Jamie P. Dwyer

Estimating Baseline Kidney Function in Hospitalized Patients with Impaired Kidney Function

BACKGROUND AND OBJECTIVES Inaccurate determination of baseline kidney function can misclassify acute kidney injury (AKI) and affect the study of AKI-related outcomes. No consensus exists on how to optimally determine baseline kidney function when multiple preadmission creatinine measurements are available. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS The accuracy of commonly used methods for estimating baseline serum creatinine was compared with that of a reference standard adjudicated by a panel of board-certified nephrologists in 379 patients with AKI or CKD admitted to a tertiary referral center. RESULTS Agreement between estimating methods and the reference standard was highest when using creatinine values measured 7-365 days before admission. During this interval, the intraclass correlation coefficient (ICC) for the mean outpatient serum creatinine level (0.91 [95% confidence interval (CI), 0.88-0.92]) was higher than the most recent outpatient (ICC, 0.84 [95% CI, 0.80-0.88]; P<0.001) and the nadir outpatient (ICC, 0.83 [95% CI, 0.76-0.87; P<0.001) serum creatinine. Using the final creatinine value from a prior inpatient admission increased the ICC of the most recent outpatient creatinine method (0.88 [95% CI, 0.85-0.91]). Performance of all methods declined or was unchanged when the time interval was broadened to 2 years or included serum creatinine measured within a week of admission. CONCLUSIONS The mean outpatient serum creatinine measured within a year of hospitalization most closely approximates nephrologist-adjudicated serum creatinine values.

Ferric Citrate Controls Phosphorus and Delivers Iron in Patients on Dialysis

Patients on dialysis require phosphorus binders to prevent hyperphosphatemia and are iron deficient. We studied ferric citrate as a phosphorus binder and iron source. In this sequential, randomized trial, 441 subjects on dialysis were randomized to ferric citrate or active control in a 52-week active control period followed by a 4-week placebo control period, in which subjects on ferric citrate who completed the active control period were rerandomized to ferric citrate or placebo. The primary analysis compared the mean change in phosphorus between ferric citrate and placebo during the placebo control period. A sequential gatekeeping strategy controlled study-wise type 1 error for serum ferritin, transferrin saturation, and intravenous iron and erythropoietin-stimulating agent usage as prespecified secondary outcomes in the active control period. Ferric citrate controlled phosphorus compared with placebo, with a mean treatment difference of -2.2±0.2 mg/dl (mean±SEM) (P<0.001). Active control period phosphorus was similar between ferric citrate and active control, with comparable safety profiles. Subjects on ferric citrate achieved higher mean iron parameters (ferritin=899±488 ng/ml [mean±SD]; transferrin saturation=39%±17%) versus subjects on active control (ferritin=628±367 ng/ml [mean±SD]; transferrin saturation=30%±12%; P<0.001 for both). Subjects on ferric citrate received less intravenous elemental iron (median=12.95 mg/wk ferric citrate; 26.88 mg/wk active control; P<0.001) and less erythropoietin-stimulating agent (median epoetin-equivalent units per week: 5306 units/wk ferric citrate; 6951 units/wk active control; P=0.04). Hemoglobin levels were statistically higher on ferric citrate. Thus, ferric citrate is an efficacious and safe phosphate binder that increases iron stores and reduces intravenous iron and erythropoietin-stimulating agent use while maintaining hemoglobin.

Renal Dysfunction in the Presence of Normoalbuminuria in Type 2 Diabetes: Results from the DEMAND Study.

Background/Aims: Microalbuminuria is associated with diabetes and is an independent risk factor for developing diabetic nephropathy. We have previously reported the overall prevalence of normoalbuminuria, microalbuminuria, and macroalbuminuria to be 51, 39, and 9.8%, respectively, in an unselected population of patients with type 2 diabetes. Renal dysfunction was present in a large proportion of these patients without proteinuria, assessed by a single random albumin-to-creatinine ratio (ACR) . We therefore undertook to characterize the nature of this association of non-proteinuric renal dysfunction in type 2 diabetes. Methods: In the DEMAND (Developing Education on Microalbuminuria for Awareness of Renal and Cardiovascular Risk in Diabetes) study, a global, cross-sectional study which described the prevalence and risk factors for albuminuria in a clinic-based cohort, kidney function was assessed in 11,573 patients; ACR was measured using the Bayer reagent strip Multistix® 10SG. Normoalbuminuria was defined as ACR <30 mg/g, microalbuminuria as 30–299 mg/g, and macroalbuminuria as >300 mg/g. Results: Among the patients with estimated kidney function determined, chronic kidney disease was noted in 17% of those with normoalbuminuria (stage 3–5), and significant kidney dysfunction was found in 27% of those with microalbuminuria and 31% of those with overt proteinuria. CrCl was <60 ml/min in 20.5% of normoalbuminurics, 30.7% of microalbuminurics, and 35.0% of macroalbuminurics (p < 0.0001). Conclusion: A large proportion of diabetic patients with completely normal urinary albumin excretion or microalbuminuria presented with significant kidney dysfunction. Therefore, further investigation is warranted.

Effect of Intensive Versus Standard Clinic-Based Hypertension Management on Ambulatory Blood Pressure: Results From the SPRINT (Systolic Blood Pressure Intervention Trial) Ambulatory Blood Pressure Study.

The effect of clinic-based intensive hypertension treatment on ambulatory blood pressure (BP) is unknown. The goal of the SPRINT (Systolic Blood Pressure Intervention Trial) ambulatory BP ancillary study was to evaluate the effect of intensive versus standard clinic-based BP targets on ambulatory BP. Ambulatory BP was obtained within 3 weeks of the 27-month study visit in 897 SPRINT participants. Intensive treatment resulted in lower clinic systolic BP (mean difference between groups=16.0 mm Hg; 95% confidence interval, 14.1–17.8 mm Hg), nighttime systolic BP (mean difference=9.6 mm Hg; 95% confidence interval, 7.7–11.5 mm Hg), daytime systolic BP (mean difference=12.3 mm Hg; 95% confidence interval, 10.6–13.9 mm Hg), and 24-hour systolic BP (mean difference=11.2 mm Hg; 95% confidence interval, 9.7–12.8 mm Hg). The night/day systolic BP ratio was similar between the intensive (0.92±0.09) and standard-treatment groups (0.91±0.09). There was considerable lack of agreement within participants between clinic systolic BP and daytime ambulatory systolic BP with wide limits of agreement on Bland–Altman plots. In conclusion, targeting a systolic BP of <120 mm Hg, when compared with <140 mm Hg, resulted in lower nighttime, daytime, and 24-hour systolic BP, but did not change the night/day systolic BP ratio. Ambulatory BP monitoring may be required to assess the effect of targeted hypertension therapy on out of office BP. Further studies are needed to assess whether targeting hypertension therapy based on ambulatory BP improves clinical outcomes. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01835249.

Ferric Citrate Reduces Intravenous Iron and Erythropoiesis-Stimulating Agent Use in ESRD

Ferric citrate (FC) is a phosphate binder with shown efficacy and additional effects on iron stores and use of intravenous (iv) iron and erythropoiesis-stimulating agents (ESAs). We provide detailed analyses of changes in iron/hematologic parameters and iv iron/ESA use at time points throughout the active control period of a phase 3 international randomized clinical trial. In all, 441 subjects were randomized (292 to FC and 149 to sevelamer carbonate and/or calcium acetate [active control (AC)]) and followed for 52 weeks. Subjects on FC had increased ferritin and transferrin saturation (TSAT) levels compared with subjects on AC by week 12 (change in ferritin, 114.1±29.35 ng/ml; P<0.001; change in TSAT, 8.62%±1.57%; P<0.001). Change in TSAT plateaued at this point, whereas change in ferritin increased through week 24, remaining relatively stable thereafter. Subjects on FC needed less iv iron compared with subjects on AC over 52 weeks (median [interquartile range] dose=12.9 [1.0-28.9] versus 26.8 [13.4-47.6] mg/wk; P<0.001), and the percentage of subjects not requiring iv iron was higher with FC (P<0.001). Cumulative ESA over 52 weeks was lower with FC than AC (median [interquartile range] dose=5303 [2023-9695] versus 6954 [2664-12,375] units/wk; P=0.04). Overall, 90.3% of subjects on FC and 89.3% of subjects on AC experienced adverse events. In conclusion, treatment with FC as a phosphate binder results in increased iron parameters apparent after 12 weeks and reduces iv iron and ESA use while maintaining hemoglobin over 52 weeks, with a safety profile similar to that of available binders.

Dose-Response and Efficacy of Ferric Citrate to Treat Hyperphosphatemia in Hemodialysis Patients: A Short-term Randomized Trial

BACKGROUND Most dialysis patients require phosphate binders to control hyperphosphatemia. Ferric citrate has been tested in phase 2 trials as a phosphate binder. This trial was designed as a dose-response and efficacy trial. STUDY DESIGN Prospective, phase 3, multicenter, open-label, randomized clinical trial. SETTING & PARTICIPANTS 151 participants with hyperphosphatemia on maintenance hemodialysis therapy. INTERVENTION Fixed dose of ferric citrate taken orally as a phosphate binder for up to 28 days (1, 6, or 8 g/d in 51, 52, and 48 participants, respectively). OUTCOMES Primary outcome is dose-response of ferric citrate on serum phosphorus level; secondary outcomes are safety and tolerability. MEASUREMENTS Serum chemistry tests including phosphorus, safety data. RESULTS 151 participants received at least one dose of ferric citrate. Mean baseline phosphorus levels were 7.3 ± 1.7 (SD) mg/dL in the 1-g/d group, 7.6 ± 1.7 mg/dL in the 6-g/d group, and 7.5 ± 1.6 mg/dL in the 8-g/d group. Phosphorus levels decreased in a dose-dependent manner (mean change at end of treatment, -0.1 ± 1.3 mg/dL in the 1-g/d group, -1.9 ± 1.7 mg/dL in the 6-g/d group, and -2.1 ± 2.0 mg/dL in the 8-g/d group). The mean difference in reduction in phosphorus levels between the 6- and 1-g/d groups was 1.3 mg/dL (95% CI, 0.69 to 1.9; P < 0.001), between the 8- and 1-g/d groups was 1.5 mg/dL (95% CI, 0.86 to 2.1; P < 0.001), and between the 8- and 6-g/d groups was 0.21 mg/dL (95% CI, -0.39 to 0.81; P = 0.5). The most common adverse event was stool discoloration. LIMITATIONS Sample size and duration confirm efficacy, but limit our ability to confirm safety. CONCLUSIONS Ferric citrate is efficacious as a phosphate binder in a dose-dependent manner. A phase 3 trial is ongoing to confirm safety and efficacy.

The Safety and Tolerability of Ferric Citrate as a Phosphate Binder in Dialysis Patients

Background: A phase II open-label study was conducted in hemodialysis patients evaluating the short-term safety, tolerability, and iron absorption with ferric citrate when used as a phosphate binder. Methods: Enrollment occurred in two periods. Period 1 recruited patients taking 6–15 pills/day of binder with phosphorus of ≥2.5 mg/dl. Period 2 recruited patients taking ≥12 pills/day of binder with phosphorus of ≥3.5 mg/dl. Participants with ferritin ≥1,000 µg/l or transferrin iron saturation (TSAT) ≥50% at screening were excluded. Subjects discontinued their previous binders and started 4.5 g/day of ferric citrate (period 1) or 6 g/day (period 2) and were titrated for 4 weeks to maintain a phosphorus of 3.5–5.5 mg/dl. Chemistries and complete blood count were obtained weekly and a gastrointestinal questionnaire was administered at drug initiation and final visit. Iron therapy was permitted if the ferritin was <500 µg/l and TSAT <30%. Results: Fifty-five subjects were enrolled. Four serious adverse events were reported; none were related to the study drug. Findings from the gastrointestinal questionnaire included stool discoloration (69%), constipation (15%), and bloating (7%). Mean iron parameters at the beginning of the study were ferritin 554 ± 296 µg/l, iron 68 ± 21 µg/dl, and iron saturation 30 ± 7.8%. At the end of study, mean ferritin was 609 ± 340 µg/l (p = 0.02), iron 75 ± 27 µg/dl (p = 0.04), and TSAT was 35 ± 13% (p = 0.001). Mean phosphorus and calcium levels were unchanged from baseline at the end of study. Conclusion: Ferric citrate was well tolerated by patients after 4 weeks with no significant clinical or biochemical adverse events related to exposure.

Estimated GFR decline as a surrogate end point for kidney failure: a post hoc analysis from the Reduction of End Points in Non-Insulin-Dependent Diabetes With the Angiotensin II Antagonist Losartan (RENAAL) study and Irbesartan Diabetic Nephropathy Trial (IDNT).

BACKGROUND A doubling of serum creatinine value, corresponding to a 57% decline in estimated glomerular filtration rate (eGFR), is used frequently as a component of a composite kidney end point in clinical trials in type 2 diabetes. The aim of this study was to determine whether alternative end points defined by smaller declines in eGFR would improve the statistical power of these clinical trials. STUDY DESIGN Post hoc analyses of 2 multinational randomized controlled trials (Reduction of End Points in Non-Insulin-Dependent Diabetes With the Angiotensin II Antagonist Losartan [RENAAL] and Irbesartan Diabetic Nephropathy Trial [IDNT]) that assessed the treatment effect of the angiotensin receptor blockers (ARBs) losartan and irbesartan. SETTING & PARTICIPANTS 1,513 (RENAAL) and 1,715 (IDNT) adult patients with type 2 diabetes and nephropathy. PREDICTOR Established versus alternative end points defined as a confirmed doubling of serum creatinine level versus confirmed eGFR decline of 57%, 40%, 30%, or 20% as a component of a composite end point of end-stage renal disease or eGFR < 15mL/min/1.73m(2). OUTCOMES Numbers of patients reaching end points, precision (standard error), and significance (z score) of ARB treatment effect (HR) during follow-up. RESULTS Lesser eGFR declines resulted in a greater number of patients reaching end points in both treatment groups and lower standard error of the HR, but the effect on z score was counterbalanced by attenuation of the HR. When calculating the eGFR decline from month 3, attenuation of the HR was less pronounced. LIMITATIONS Post hoc analysis. CONCLUSIONS Despite increases in precision of the treatment effect, eGFR declines less than a doubling of serum creatinine value did not consistently improve statistical power of the clinical trials due to attenuation of the treatment effect. Attenuation of the treatment effect appears to be due in part to acute effects of ARBs on eGFR. These findings should be taken into account when using lesser eGFR declines as alternative end points for clinical trials.

Membranous Nephropathy with Crescents

Membranous nephropathy is a common cause of nephrotic syndrome in adults and can be primary or secondary to systemic lupus erythematosus, chronic infection, or drugs. Rapid decline in renal function in patients with membranous nephropathy may be due to renal vein thrombosis, malignant hypertension, or an additional superimposed destructive process involving the renal parenchyma. Crescents are rare in primary membranous nephropathy and thus suggest another underlying disease process, such as combined membranous and focal or diffuse lupus nephritis. However, in some patients with membranous nephropathy and crescents, the crescentic lesion may be due to a distinct, separate disease process, such as anti-glomerular basement membrane antibodies or anti-neutrophil cytoplasmic antibodies-related pauci-immune glomerulonephritis. Here we describe a case with such renal biopsy findings, review previous reported cases, and discuss possible implications for pathogenesis of the coexistence of these lesions.

Visit-to-Visit Variability in Blood Pressure and Kidney and Cardiovascular Outcomes in Patients With Type 2 Diabetes and Nephropathy: A Post Hoc Analysis From the RENAAL Study and the Irbesartan Diabetic Nephropathy Trial

BACKGROUND Increased systolic blood pressure variability between outpatient visits is associated with increased incidence of cardiovascular end points. However, few studies have examined the association of visit-to-visit variability in systolic blood pressure with clinically relevant kidney disease outcomes. We analyzed the association of systolic blood pressure visit-to-visit variability with renal and cardiovascular morbidity and mortality among individuals with diabetes and nephropathy. STUDY DESIGN Observational analysis of IDNT (Irbesartan Diabetic Nephropathy Trial) and the RENAAL (Reduction of End Points in Non-Insulin-Dependent Diabetes With the Angiotensin II Antagonist Losartan) Study. SETTING & PARTICIPANTS 2,739 participants with type 2 diabetes and nephropathy with at least 1 year of blood pressure measurements available. PREDICTORS Systolic blood pressure visit-to-visit variability was calculated from the SD of the systolic blood pressure from 4 visits occurring 3-12 months postrandomization. OUTCOMES The kidney disease outcome was defined as time to confirmed doubling of serum creatinine level, end-stage renal disease, or death; the cardiovascular outcome was defined as time to cardiovascular death, myocardial infarction, stroke, hospitalization for heart failure, or revascularization. RESULTS Mean visit-to-visit variability in systolic blood pressure from 3 to 12 months postrandomization was 12.0±6.8(SD)mmHg. Following this ascertainment period, there were 954 kidney disease and 542 cardiovascular events. Greater systolic blood pressure visit-to-visit variability was associated independently with increased risk of the composite kidney disease end point (HR per 1-SD increment, 1.08 [95%CI, 1.01-1.16]; P=0.02) and end-stage renal disease, but not with the cardiovascular outcome. LIMITATIONS Observational study with the potential for confounding. CONCLUSIONS In diabetic individuals with nephropathy, systolic blood pressure visit-to-visit variability is associated independently with hard kidney disease outcomes.