysis Patients.

Clinical Journal of the American

Intravenous iron therapy for chronic anemia management is largely driven by dosing protocols that differ in intensity with respect to dosing approach (i.e., dose, frequency, and duration). Little is known about the safety of these protocols.

Using clinical data from a large United States dialysis provider linked to health care utilization data from Medicare, we constructed a cohort of patients with ESKD aged ≥65 years who initiated and continued center-based hemodialysis for ≥90 days between 2009 and 2012, and initiated at least one of the five common intravenous iron administration strategies; ranked by intensity (the amount of iron given at moderate-to-high iron indices), the order of strategies was 3 (least intensive), 2 (less intensive), 1 (reference), 4 (more intensive), and 5 (most intensive). We estimated the effect of continuous exposure to these strategies on cumulative risks of mortality and infection-related events with dynamic Cox marginal structural models.

Of 13,249 eligible patients, 1320 (10%) died and 1627 (12%) had one or more infection-related events during the 4-month follow-up. The most and least commonly initiated strategy was strategy 2 and 5, respectively. Compared with the reference strategy 1, more intensive strategies (4 and 5) demonstrated a higher risk of all-cause mortality (e.g., most intensive strategy 5: 60-day risk difference: 1.3%; 95% confidence interval [95% CI], 0.8% to 2.1%; 120-day risk difference: 3.1%; 95% CI, 1.0% to 5.6%). Similarly, higher risks were observed for infection-related morbidity and mortality among more intensive strategies (e.g., strategy 5: 60-day risk difference: 1.8%; 95% CI, 1.2% to 2.6%; 120-day risk difference: 4.3%; 95% CI, 2.2% to 6.8%). Less intensive strategies (2 and 3) demonstrated lower risks of all-cause mortality and infection-related events.

Among dialysis patients surviving 90 days, subsequent intravenous iron administration strategies promoting more intensive iron treatment at moderate-to-high iron indices levels are associated with higher risks of mortality and infection-related events.

Hepatorenal Syndrome.

Clinical Journal of the American

Hepatorenal syndrome is a severe complication of end-stage cirrhosis characterized by increased splanchnic blood flow, hyperdynamic state, a state ...

Hypoglycemia in People with Type 2 Diabetes and CKD.

Clinical Journal of the American

Among people with diabetes mellitus, CKD may promote hypoglycemia through altered clearance of glucose-lowering medications, decreased kidney gluconeogenesis, and blunted counter-regulatory response. We conducted a prospective observational study of hypoglycemia among 105 individuals with type 2 diabetes treated with insulin or a sulfonylurea using continuous glucose monitors.

We enrolled 81 participants with CKD, defined as eGFR<60 ml/min per 1.73 m2, and 24 control participants with eGFR≥60 ml/min per 1.73 m2 frequency-matched on age, duration of diabetes, hemoglobin A1c, and glucose-lowering medications. Each participant wore a continuous glucose monitor for two 6-day periods. We examined rates of sustained level 1 hypoglycemia (<70 mg/dl) and level 2 hypoglycemia (<54 mg/dl) among participants with CKD. We then tested differences compared with control participants as well as a second control population (n=73) using Poisson and linear regression, adjusting for age, sex, and race.

Over 890 total days of continuous glucose monitoring, participants with CKD were observed to have 255 episodes of level 1 hypoglycemia, of which 68 episodes reached level 2 hypoglycemia. Median rate of hypoglycemic episodes was 5.3 (interquartile range, 0.0-11.7) per 30 days and mean time spent in hypoglycemia was 28 (SD 37) minutes per day. Hemoglobin A1c and the glucose management indicator were the main clinical correlates of time in hypoglycemia (adjusted differences 6 [95% confidence interval, 2 to 10] and 13 [95% confidence interval, 7 to 20] fewer minutes per day per 1% higher hemoglobin A1c or glucose management indicator, respectively). Compared with control populations, participants with CKD were not observed to have significant differences in time in hypoglycemia (adjusted differences 4 [95% confidence interval, -12 to 20] and -12 [95% confidence interval, -29 to 5] minutes per day).

Among people with type 2 diabetes and moderate to severe CKD, hypoglycemia was common, particularly with tighter glycemic control, but not significantly different from groups with similar clinical characteristics and preserved eGFR.

Major Adverse Kidney Events in Pediatric Sepsis.

Clinical Journal of the American

Major adverse kidney events, a composite of death, new kidney replacement therapy, or persistent kidney dysfunction, is a potential patient-centered outcome for clinical trials in sepsis-associated kidney injury. We sought to determine the incidence of major adverse kidney events within 30 days and validate this end point in pediatric sepsis.

We conducted a retrospective observational study using the Pediatric Health Information Systems Plus database of patients >6 months to <18 years old with a diagnosis of severe sepsis/septic shock; orders for bacterial blood culture, antibiotics, and at least one fluid bolus on hospital day 0/1; and known hospital disposition between January 2007 and December 2011. The primary outcome was incidence of major adverse kidney events within 30 days. Major adverse kidney events within 30 days were validated against all-cause mortality at hospital discharge, hospital length of stay, total hospital costs, hospital readmission within 30 days and 1 year, and lowest eGFR between 3 months and 1 year after discharge. We reported incidence of major adverse kidney events within 30 days with 95% confidence intervals using robust SEM and used multivariable logistic regression to test the association of major adverse kidney events within 30 days with hospital costs and mortality.

Of 1685 admissions, incidence of major adverse kidney events within 30 days was 9.6% (95% confidence interval, 8.1% to 11.0%), including 4.5% (95% confidence interval, 3.5% to 5.4%) death, 1.7% (95% confidence interval, 1.1% to 2.3%) kidney replacement therapy, and 5.8% (95% confidence interval, 4.7% to 6.9%) persistent kidney dysfunction. Patients with versus without major adverse kidney events within 30 days had higher all-cause mortality at hospital discharge (28% versus 1%; P<0.001), higher total hospital costs ($61,188; interquartile range, $21,272-140,356 versus $28,107; interquartile range, $13,056-72,697; P<0.001), and higher proportion with eGFR<60 ml/min per 1.73 m2 between 3 months and 1 year after discharge (19% versus 4%; P=0.001). Major adverse kidney events within 30 days was not associated with length of stay or readmissions.

In children with sepsis, major adverse kidney events within 30 days are common, feasible to measure, and a promising end point for future clinical trials.

This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2019_04_18_CJASNPodcast_19_05_.mp3.

Prompt apoptotic response to high glucose in SGLT expressing renal cells.

American Journal of

It is generally believed that cells that are unable to downregulate glucose transport are particularly vulnerable to hyperglycemia. Yet little is k...

Chronic Kidney Disease and the Gut Microbiome.

American Journal of

The gut microbiome is composed of a diverse population of bacteria which have beneficial and adverse effects on human health. The microbiome has re...

Vitamin D receptor activation protects against lipopolysaccharide-induced acute kidney injury through suppression of tubular cell apoptosis.

American Journal of

Acute kidney injury (AKI) is a common complication of sepsis characterized by a rapid degradation of renal function. The effect of vitamin D on AKI...

Risks of Living Kidney Donation: Current State of Knowledge on Outcomes Important to Donors.

Clinical Journal of the American

In the past decade, there have been increasing efforts to better define and quantify the short- and long-term risks of living kidney donation. Rece...