Paweena Susantitaphong

World Incidence of AKI: A Meta-Analysis

BACKGROUND AND OBJECTIVES The burden of AKI around the globe has not been systematically examined. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS A systematic review (2004-2012) of large cohort studies was conducted to estimate the world incidence of AKI and its stages of severity and associated mortality, and to describe geographic variations according to countries, regions, and their economies. AKI definitions were reclassified according to the Kidney Disease Improving Global Outcomes (KDIGO) staging system. Random-effects model meta-analyses and meta-regressions were used to generate summary estimates and explore sources of heterogeneity. RESULTS There were 312 studies identified (n=49,147,878) , primarily in hospital settings. Most studies originated from North America, Northern Europe, and Eastern Asia, from high-income countries, and from nations that spent ≥5% of the gross domestic product on total health expenditure. Among the 154 studies (n=3,585,911) that adopted a KDIGO-equivalent AKI definition, the pooled incidence rates of AKI were 21.6% in adults (95% confidence interval [95% CI], 19.3 to 24.1) and 33.7% in children (95% CI, 26.9 to 41.3). The pooled AKI-associated mortality rates were 23.9% in adults (95% CI, 22.1 to 25.7) and 13.8% in children (95% CI, 8.8 to 21.0). The AKI-associated mortality rate declined over time, and was inversely related to income of countries and percentage of gross domestic product spent on total health expenditure. CONCLUSIONS Using the KDIGO definition, 1 in 5 adults and 1 in 3 children worldwide experience AKI during a hospital episode of care. This analysis provides a platform to raise awareness of AKI with the public, government officials, and health care professionals.

International Society of Nephrology's 0by25 initiative for acute kidney injury (zero preventable deaths by 2025): a human rights case for nephrology

Executive summary Acute kidney injury (AKI) is a major contributor to poor patient outcomes. AKI occurs in about 13·3 million people per year, 85% of whom live in the developing world, and, although no direct link between AKI and death has yet been shown, AKI is thought to contribute to about 1·7 million deaths every year. The course of AKI varies with the setting in which it occurs, and the severity and duration of AKI aff ects outcomes such as dialysis requirement, renal functional recovery, and survival. Recognition is increasing for the eff ect of AKI on patients, and the resulting societal burden from its longterm eff ects, including development of chronic kidney disease and end-stage renal disease needing dialysis or trans plantation. Few systematic eff orts to manage (prevent, diagnose, and treat) AKI have been put in place and few resources have been allocated to inform health-care professionals and the public of the importance of AKI as a preventable and treatable disease. Several factors have contributed to the paucity of information. Most importantly, there have been few population-level epidemiological studies in several regions of the world. Diffi culties in defi nition of the incidence of AKI are especially evident in searches for data from low-income and middle-income countries, where more than 85% of the world’s population resides. No nationwide data collection systems are available, and data are usually from isolated centres and probably largely underestimate the true extent of AKI because they mostly do not include patients with AKI who were not able to reach a hospital for treatment. A recent metaanalysis that included 312 cohort studies and more than 49 million patients shows a scarcity of data from Africa and large parts of southeast Asia. We did an updated meta-analysis that used the most recent KDIGO (Kidney Disease: Improving Global Outcomes) defi nitions, which confi rms the high incidence and resulting outcomes of AKI, particularly in Africa, Asia, and Latin America, for which data were previously absent. The strong relation between the severity of AKI and consequent mortality is reiterated by our fi ndings and is evident across heterogeneous populations and specifi c disease cohorts. However, large gaps remain in knowledge about the factors that aff ect the geographical variation of AKI and poor outcomes. Many diff erences exist in the aetiology, pathophysiology, and management of AKI across the world. In high-income countries, AKI develops mainly in patients in hospitals. In low-income and middle-income countries, AKI occurs mainly in the community setting in acute illness, usually in association with diarrhoeal states and dehydration, infections such as malaria, and toxins (venoms and poisons). Public health issues (eg, contaminated water, poor sanitation, endemic infections such as malaria and dengue fever, venomous snakes, and toxic traditional medicines) and socioeconomic factors (eg, availability of health-care facilities) aff ect the epidemiology of AKI. Additionally availability of trained personnel and access to diagnostic tests and dialysis aff ect practice patterns and impose barriers to care. The extent to which these factors contribute to mortality and non-recovery of renal function has not been quantifi ed. AKI is potentially preventable and treatable with timely intervention, but there continues to be a high human burden. Which specifi c factors account for the poor outcomes and to what extent variations in care delivery contribute are unclear. The ability to provide lifesaving treatments for AKI provides a compelling argument to consider therapy for AKI as much of a basic right as it is to give antiretroviral drugs to treat HIV in low-resource regions, especially because care needs only be given for a Published Online March 13, 2015 http://dx.doi.org/10.1016/ S0140-6736(15)60126-X

GFR at Initiation of Dialysis and Mortality in CKD: A Meta-analysis

BACKGROUND The proportion of patients with advanced chronic kidney disease (CKD) initiating dialysis therapy at a higher glomerular filtration rate (GFR) has increased during the past decade. Recent data suggest that higher GFR may be associated with increased mortality. STUDY DESIGN A meta-analysis of cohort studies and trials. SETTING & POPULATION Patients with advanced CKD. SELECTION CRITERIA FOR STUDIES We performed a systematic literature search in MEDLINE, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, American Society of Nephrology abstracts, and bibliographies of retrieved articles to identify studies reporting on GFR at dialysis therapy initiation and mortality. PREDICTOR Estimated or calculated GFR at dialysis therapy initiation. OUTCOME Pooled adjusted hazard ratio (HR) of continuous GFR for all-cause mortality. RESULTS 16 cohort studies and 1 randomized controlled trial were identified (n = 1,081,116). By meta-analysis restricted to 15 cohorts (n = 1,079,917), higher GFR at dialysis therapy initiation was associated with a higher pooled adjusted HR for all-cause mortality (1.04; 95% CI, 1.03-1.05; P < 0.001). However, there was significant heterogeneity (I(2) = 97%; P < 0.001). The association persisted among the 9 cohorts that adjusted analytically for nutritional covariates (HR, 1.03; 95% CI, 1.02-1.04; P < 0.001; residual I(2) = 97%). The highest mortality risk was observed in hemodialysis cohorts (HR, 1.05; 95% CI, 1.02-1.08; P < 0.001), whereas there was no association between GFR and mortality in peritoneal dialysis cohorts (HR, 1.04; 95% CI, 0.99-1.08, P = 0.1; residual I(2) = 98%). Finally, higher GFR was associated with a lower mortality risk in cohorts that calculated GFR (HR, 0.80; 95% CI, 0.71-0.91; P = 0.003), contrasting with a higher mortality risk in cohorts that estimated GFR (HR, 1.04; 95% CI, 1.03-1.05; P < 0.001; residual I(2) = 97%). LIMITATIONS Paucity of randomized controlled trials, different methods for determining GFR, and substantial heterogeneity. CONCLUSIONS Higher estimated rather than calculated GFR at dialysis therapy initiation is associated with a higher mortality risk in patients with advanced CKD, independent of nutritional status. Although there was substantial heterogeneity of effect size estimates across studies, this observation requires further study.

Convective therapies versus low-flux hemodialysis for chronic kidney failure: a meta-analysis of randomized controlled trials

BACKGROUND Although convective therapies have gained popularity for the optimal removal of uremic solutes, their benefits and potential risks have not been fully elucidated. We conducted a meta-analysis of all randomized controlled trials comparing convective therapies with low-flux hemodialysis in patients with chronic kidney failure. METHODS We performed a literature search using MEDLINE (inception-December 2012), Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, scientific abstracts from meetings and bibliographies of retrieved articles. Randomized controlled trials comparing the effect of convective therapies including high-flux hemodialysis, hemofiltration or hemodiafiltration versus low-flux hemodialysis were included. Random-effects model meta-analyses were used to examine continuous and binary outcomes. RESULTS Sixty-five (29 crossover and 36 parallel-arm) trials were identified (n = 12 182). Convective therapies resulted in a decrease in all-cause mortality [relative risk (RR) 0.88; 95% confidence interval (CI) 0.76, 1.02, P = 0.09], cardiovascular mortality (RR 0.84; 95% CI 0.71, 0.98, P = 0.03), all-cause hospitalization (RR 0.91; 95% CI 0.82, 1.01; P = 0.08) and therapy-related hypotension (RR 0.55, 95% CI 0.35, 0.87, P = 0.01). Convective therapies also resulted in an increase in the clearance of several low-molecular-weight (urea, creatinine and phosphate), middle-sized (β-2 microglobulin and leptin) and protein-bound (homocysteine, advanced glycation end-products and pentosidine) solutes and a decrease in inflammatory markers (interleukin-6). There was no impact of convective therapies on cardiac morphological and functional parameters, and blood pressure and anemia parameters. CONCLUSIONS Although convective therapies are associated with improved clearance of uremic solutes, the potential long-term benefits of specific convective modalities require further study.

Short- and Long-Term Effects of Alkali Therapy in Chronic Kidney Disease: A Systematic Review

Background: Clinical practice guidelines recommend alkali therapy in patients with non-dialysis-dependent chronic kidney disease (CKD) and metabolic acidosis to prevent complications from metabolic acidosis. We systematically reviewed the effect of sodium bicarbonate on benefits and harms in patients with CKD. Methods: We searched for randomized controlled trials in MEDLINE (through July 2011), Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and scientific abstracts. We included trials that compared sodium bicarbonate to standard-of-care therapy or placebo that reported on kidney-related outcomes. We performed random-effects model meta-analyses to compute net changes (for continuous variables) and risk ratios (for binary variables). Results: Two short-term (≤7 days) crossover trials and 4 long-term (≥2 months) parallel-design randomized controlled trials met eligibility (312 patients). All 6 trials prescribed sodium bicarbonate in the alkali-treated group. In the long-term studies, alkali therapy was associated with a net decrease in serum creatinine (–0.07 mg/dl, 95% CI –0.09, –0.05; p < 0.001; I2 = 0), a net improvement in GFR (3.2 ml/min/1.73 m2, 95% CI 1.6, 4.7; p < 0.001; I2 = 0), and a lower incidence of dialysis initiation (risk ratio 0.21, 95% CI 0.08, 0.54; p = 0.001; I2 = 0). No benefit was observed on the serum creatinine or GFR in short-term studies. Alkali therapy was not associated with a higher likelihood of initiating or escalating anti-hypertensive medications. Conclusions: Alkali therapy is associated with an improvement in kidney function, which may afford a long-term benefit in slowing the progression of CKD. However, differences in study protocols and small sample sizes preclude definitive conclusions.

Efficacy and Safety of Combined vs. Single Renin–Angiotensin–Aldosterone System Blockade in Chronic Kidney Disease: A Meta-Analysis

BACKGROUND Although dual blockade of the renin-angiotensin-aldosterone system (RAAS) has gained popularity for the treatment of kidney disease, its benefits and potential risks have not been fully elucidated. We conducted a meta-analysis of all randomized controlled trials comparing the efficacy and safety of combined vs. single RAAS blockade therapy in chronic kidney disease (CKD). METHODS We performed a literature search using MEDLINE, the Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, scientific abstracts from meetings, and bibliographies of retrieved articles. We used random-effects models to compute net changes and rate differences in variables. RESULTS Fifty-nine (25 crossover and 34 parallel-arm) randomized controlled trials (RCTs) comparing the efficacy and safety of combined vs. single RAAS blockade therapy in CKD were identified (4,975 patients). Combined RAAS blockade therapy was associated with a significant net decrease in glomerular filtration rate (GFR) (-1.8ml/min or ml/min/1.73 m(2); P = 0.005), albuminuria (-90mg/g of creatinine; P = 0.001 or -32mg/day; P = 0.03), and proteinuria (-291mg/g; P = 0.003 or -363mg/day; P < 0.001). Combined RAAS blockade therapy was associated with a 9.4% higher rate of regression to normoalbuminuria and a 5% higher rate of achieving the blood pressure (BP) goal (as defined in individual trials). However, combined RAAS blockade therapy was associated with a significant net increase in serum potassium level, a 3.4% higher rate of hyperkalemia, and a 4.6% higher rate of hypotension. There was no effect on doubling of the serum creatinine level, hospitalization, or mortality. CONCLUSIONS Although combined RAAS blockade therapy in CKD is associated with a decrease in albuminuria and proteinuria, it is associated with a decrease in GFR and a higher incidence of hyperkalemia and hypotension relative to monotherapy. The potential long-term kidney benefits of combined RAAS blockade therapy require further study.

Effect of ultrapure dialysate on markers of inflammation, oxidative stress, nutrition and anemia parameters: a meta-analysis

BACKGROUND Markers of inflammation are linked to malnutrition and confer an increased mortality risk in hemodialysis patients. Ultrapure dialysate might have a beneficial effect on markers of inflammation. We conducted a meta-analysis that examined the effect of ultrapure versus standard dialysate on markers of inflammation, oxidative stress, nutrition and anemia parameters. METHODS We performed a literature search using MEDLINE, Scopus, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov and scientific abstracts. Single-arm studies, nonrandomized and randomized controlled trials were included. We conducted random effects model meta-analyses to assess changes in the aforementioned outcomes. RESULTS We identified 16 single-arm studies, 2 crossover and 3 parallel-arm nonrandomized controlled trials and 5 crossover and 5 parallel-arm randomized controlled trials. In an analysis of 23 study arms or cohorts (n = 2221), ultrapure dialysate resulted in a significant decrease in C-reactive protein (-3.2 mg/L; 95% CI -4.6, -1.8; P < 0.001). Other markers of inflammation and oxidative stress displayed similar significant improvements. Ultrapure dialysate also resulted in a significant increase in serum albumin (0.11 g/dL; 95% CI 0.02, 0.19; P = 0.011) and hemoglobin (0.40 g/dL; 95% CI 0.06, 0.75; P = 0.022), and a decrease in the weekly erythropoietin dose (-273 units; 95% CI -420, -126; P < 0.001). The results remained significant in analyses restricted to controlled trials. CONCLUSIONS Use of ultrapure dialysate in hemodialysis patients results in a decrease in markers of inflammation and oxidative stress, an increase in serum albumin and hemoglobin and a decrease in erythropoietin requirement. Although improvement in these surrogate endpoints might confer a cardiovascular benefit, a large trial with hard clinical endpoints is required.

Regional Citrate Anticoagulation Reduces Polymorphonuclear Cell Degranulation in Critically Ill Patients Treated With Continuous Venovenous Hemofiltration

Citrate which chelates ionized calcium can be used as regional anticoagulation in continuous venovenous hemofiltration (CVVH). This is the first study conducted to examine the potentially additive benefit effect of regional citrate anticoagulation (RCA) on polymorphonuclear (PMN) cell degranulation of myeloperoxidase (MPO) and cytokines production in patients with critically acute kidney injury (AKI) undergoing CVVH treatment. This prospective randomized controlled trial was conducted in 20 critically ill patients with AKI who underwent CVVH. The patients were randomized into regional citrate group (n = 10) and heparin group (n = 10). The pre‐dilution CVVH with polyethersulfone dialyzers were utilized in both groups. The levels of pre‐filter and post‐filter MPO as well as inflammatory and anti‐inflammatory cytokines were measured at baseline, 6 h, and 24 h after initiating CVVH. In the heparin group, the post‐filter serum MPO levels were significantly higher than the pre‐filter (median 49.0 vs. 60.5 ng/mL, P < 0.05) at 6 h. There were no significant differences between pre‐ and post‐dialyzer MPO levels in the citrate group. Citrate could significantly decrease systemic pre‐filter serum MPO levels from baseline at 6 h (median 43.5 vs. 17.3 ng/mL, P < 0.01) as well as IL‐8 levels (P < 0.05) whereas heparin provided only significant TNF‐α reduction (P < 0.05). The CVVH circuit survival in the citrate group was longer than the heparin group. In conclusion, citrate, utilized as a regional anticoagulant in CVVH, can reduce both membrane bioincompatibility‐induced and systemic oxidative stress and inflammation, and can prolong CVVH circuit survival time.

Efficacy and safety of intravenous iron therapy for functional iron deficiency anemia in hemodialysis patients: a meta-analysis.

Background: Studies on benefits of intravenous iron therapy among hemodialysis patients with functional iron deficiency anemia have shown conflicting results. We conducted a meta-analysis to assess the efficacy and safety of intravenous iron in this subset of patients. Methods: We searched MEDLINE (through December 2012), the Cochrane Central Register of Controlled Trials and ClinicalTrials.gov for single-arm studies and randomized controlled trials (RCT) that examined the effect of intravenous iron for functional iron deficiency anemia in hemodialysis patients on anemia parameters and markers of oxidative stress and inflammation. Studies of absolute iron deficiency were excluded. Random-effect model meta-analyses were used to compute changes in outcomes of interest. Results: We identified 34 studies (2,658 patients), representing 24 single-arm studies, and 10 parallel-arm RCT. In the analyses of the study arms, intravenous iron therapy resulted in a significant increase in hemoglobin, serum ferritin, transferrin saturation rate, serum iron, reticulocyte hemoglobin content as well as a significant decrease in the percentage of hypochromic erythrocytes and erythropoietin dose. There were significant increases in plasma malonyldialdehyde level and thiobarbituric acid-reactive substances, and a decrease in neutrophil respiratory burst. The analyses of the RCT revealed less robust net changes in these parameters, and there was no increased risk of adverse events including infections, cardiac events and mortality. Conclusions: Intravenous iron therapy for functional iron deficiency anemia in hemodialysis patients improves anemia parameters but exerts some effects on markers of oxidative stress that are of unclear clinical significance. The long-term safety and efficacy of this treatment strategy requires further study.

Therapeutic hypothermia and prevention of acute kidney injury: A meta-analysis of randomized controlled trials

BACKGROUND Therapeutic hypothermia has been shown to reduce neurological morbidity and mortality in the setting of out-of-hospital cardiac arrest and may be beneficial following brain injury and cardiopulmonary bypass. We conducted a systematic review to ascertain the effect of therapeutic hypothermia on development of acute kidney injury (AKI) and mortality. METHODS We searched for randomized controlled trials in MEDLINE through February 2011. We included trials comparing hypothermia to normothermia that reported kidney-related outcomes including, development of AKI, dialysis requirement, changes in serum creatinine, and mortality. We performed Peto fixed-effect and random-effects model meta-analyses, and meta-regressions. RESULTS Nineteen trials reporting on 2218 patients were included; in the normothermia group, the weighted rate of AKI was 4.2%, dialysis requirement 3.7%, and mortality 10.8%. By meta-analysis, hypothermia was not associated with a lower odds of AKI (odds ratio [OR] 1.01, 95% confidence interval [CI] 0.68, 1.51; P=0.95) or dialysis requirement (OR 0.81; 95% CI 0.30, 2.19; P=0.68); however, by meta-regression, a lower target cooling temperature was associated with a lower odds of AKI (P=0.01). Hypothermia was associated with lower mortality (OR 0.69; 95% CI 0.51, 0.92; P=0.01). CONCLUSIONS In trials that ascertained kidney endpoints, therapeutic hypothermia prevented neither the development of AKI nor dialysis requirement, but was associated with lower mortality. Different definitions and rates of AKI, differences in mortality rates, and concerns about the optimal target cooling temperature preclude definitive conclusions.