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Background: Exposure to high doses or a high cumulative dose of erythropoiesis-stimulating agents (ESAs) may contribute to cardiovascular events in patients with CKD and anemia. Whether using a low fixed ESA dose versus dosing based on a hemoglobin-based, titration-dose algorithm in such patients might reduce risks associated with high ESA doses and decrease the cumulative exposure-while reducing the need for red blood cell transfusions-is unknown., Methods: In this phase-3, randomized trial involving 756 adults with stage-3 to -5 CKD and anemia, we evaluated incidence of red blood cell transfusions for participants randomized to receive darbepoetin given as a fixed dose (0.45 µ g/kg every 4 weeks) versus administered according to a hemoglobin-based, titration-dose algorithm, for up to 2 years. Participants received transfusions as deemed necessary by the treating physician., Results: There were 379 patients randomized to the fixed-dose group, and 377 to the titration-dose group. The percentage of participants transfused did not differ (24.1% and 24.4% for the fixed-dose and titration-dose group, respectively), with similar time to first transfusion. The titration-dose group achieved significantly higher median hemoglobin (9.9 g/dl) compared with the fixed-dose group (9.4 g/dl). The fixed-dose group had a significantly lower median cumulative dose of darbepoetin (median monthly dose of 30.9 µ g) compared with the titration-dose group (53. 6 µg median monthly dose). The FD and TD group received a median (Q1, Q3) cumulative dose per 4 weeks of darbepoetin of 30.9 (21.8, 40.0) µ g and 53.6 (31.1, 89.9) µ g, respectively; the median of the difference between treatment groups was -22.1 (95% CI, -26.1 to -18.1) µ g., Conclusions: These findings indicate no evidence of difference in incidence of red blood cell transfusion for a titration-dose strategy versus a fixed-dose strategy for darbepoetin. This suggests that a low fixed dose of darbepoetin may be used as an alternative to a dose-titration approach to minimize transfusions, with less cumulative dosing., (Copyright © 2021 by the American Society of Nephrology.)

We recently showed an association between strict BP control and lower mortality risk during two decades of follow-up of prior participants in the Modification of Diet in Renal Disease (MDRD) trial. Here, we determined the risk of ESRD and mortality during extended follow-up of the African American Study of Kidney Disease and Hypertension (AASK) trial. We linked 1067 former AASK participants with CKD previously randomized to strict or usual BP control (mean arterial pressure ≤92 mmHg or 102-107 mmHg, respectively) to the US Renal Data System and Social Security Death Index; 397 patients had ESRD and 475 deaths occurred during a median follow-up of 14.4 years from 1995 to 2012. Compared with the usual BP arm, the strict BP arm had unadjusted and adjusted relative risks of ESRD of 0.92 (95% confidence interval [95% CI], 0.75 to 1.12) and 0.95 (95% CI, 0.78 to 1.16; P=0.64), respectively, and unadjusted and adjusted relative risks of death of 0.92 (95% CI, 0.77 to 1.10) and 0.81 (95% CI, 0.68 to 0.98; P=0.03), respectively. In meta-analyses of individual-level data from the MDRD and the AASK trials, unadjusted relative risk of ESRD was 0.88 (95% CI, 0.78 to 1.00) and unadjusted relative risk of death was 0.87 (95% CI, 0.76 to 0.99) for strict versus usual BP arms. Our findings suggest that, during long-term follow-up, strict BP control does not delay the onset of ESRD but may reduce the relative risk of death in CKD., (Copyright © 2017 by the American Society of Nephrology.)

Despite optimal treatment, including renin-angiotensin system (RAS) inhibitors, patients with type 2 diabetic nephropathy have high cardiorenal morbidity and mortality related to residual albuminuria. We evaluated whether or not atrasentan, a selective endothelin A receptor antagonist, further reduces albuminuria when administered concomitantly with maximum tolerated labeled doses of RAS inhibitors. We enrolled 211 patients with type 2 diabetes, urine albumin/creatinine ratios of 300-3500 mg/g, and eGFRs of 30-75 ml/min per 1.73 m(2) in two identically designed, parallel, multinational, double-blind studies. Participants were randomized to placebo (n=50) or to 0.75 mg/d (n=78) or 1.25 mg/d (n=83) atrasentan for 12 weeks. Compared with placebo, 0.75 mg and 1.25 mg atrasentan reduced urine albumin/creatinine ratios by an average of 35% and 38% (95% confidence intervals of 24 to 45 and 28 to 47, respectively) and reduced albuminuria≥30% in 51% and 55% of participants, respectively. eGFR and office BP measurements did not change, whereas 24-hour systolic and diastolic BP, LDL cholesterol, and triglyceride levels decreased significantly in both treatment groups. Use of atrasentan was associated with a significant increase in weight and a reduction in hemoglobin, but rates of peripheral edema, heart failure, or other side effects did not differ between groups. However, more patients treated with 1.25 mg/d atrasentan discontinued due to adverse events. After stopping atrasentan for 30 days, measured parameters returned to pretreatment levels. In conclusion, atrasentan reduced albuminuria and improved BP and lipid spectrum with manageable fluid overload-related adverse events in patients with type 2 diabetic nephropathy receiving RAS inhibitors., (Copyright © 2014 by the American Society of Nephrology.)

Whereas much research has investigated equations for obtaining estimated GFR (eGFR) from serum creatinine in cross-sectional settings, little attention has been given to validating these equations as outcomes in longitudinal studies of chronic kidney disease. A common objective of chronic kidney disease studies is to identify risk factors for progression, characterized by slope (rate of change over time) or time to event (time until a designated decline in kidney function or ESRD). The relationships of 35 baseline factors with eGFR-based outcomes were compared with the relationships of the same factors with iothalamate GFR (iGFR)-based outcomes in the African American Study of Kidney Disease and Hypertension (AASK; n = 1094). With the use of the AASK equation to calculate eGFR, results were compared between time to halving of eGFR or ESRD and time to halving of iGFR or ESRD (with effect sizes expressed per 1 SD) and between eGFR and iGFR slopes starting 3 mo after randomization. The effects of the baseline factors were similar between the eGFR- and iGFR-based time-to-event outcomes (Pearson R = 0.99, concordance R = 0.98). Small but statistically significant differences (P < 0.05, without adjustment for multiple analyses) were observed for seven of the 35 factors. Agreement between eGFR and iGFR was somewhat weaker, although still relatively high for slope-based outcomes (Pearson R = 0.93, concordance R = 0.92). Effects of covariate adjustment for age, gender, baseline GFR, and urine proteinuria also were similar between the eGFR and iGFR outcomes. Sensitivity analyses including death in the composite time-to-event outcomes or using the Modification of Diet in Renal Disease equation instead of the AASK equation provided similar results. In conclusion, the data from the AASK provide tentative support for use of outcomes that are based on an established eGFR formula using serum creatinine as a surrogate for measured iGFR-based outcomes in analyses of risk factors for the progression of kidney disease.

Previous studies suggested that the non-contrast-enhanced computerized tomography (CT) scan is a highly reliable tool for the diagnosis of analgesic-associated renal disease. However, this issue has not been addressed in the US population. A total of 221 incident patients with ESRD from different regions of the United States underwent a helical CT scan and detailed questioning about drug history. Specific renal anatomic criteria were developed to determine whether a constellation of CT findings (small indented calcified kidneys [SICK]) is linked to analgesic ingestion. For approximating use before the onset of renal disease, only analgesic ingestion at least 9 yr before starting dialysis was considered relevant. Fifteen patients met the criteria for SICK. This represented 7% of the enrolled patients and approximately 1% of the total ESRD population. There was a significant increase in the estimated risk among patients with a history of heavy aspirin ingestion (odds ratio [OR] 7.4 [95% confidence interval (CI) 1.2 to 43] for > or =1 kg lifetime; OR 8.8 [95% CI 1.2 to 66] for > or =0.3 kg/yr). Total analgesic ingestion of > or =0.3 kg/yr also was significantly associated with SICK (OR 8.2; 95% CI 1.5 to 45). These findings were accounted for largely by combination products that contained aspirin and phenacetin (used by three patients with SICK), which are no longer available. In addition, the CT finding of SICK was present only in a minority of heavy analgesic users, yielding a sensitivity of 5 to 26%. Findings of SICK are infrequent in the US ESRD population and do not occur among a sufficient proportion of heavy analgesic users to render the non-contrast-enhanced CT scan a sensitive tool to detect analgesic-associated kidney injury.

In the intention-to-treat analysis of the Hemodialysis Study, all-cause mortality did not differ significantly between the high versus standard hemodialysis dose groups. The association of mortality with delivered dose within each of the two randomized treatment groups was examined, and implications for observational studies were considered. Time-dependent Cox regression was used to relate the relative risk (RR) for mortality to the running mean of the achieved equilibrated Kt/V (eKt/V) over the preceding 4 mo. eKt/V was categorized by quintiles within each dose group. Analyses were controlled for case-mix factors and baseline anthropometric volume. Within each randomized dose group, mortality was elevated markedly when achieved eKt/V was in the lowest quintile (RR, 1.93; 95% confidence interval [CI], 1.40 to 2.66; P < 0.0001 in the standard-dose group; RR, 2.04; 95% CI, 1.50 to 2.76; P < 0.0001 in the high-dose group; RR relative to the middle quintiles). The mortality rate in the lowest eKt/V quintile of the high-dose group was higher than in the full standard-dose group (RR, 1.59; 95% CI, 1.29 to 1.96; P < 0.0001). Each 0.1 eKt/V unit below the group median was associated with a 58% higher mortality in the standard-dose group (P < 0.001) and a 37% higher mortality in the high-dose group (P < 0.001). The magnitude of these dose-mortality effects was seven- to 12-fold higher than the upper limit of the 95% CI from the intention-to-treat analysis. The effects were attenuated in lagged analyses but did not disappear. When dialysis dose is targeted closely, as under the controlled conditions of the Hemodialysis Study, patients with the lowest achieved dose relative to their target dose experience markedly increased mortality, to a degree that is not compatible with a biologic effect of dose. The possibility of similar (albeit smaller) biases should be considered when analyzing observational data sets relating mortality to achieved dose of dialysis.

The hypothesis that chronic kidney disease (CKD) is associated with increased coronary artery calcification (CAC) was tested using data from the Dallas Heart Study, a representative sample of Dallas County residents aged 30 to 65 yr. CKD was defined as presence of microalbuminuria and GFR > or =60 ml/min per 1.73 m(2) (stage 1 to 2), or GFR <60 ml/min per 1.73 m(2) (stage 3 to 5), excluding end-stage kidney disease. Logistic regression was used to examine the association between stages of CKD and CAC scores >10, >100, and >400 versus scores < or =10 compared with no CKD while adjusting for covariates. Analyses were repeated after stratifying by presence of diabetes. The mean age was 43.9 yr, and hypertension and diabetes were noted in 31.0 and 9.8%, respectively. No association was noted between stage 1 to 2 CKD and increased CAC scores. Compared with no CKD, stage 3 to 5 CKD was associated with CAC scores >100 (odds ratio, 2.85; 95% confidence interval, 0.92 to 8.80) and >400 (odds ratio, 8.35; 95% confidence interval, 1.94 to 35.95) in the total population after adjustment for covariates, but these associations were substantially reduced after exclusion of participants with diabetes. Participants with diabetes and stage 3 to 5 CKD had a ninefold increased odds of CAC scores >10 versus scores < or =10 compared with participants with diabetes and without CKD, whereas no association was noted between stage 3 to 5 CKD and CAC scores >10 in the nondiabetic population. In conclusion, stage 3 to 5 CKD is associated with increased CAC scores, but this association may be substantially stronger among adults with diabetes. These findings need to be confirmed in study populations that include adults >65 yr of age and a larger number of CKD cases.

In renal clinical trials, both slope-based and time-to-event renal outcomes have been used. These outcomes are typically based on estimates of GFR obtained using creatinine or iothalamate GFR (iGFR). The African American Study of Kidney Disease and Hypertension (AASK) was a trial in 1094 African Americans with hypertensive nephrosclerosis, which examined the effects of two levels of BP control and three antihypertensive regimens. This study compared the effects of the AASK interventions on outcomes based on serum creatinine with corresponding outcomes based on iGFR using 9742 matched pairs of iGFR and serum creatinine measurements. The iGFR-based outcomes included (1) a time-to-event composite outcome including a 50% GFR decline, ESRD, or death; (2) a composite outcome including a 50% GFR decline or ESRD; (3) mean decline in GFR in the first 3 mo after randomization (acute slope); (4) mean decline in GFR starting 3 mo after randomization (chronic slope); and (5) mean decline in GFR from baseline (total slope). The corresponding creatinine-based outcomes were (1) a composite of doubling of serum creatinine, ESRD, or death and (2) a composite of doubling of serum creatinine or ESRD and acute, chronic, and total slopes defined by the mean change in estimated GFR (eGFR), where eGFR was estimated from a regression equation for GFR depending primarily on serum creatinine and developed in AASK enrollees. Mean changes in iGFR and eGFR were also compared under extended models that allowed for the possibility that the rate of GFR decline may change over time during the chronic phase. an apparent acceleration in rate of decline of renal function over time was found. Subtle differences were observed between effects of the interventions on some of the creatinine and iGFR slope-based outcomes, but the main conclusions of the trial were similar for the serum creatinine and iothalamate-based measurements. This has important implications for the design of clinical trials with renal outcomes.

Measurement of GFR is considered the standard for estimating renal function. However, standardized accurate GFR methodology is expensive and cumbersome; therefore, estimates of GFR based on serum creatinine concentration have been employed. The purpose of the study presented here was to assess the accuracy and precision of using serum creatinine measurements to estimate GFR in the screen cohort of The African-American Study of Kidney Disease and Hypertension (AASK) Pilot Study. GFR was estimated by four methods: 100/serum creatinine, Cockcroft-Gault equation, creatinine clearance from 24-h urine collection, and a new regression equation derived from the pilot study data. These methods were compared with renal clearance of 125I-iothalamate GFR (GFR1) in 193 hypertensive (diastolic blood pressure > or = 95 mm Hg) African-American screen (142 men, 51 women). A second GFR (GFR2) was performed in 98 screen who were eligible (GFR1 25-70 mL/min per 1.73 m2) for the pilot study. Accuracy was assessed by the difference of 125I-iothalamate GFR-estimated GFR (delta GFR), and precision was estimated from the combined root mean squared error (CRMSE) and the coefficient of determination (r2). The results for accuracy (+/- SD) and precision were as follows: (1) 100/Scr, delta GFR = -0.76 +/- 16.5, CRMSE = 16.5, r2 = 0.69; (2) Cockcroft-Gault, delta GFR = 9.56 +/- 14.9, CRMSE = 17.7, r2 = 0.66; 3) 24-h creatinine clearance, delta GFR = 0.79 +/- 20.7, CRMSE = 20.7, r2 = 0.49; 4) New equation delta GFR = -0.08 +/- 12.8, CRMSE 12.7, r2 = 0.75. In comparison, a second GFR (GFR2, N = 98) had delta GFR = 1.36 +/- 8.48, CRMSE 8.6, r2 = 0.75. Estimates based on 100/SCr and the new equation were the most precise. It was concluded that GFR estimated by serum creatinine is superior to outpatient 24-h urine creatinine clearance in this population. Serum creatinine values can be used to provide a reasonably accurate estimate of GFR in hypertensive African Americans.