GRADE guidance 24 optimizing the integration of randomized and non-randomized studies of interventions in evidence syntheses and health guidelines.

BACKGROUND AND OBJECTIVE: This is the 24th in the ongoing series of articles describing the GRADE approach for assessing the certainty of a body of evidence in systematic reviews and health technology assessments and how to move from evidence to recommendations in guidelines. METHODS: Guideline developers and authors of systematic reviews and other evidence syntheses use randomized controlled studies (RCTs) and non-randomized studies of interventions (NRSI) as sources of evidence for questions about health interventions. RCTs with low risk of bias are the most trustworthy source of evidence for estimating relative effects of interventions because of protection against confounding and other biases. However, in several instances, NRSI can still provide valuable information as complementary, sequential, or replacement evidence for RCTs. RESULTS: In this article we offer guidance on the decision regarding when to search for and include either or both types of studies in systematic reviews to inform health recommendations. CONCLUSION: This work aims to help methodologists in review teams, technology assessors, guideline panelists, and anyone conducting evidence syntheses using GRADE.

Effect of highly active antiretroviral therapy on biomarkers of B-lymphocyte activation and inflammation.

OBJECTIVE: Chronic inflammation and B-cell hyperactivation are seen in HIV infection, contributing to an increased risk for the accrual of genetic errors that may result in B-cell lymphoma. The primary objective of this study was to determine the effect of highly active antiretroviral therapy (HAART) on serum levels of molecules that are associated with immune activation and/or inflammation, including several that are associated with B-cell activation, specifically IL-6, sCD30, sCD27, IgG, IgA, CXCL13 (B lymphocyte chemoattractant, BLC), a B-lymphocyte chemokine involved in B-cell trafficking, as well as C-reactive protein, an acute-phase protein. DESIGN: We used a retrospective cohort study design, measuring serum levels of these markers at each of four 1-year intervals, 2 years before and 2 years after HAART initiation, in a subgroup of 290 HIV-infected men enrolled in the Multicenter AIDS Cohort Study (MACS). METHODS: Serum levels of immune activation-associated molecules were measured by ELISA and multiplexed immunometric assays. Reference values were determined by the 5th to 95th percentiles from a sample of 109 HIV-uninfected MACS men. RESULTS: HAART use was associated with a reduction, but not normalization, of most biomarkers tested. Serum levels of IL-6 and C-reactive protein appeared to be unaffected by HAART. CONCLUSIONS: These results suggest a partial normalization of serum cytokine levels post HAART. However, a chronic state of B-cell hyperactivation continues 2-3 years after HAART initiation. These findings may explain, in part, the excess incidence of lymphoma still occurring in HIV-infected persons in the post-HAART era.

Fluid retention is associated with cardiovascular mortality in patients undergoing long-term hemodialysis.

BACKGROUND: Patients with chronic kidney disease (stage 5) who undergo hemodialysis treatment have similarities to heart failure patients in that both populations retain fluid frequently and have excessively high mortality. Volume overload in heart failure is associated with worse outcomes. We hypothesized that in hemodialysis patients, greater interdialytic fluid gain is associated with poor all-cause and cardiovascular survival. METHODS AND RESULTS: We examined 2-year (July 2001 to June 2003) mortality in 34,107 hemodialysis patients across the United States who had an average weight gain of at least 0.5 kg above their end-dialysis dry weight by the time the subsequent hemodialysis treatment started. The 3-month averaged interdialytic weight gain was divided into 8 categories of 0.5-kg increments (up to > or =4.0 kg). Eighty-six percent of patients gained >1.5 kg between 2 dialysis sessions. In unadjusted analyses, higher weight gain was associated with better nutritional status (higher protein intake, serum albumin, and body mass index) and tended to be linked to greater survival. However, after multivariate adjustment for demographics (case mix) and surrogates of malnutrition-inflammation complex, higher weight-gain increments were associated with increased risk of all-cause and cardiovascular death. The hazard ratios (95% confidence intervals) of cardiovascular death for weight gain <1.0 kg and > or =4.0 kg (compared with 1.5 to 2.0 kg as the reference) were 0.67 (0.58 to 0.76) and 1.25 (1.12 to 1.39), respectively. CONCLUSIONS: In hemodialysis patients, greater fluid retention between 2 subsequent hemodialysis treatment sessions is associated with higher risk of all-cause and cardiovascular death. The mechanisms by which fluid retention influences cardiovascular survival in hemodialysis may be similar to those in patients with heart failure and warrant further research.

Serum alkaline phosphatase predicts mortality among maintenance hemodialysis patients.

Several observational studies have demonstrated that serum levels of minerals and parathyroid hormone (PTH) have U- or J-shaped associations with mortality in maintenance hemodialysis patients, but the relationship between serum alkaline phosphatase (AlkPhos) and risk for all-cause or cardiovascular death is unknown. In this study, a 3-yr cohort of 73,960 hemodialysis patients in DaVita outpatient dialysis were studied, and the hazard ratios for all-cause and cardiovascular death were higher across 20-U/L increments of AlkPhos, including within the various strata of intact PTH and serum aspartate aminotransferase. In the fully adjusted model, which accounted for demographics, comorbidity, surrogates of malnutrition and inflammation, minerals, PTH, and aspartate aminotransferase, AlkPhos > or =120 U/L was associated with a hazard ratio for death of 1.25 (95% confidence interval 1.21 to 1.29; P < 0.001). This association remained among diverse subgroups of hemodialysis patients, including those positive for hepatitis C antibody. A rise in AlkPhos by 10 U/L during the first 6 mo was incrementally associated with increased risk for death during the subsequent 2.5 yr. In summary, high levels of serum AlkPhos, especially >120 U/L, are associated with mortality among hemodialysis patients. Prospective controlled trials will be necessary to test whether serum AlkPhos measurements could be used to improve the management of renal osteodystrophy.

Serum and dialysate potassium concentrations and survival in hemodialysis patients.

BACKGROUND AND OBJECTIVES: Controlling serum potassium is an important goal in maintenance hemodialysis patients. We examined the achievement of potassium balance through hemodialysis treatments and the associated fluctuations in serum potassium. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A 3-yr (July 2001 to June 2004) cohort of 81,013 maintenance hemodialysis patients from all DaVita dialysis clinics across the United States were studied. Nine quarterly-averaged serum potassium groups (< 4.0, > or = 6.3 mEq/L and seven increments in-between) and four dialysate potassium concentration groups were created in each of the 12 calendar quarters. The death risk associated with predialysis potassium level and dialysate potassium concentration was examined using unadjusted, case-mix adjusted, and malnutrition-inflammation-adjusted time-dependent survival models. RESULTS: Serum potassium correlated with nutritional markers. Serum potassium between 4.6 and 5.3 mEq/L was associated with the greatest survival, whereas potassium < 4.0 or > or = 5.6 mEq/L was associated with increased mortality. The death risk of serum potassium > or = 5.6 mEq/L remained consistent after adjustments. Higher dialysate potassium concentration was associated with increased mortality in hyperkalemic patients with predialysis serum potassium > or = 5.0 mEq/L. CONCLUSIONS: A predialysis serum potassium of 4.6 to 5.3 mEq/L is associated with the greatest survival in maintenance hemodialysis patients. Hyperkalemic patients who undergo maintenance hemodialysis against lower dialysate bath may have better survival. Limitations of observational studies including confounding by indication should be considered when interpreting these results.

A1C and survival in maintenance hemodialysis patients.

OBJECTIVE: The optimal target for glycemic control has not been established in diabetic dialysis patients. RESEARCH DESIGN AND METHODS: To address this question, the national database of a large dialysis organization (DaVita) was analyzed via time-dependent survival models with repeated measures. RESULTS: Of 82,933 patients undergoing maintenance hemodialysis (MHD) in DaVita outpatient clinics over 3 years (July 2001 through June 2004), 23,618 diabetic MHD patients had A1C measurements at least once. Unadjusted survival analyses indicated paradoxically lower death hazard ratios (HRs) with higher A1C values. However, after adjusting for potential confounders (demographics, dialysis vintage, dose, comorbidity, anemia, and surrogates of malnutrition and inflammation), higher A1C values were incrementally associated with higher death risks. Compared with A1C in the 5-6% range, the adjusted all-cause and cardiovascular death HRs for A1C > or = 10% were 1.41 (95% CI 1.25-1.60) and 1.73 (1.44-2.08), respectively (P < 0.001). The incremental increase in death risk for rising A1C values was monotonic and robust in nonanemic patients (hemoglobin > 11.0 g/dl). In subgroup analyses, the association between A1C > 6% and increased death risk was more prominent among younger patients, those who had undergone dialysis for > 2 years, and those with higher protein intake (> 1 g x kg(-1) x day(-1)), blood hemoglobin (> 11 g/dl), or serum ferritin values (> 500 ng/ml). CONCLUSIONS: In diabetic MHD patients, the apparently counterintuitive association between poor glycemic control and greater survival is explained by such confounders as malnutrition and anemia. All things equal, higher A1C is associated with increased death risk. Lower A1C levels not related to malnutrition or anemia appear to be associated with improved survival in MHD patients.

Impact of kidney bone disease and its management on survival of patients on dialysis.

Despite the enormous cardiovascular disease epidemic and poor survival among individuals with chronic kidney disease (CKD), traditional risk factors such as hypercholesterolemia, hypertension, and obesity appear not as relevant as was previously thought, nor would their management improve survival in patients with CKD who are undergoing dialysis. On the contrary, kidney disease wasting (KDW) (also known as the malnutrition-inflammation complex), renal anemia, and kidney bone disease (KBD) appear to be the 3 most important nontraditional risk factors associated with cardiovascular disease in CKD. KBD-associated hyperparathyroidism may contribute to worsening refractory anemia and KDW/inflammation. The main cause of secondary hyperparathyroidism is active vitamin D deficiency. Hence, treatment of patients with KBD with vitamin D analogs, especially those with lesser effects on calcium and phosphorus such as paricalcitol, may be the most promising option for improving CKD outcomes. By conducting survival analyses in a 2-year (7/2001 to 6/2003) cohort of 58,058 patients on hemodialysis, we recently found that associations between high serum parathyroid hormone and increased death risk were masked by the demographic and clinical characteristics of patients, and that alkaline phosphatase had an incremental association with mortality. Administration of paricalcitol was associated with improved survival in time-varying models. We now present additional subgroup analyses that show that administration of any dose of paricalcitol, when compared with no paricalcitol, is associated with better likelihood of survival in virtually all subgroups of patients on hemodialysis. Because these associations may be secondary to bias by indication, randomized clinical trials are necessary to verify the findings of this and similar observational studies.

Longitudinal associations between dietary protein intake and survival in hemodialysis patients.

BACKGROUND: Decreased dietary protein intake may be associated with increased mortality risk in individuals with kidney failure undergoing maintenance hemodialysis (MHD). We hypothesized that longitudinal changes in dietary protein intake have independent associations with survival in MHD patients. METHODS: The relation between urea kinetic-based normalized protein nitrogen appearance (nPNA) and all-cause and cardiovascular mortality was examined in a 2-year (July 2001 to June 2003) cohort of 53,933 MHD patients from virtually all DaVita dialysis clinics in the United States, using both conventional and time-dependent (repeated-measure) Cox models to estimate death hazard ratios for quarterly averaged nPNA categories controlled for case-mix, comorbidity, dialysis dose (Kt/V), and available markers of malnutrition-inflammation complex syndrome (MICS). RESULTS: The best survival was associated with nPNA between 1.0 and 1.4 g/kg/d, whereas nPNA less than 0.8 or greater than 1.4 g/kg/d was associated with greater mortality in almost all models. Adjustment for MICS mitigated the associations substantially. A decrease in protein intake during the first 6 months in patients with an nPNA in the 0.8- to 1.2-g/kg/d range was associated incrementally with greater death risks in the subsequent 18 months, whereas an increase in nPNA tended to correlate with reduced death risk. CONCLUSION: Low daily protein intake or decrease in its magnitude over time is associated with increased risk for death in MHD patients. Whether the association between time-varying protein intake and survival is causal or a consequence of anorexia secondary to MICS or other factors needs to be explored further in interventional trials.

Associations between changes in hemoglobin and administered erythropoiesis-stimulating agent and survival in hemodialysis patients.

Although treating anemia of chronic kidney disease by erythropoiesis-stimulating agents (ESA) may improve survival, most studies have examined associations between baseline hemoglobin values and survival and ignored variations in clinical and laboratory measures over time. It is not clear whether longitudinal changes in hemoglobin or administered ESA have meaningful associations with survival after adjustment for time-varying confounders. With the use of time-dependent Cox regression models, longitudinal associations were examined between survival and quarterly (13-wk averaged) hemoglobin values and administered ESA dose in a 2-yr (July 2001 to June 2003) cohort of 58,058 maintenance hemodialysis patients from a large dialysis organization (DaVita) in the United States. After time-dependent and multivariate adjustment for case mix, quarterly varying administered intravenous iron and ESA doses, iron markers, and nutritional status, hemoglobin levels between 12 and 13 g/dl were associated with the greatest survival. Among prevalent patients, the lower range of the recommended Kidney Disease Quality Outcomes Initiative hemoglobin target (11 to 11.5 g/dl) was associated with a higher death risk compared with the 11.5- to 12-g/dl range. A decrease or increase in hemoglobin over time was associated with higher or lower death risk, respectively, independent of baseline hemoglobin. Administration of any dose of ESA was associated with better survival, whereas among those who received ESA, requiring higher doses were surrogates of higher death risk. In this observational study, greater survival was associated with a baseline hemoglobin between 12 and 13 g/dl, treatment with ESA, and rising hemoglobin. Falling hemoglobin and requiring higher ESA doses were associated with decreased survival. Randomized clinical trials are required to examine these associations.

Association between serum bicarbonate and death in hemodialysis patients: is it better to be acidotic or alkalotic?

The optimal acid-base status for survival in maintenance hemodialysis (MHD) patients remains controversial. According to recent reports, acidosis is associated with improved survival in MHD patients. It was hypothesized that this inverse association is due to a confounding effect of the malnutrition-inflammation complex syndrome (MICS). Associations between baseline (first 3 mo averaged) predialysis serum bicarbonate (HCO3(-)) and 2-yr mortality were examined in 56,385 MHD patients who were treated in virtually all DaVita dialysis clinics across the United States. The range of HCO3(-) was divided into 12 categories (< 17, > or = 27, and 10 groups in between). Three sets of Cox regression models were evaluated to estimate hazard ratios of all-cause and cardiovascular death in both incident and prevalent patients: (1) Unadjusted, (2) multivariate case mix adjusted (which also included dialysate HCO3(-) and Kt/V), and (3) adjusted for case mix and nine markers of MICS (body mass index; erythropoietin dose; protein intake; serum albumin; creatinine; phosphorus; calcium; ferritin and total iron binding capacity; and blood hemoglobin, WBC, and lymphocytes). There were significant inverse associations between serum HCO3(-) and serum phosphorus and estimated protein intake. The lowest unadjusted mortality was associated with predialysis HCO3(-) in the 17- to 23-mEq/L range, whereas values > or = 23 mEq/L were associated with progressively higher all-cause and cardiovascular death rates. This association, however, reversed after case-mix and MICS multivariate adjustment, so that HCO3(-) values >22 mEq/L had lower death risk. Although previous epidemiologic studies indicated an association between high serum HCO3(-) and increased mortality in MHD patients, this effect seems to be due substantially to the effect of MICS on survival.

Time-dependent associations between iron and mortality in hemodialysis patients.

The independent association between the indices of iron stores or administered intravenous iron, both of which vary over time, and survival in patients who are on maintenance hemodialysis (MHD) is not clear. It was hypothesized that the observed associations between moderately high levels of three iron markers (serum ferritin, iron, and iron saturation ratio) or administered intravenous iron and all-cause and cardiovascular death is due to the time-varying confounding effect of malnutrition-inflammation-cachexia syndrome (MICS). Time-dependent Cox regression models were examined using prospectively collected data of the 2-yr (July 2001 to June 2003) historical cohort of 58,058 MHD patients from virtually all DaVita dialysis clinics in the United States. After time-dependent and multivariate adjustment for case mix, administered intravenous iron and erythropoietin doses, and available surrogates of MICS, serum ferritin levels between 200 and 1200 ng/ml (reference 100 to 199 ng/ml), serum iron levels between 60 and 120 microg/ml (reference 50 to 59 microg/ml), and iron saturation ratio between 30 and 50% (reference 45 to 50%) were associated with the lowest all-cause and cardiovascular death risks. Compared with those who did not receive intravenous iron, administered intravenous iron up to 400 mg/mo was associated with improved survival, whereas doses >400 mg/mo tended to be associated with higher death rates. The association between serum ferritin levels >800 ng/ml and mortality in MHD patients seems to be due mostly to the confounding effects of MICS. For ascertaining whether the observed associations between moderate doses of administered intravenous iron and improved survival are causal or due to selection bias by indication, clinical trials are warranted.