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Rationale & Objective: Patients with advanced kidney disease are at risk for cognitive impairment, which may persist after kidney transplantation. We sought to understand changes in neurocognitive function domains utilizing comprehensive cognitive assessments., Study Design: Prospective cohort study., Setting & Population: Single-center study of patients undergoing kidney transplantation., Exposure: Kidney transplantation., Outcomes: Changes in neurocognitive function as measured by the Repeatable Battery for Assessment of Neuropsychological Status (RBANS) and the Trail Making Test Parts A and B (TRAIL A and B) before transplantation (baseline) and compared to 3 months and 12 months posttransplant., Analytical Approach: Wilcoxon signed-rank and linear mixed effect models were utilized to assess changes in neurocognitive scores at 3 months and 12 months compared to baseline., Results: Thirty-two patients were included with a mean age of 45 years, 47% female, 85% White, and 62% with at least some college education. Hypertension and diabetes were etiologies of kidney disease in 31% and 25% of patients, respectively. Baseline RBANS and TRAIL A and B scores averaged 84.7 ± 14, 40.4 ± 9.9, and 41 ± 11.5, respectively. Although there were posttransplant improvements in immediate and delayed memory at 3 months, these were not sustained at 12 months. There were no significant differences from baseline at 3 months and 12 months in RBANS index scores for language, visuospatial/constructional abilities, and attention. Compared to baseline, TRAIL A scores were not significantly different at 3 months but were significantly improved at 12 months, whereas TRAIL B scores improved significantly at both 3 months and 12 months., Limitations: Single-center design and small sample size., Conclusions: Utilizing comprehensive cognitive assessments, we found improvements in attention and executive function in the first posttransplant year as measured by TRAIL A and B. However, there was no significant change in global cognition as measured by RBANS. These findings identify cognitive domains for potential intervention in the posttransplant population., (© 2022 The Authors.)

Introduction: Oral phosphate binders are the main stay of treatment of hyperphosphatemia. Adherence rates to ferric citrate, a recently approved phosphate binder, are unknown., Methods: We conducted a post-hoc analysis to evaluate whether adherence rates were different for ferric citrate vs. active control in 412 subjects with end stage kidney disease (ESKD) who were randomized to ferric citrate vs. active control (sevelamer carbonate and/or calcium acetate). Adherence was defined as percent of actual number of pills taken to total number of pills prescribed., Findings: There were no significant differences in baseline characteristics including gender, race/ethnicity, and age between the ferric citrate and active control groups. Baseline phosphorus, calcium, and parathyroid hormone levels were similar. Mean (SD) adherence was 81.4% (17.4) and 81.7% (15.9) in the ferric citrate and active control groups, respectively (P = 0.88). Adherence remained similar between both groups after adjusting for gender, race/ethnicity, age, cardiovascular disease (CVD), and diabetic nephropathy (mean [95% CI]: 81.4% [78.2, 84.6] and 81.5% [77.7, 85.2] for ferric citrate and active control, respectively). Gender, race/ethnicity, age, and diagnosis of diabetic nephropathy did not influence adherence to the prescribed phosphate binder. Subjects with CVD had lower adherence rates to phosphate binder; this was significant only in the active control group., Discussion: Adherence rates to the phosphate binder, ferric citrate, were similar to adherence rates to active control. Similar adherence rates to ferric citrate are notable since tolerance to active control was an entry criteria and the study was open label. Gender, race/ethnicity, nor age influenced adherence., (© 2016 International Society for Hemodialysis.)

Iron stores assuring optimal efficacy/safety for erythropoiesis are unknown in the dialysis population. Using multicenter trial data, we related safety profiles, erythropoiesis-stimulating agent (ESA), and intravenous iron dosing to achieved iron stores in 441 subjects randomized 2 : 1 to ferric citrate or active control as their phosphate binder over 52 weeks. Intravenous iron was given at each site's discretion if ferritin ≤ 1,000 ng/mL and transferrin saturation ≤ 30%. Multivariable time-dependent Cox regression jointly related the primary safety outcome (composite of cardiac, infection, gastrointestinal, and hepatobiliary serious adverse events) to moving averages of ferritin and transferrin saturation over the preceding 90 days with covariate adjustment. Multivariable generalized estimating equations related elevated ESA and intravenous iron doses to trailing 90-day averages of ferritin and transferrin saturation with covariate adjustment. The adjusted hazard ratio for the safety composite per 10% increase in transferrin saturation was 0.84 (95% confidence interval 0.68 - 1.02, p = 0.08) and 1.09 (0.86 - 1.35, p = 0.48) per 400 ng/mL increase in ferritin. The adjusted hazard ratio for the safety composite was 0.50 (0.29 - 0.88, p = 0.016) for the highest transferrin saturation tertile vs. the lowest. Adjusted odds ratios for higher intravenous iron dose were lower in the highest (0.23 [0.16 - 0.35], p < 0.001) and middle transferrin saturation tertile (0.42 [0.31 - 0.57], p < 0.001) vs. lowest. Incidence of elevated ESA dose was lower in the highest transferrin saturation tertile (p = 0.01). Ferritin did not predict clinical events or ESA dose. Transferrin saturation may be a better marker than serum ferritin to judge optimal iron stores in dialysis patients. Transferrin saturations > 34% are safe and provide maximal efficacy.
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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.)

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., (Copyright © 2015 by the American Society of Nephrology.)

Background: Patients with end-stage renal disease (ESRD) require phosphate binders for hyperphosphatemia and erythropoiesis-stimulating agents (ESAs) and intravenous (i.v.) iron for anemia. Ferric citrate (FC) is a novel, iron-based phosphate binder that increases iron stores and decreases i.v. iron and ESA usage while maintaining hemoglobin levels, and may decrease the cost of ESRD care. The study objectives were to (1) quantify differences in ESA and i.v. iron usage among ESRD patients receiving FC compared with active control (AC) (sevelamer carbonate and/or calcium acetate) on the basis of data from a 52-week phase III clinical trial and (2) standardize trial data to the general United States (US) ESRD population and calculate the potential impact of FC on ESRD cost/patient/year in the USA., Study Design: The study was a randomized, controlled clinical trial., Setting and Population: A total of 441 adult subjects with ESRD who received FC or AC for 52 weeks were included., Model, Perspective, and Timeline: Differences in ESA and i.v. iron usage between the treatment groups were modeled over time using generalized linear mixed models and zero-inflated Poisson models. Trends were modeled via logarithmic curves, and utilization patterns were applied to the general dialysis population to estimate expected resource savings., Outcomes: Study outcomes were costs saved/patient/year using FC versus AC (US dollars)., Results: Our model suggests an annual decrease of 129,106 U of ESAs and 1960 mg of i.v. iron per patient in the second year after a switch from AC to FC. Applying 2013 Medicare pricing, this would save $1585 in ESAs and $516 in i.v. iron: a total of $2101/patient/year; these savings would be expected to double for managed care plans., Limitations: The projections were made on 1 year of trial data., Conclusions: Phosphate binding with FC reduces i.v. iron and ESA usage. Given the high cost burden of ESRD, our model demonstrates significant potential cost savings., Trial Registration: ClinicalTrials.gov (NCT01191255) http://clinicaltrials.gov/ct2/show/NCT01191255 .

Background: Phosphate binders are the cornerstone of hyperphosphatemia management in dialysis patients. Ferric citrate is an iron-based oral phosphate binder that effectively lowers serum phosphorus levels., Study Design: 52-week, open-label, phase 3, randomized, controlled trial for safety-profile assessment., Setting & Participants: Maintenance dialysis patients with serum phosphorus levels ≥6.0 mg/dL after washout of prior phosphate binders., Intervention: 2:1 randomization to ferric citrate or active control (sevelamer carbonate and/or calcium acetate)., Outcomes: Changes in mineral bone disease, protein-energy wasting/inflammation, and occurrence of adverse events after 1 year., Measurements: Serum calcium, intact parathyroid hormone, phosphorus, aluminum, white blood cell count, percentage of lymphocytes, serum urea nitrogen, and bicarbonate., Results: There were 292 participants randomly assigned to ferric citrate, and 149, to active control. Groups were well matched. For mean changes from baseline, phosphorus levels decreased similarly in the ferric citrate and active control groups (-2.04±1.99 [SD] vs -2.18±2.25 mg/dL, respectively; P=0.9); serum calcium levels increased similarly in the ferric citrate and active control groups (0.22±0.90 vs 0.31±0.95 mg/dL; P=0.2). Hypercalcemia occurred in 4 participants receiving calcium acetate. Parathyroid hormone levels decreased similarly in the ferric citrate and active control groups (-167.1±399.8 vs -152.7±392.1 pg/mL; P=0.8). Serum albumin, bicarbonate, serum urea nitrogen, white blood cell count and percentage of lymphocytes, and aluminum values were similar between ferric citrate and active control. Total and low-density lipoprotein cholesterol levels were lower in participants receiving sevelamer than those receiving ferric citrate and calcium acetate. Fewer participants randomly assigned to ferric citrate had serious adverse events compared with active control., Limitations: Open-label study, few peritoneal dialysis patients., Conclusions: Ferric citrate was associated with similar phosphorus control compared to active control, with similar effects on markers of bone and mineral metabolism in dialysis patients. There was no evidence of protein-energy wasting/inflammation or aluminum toxicity, and fewer participants randomly assigned to ferric citrate had serious adverse events. Ferric citrate is an effective phosphate binder with a safety profile comparable to sevelamer and calcium acetate., (Copyright © 2015 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Ferric citrate is a novel phosphate binder that allows the simultaneous treatment of hyperphosphatemia and iron deficiency in patients being treated for end-stage renal disease with hemodialysis (HD). Multiple clinical trials in HD patients have uniformly and consistently demonstrated the efficacy of the drug in controlling hyperphosphatemia with a good safety profile, leading the US Food and Drug Administration in 2014 to approve its use for that indication. A concurrent beneficial effect, while using ferric citrate as a phosphate binder, is its salutary effect in HD patients with iron deficiency being treated with an erythropoietin-stimulating agent (ESA) in restoring iron that becomes available for reversing chronic kidney disease (CKD)-related anemia. Ferric citrate has also been shown in several studies to diminish the need for intravenous iron treatment and to reduce the requirement for ESA. Ferric citrate is thus a preferred phosphate binder that helps resolve CKD-related mineral bone disease and iron-deficiency anemia.

Background: Ferric citrate (FC) is a new phosphorus binder shown to increase serum iron stores while reducing intravenous iron and erythropoiesis-stimulating agent usage. Such reductions could lower hospitalization rates and associated costs., Methods: Hospitalizations during a Phase III trial were compared between FC and active control (AC). Hospitalization costs were estimated using the 2013 US Renal Data System Annual Data Report., Results: 34.6% of FC patients were hospitalized at least once versus 45.6% of the AC group (risk reduction 24.2%; p = 0.02). There were 181 unique hospitalizations in the FC group versus 239 in the AC group, for a difference of 58 hospitalizations. Total potential savings was US$ 867,622 in hospitalization costs in the FC group. If the hospitalization reduction in our study was applied to the general end-stage renal disease population, this could translate into a savings of US$ 3002/patient/year., Conclusions: Patients receiving FC experienced fewer hospitalizations with the potential for significant savings.

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., (Copyright © 2015 by the American Society of Nephrology.)

Background/aims: Pyridoxamine dihydrochloride (Pyridorin™) blocks pathogenic oxidative pathways in the progression of diabetic nephropathy. The pyridoxamine pilot study was designed to test entry criteria and outcomes. Subjects had SCr 1.3-3.5 mg/dl, protein-to-creatinine ≥1,200 mg/g and used a surrogate outcome of ΔSCr over 52 weeks. Subjects had to be on a maximally tolerated dose of ACE/ARB for 3 months; stable other antihypertensive doses for 2 months; stable diuretic dose for 2 weeks, and BP ≤160/90 mm Hg; or enter a Pharmaco-Stabilization Phase (PSP). This pilot failed to detect an effect on ΔSCr in intent-to-treat analysis., Methods: We queried the locked clinical trial database for subgroups in which there was a treatment effect., Results: Subjects not requiring PSP and those with entry SCr <2.0 mg/dl had a treatment effect. Subjects entering PSP required more changes in antihypertensive medications and experienced larger ΔSCr over 52 weeks. PSP subjects with BP >140/90 mm Hg had no treatment effect, but those ≤140/90 mm Hg did., Conclusion: Time required for acute effects of ACE/ARB to stabilize is unknown, but these data suggest >3 months. Thus, subjects in the pivotal trial must be on ACE/ARB for 6 months. Frequent antihypertensive adjustment could engender SCr changes unrelated to CKD progression. Thus, we will require subjects to have BP ≤150/90 mm Hg and on stable antihypertensives for 26 weeks, or ≤140/90 mm Hg and on stable antihypertensives for 13 weeks. Since ΔSCr over 52 weeks is limited as a surrogate outcome, the pivotal trial uses a time-to-event analysis of baseline SCr to at least a 50% increase in SCr or ESRD as the primary outcome. This substantial ΔSCr is protected from noise and is clinically relevant. The pyridoxamine pilot provided critical information to inform the design of PIONEER-CSG-17, which we conducted under the SPA agreement with FDA.

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., (Copyright © 2013 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Chronic kidney disease associated mineral and bone disorders arise as a result of aberrant bone mineral metabolism in patients with advancing levels of renal dysfunction and end-stage renal disease. One of the cornerstones of treatment is the use of phosphate-binding agents. We describe the rationale and study design for a clinical trial to assess the safety and efficacy of ferric citrate as a phosphate binder. This trial is a three-period, international, multicenter, randomized, controlled clinical trial to assess the safety and efficacy of ferric citrate as a phosphate binder, consisting of a 2-week washout period, a 52-week safety assessment period in which subjects are randomized to ferric citrate or active control, and a 4-week efficacy assessment period in which subjects randomized to ferric citrate in the safety assessment period are randomized to ferric citrate or placebo. Eligible subjects include end-stage renal disease patients who have been treated with thrice-weekly hemodialysis or peritoneal dialysis for at least 3 months in dialysis clinics in the United States and Israel. Primary outcome measure will be the effect of ferric citrate vs. placebo on the change in serum phosphorus. Safety assessments will be performed by monitoring adverse events, concomitant medication use, and sequential blood chemistries (including iron parameters, phosphorus, and calcium). This three-period trial will assess the efficacy of ferric citrate as a phosphate binder. If proven safe and efficacious, ferric citrate will likely provide an additional phosphate binder to treat chronic kidney disease associated mineral and bone disorders., (© 2012 The Authors. Hemodialysis International © 2012 International Society for Hemodialysis.)

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., (Copyright © 2012 S. Karger AG, Basel.)

Background: Few studies have examined the association between obesity and markers of kidney injury in a chronic kidney disease population. We hypothesized that obesity is independently associated with proteinuria, a marker of chronic kidney disease progression., Study Design: Observational cross-sectional analysis., Setting & Participants: Post hoc analysis of baseline data for 652 participants in the African American Study of Kidney Disease (AASK)., Predictors: Obesity, determined using body mass index (BMI)., Measurements & Outcomes: Urine total protein-creatinine ratio and albumin-creatinine ratio measured in 24-hour urine collections., Results: AASK participants had a mean age of 60.2 ± 10.2 years and serum creatinine level of 2.3 ± 1.5 mg/dL; 61.3% were men. Mean BMI was 31.4 ± 7.0 kg/m(2). Approximately 70% of participants had a daily urine total protein excretion rate <300 mg/d. In linear regression analyses adjusted for sex, each 2-kg/m(2) increase in BMI was associated with a 6.7% (95% CI, 3.2-10.4) and 9.4% (95% CI, 4.9-14.1) increase in urine total protein-creatinine and urine albumin-creatinine ratios, respectively. In multivariable models adjusting for age, sex, systolic blood pressure, serum glucose level, uric acid level, and creatinine level, each 2-kg/m(2) increase in BMI was associated with a 3.5% (95% CI, 0.4-6.7) and 5.6% (95% CI, 1.5-9.9) increase in proteinuria and albuminuria, respectively. The interaction between older age and BMI was statistically significant, indicating that this relationship was driven by younger AASK participants., Limitations: May not generalize to other populations; cross-sectional analysis precludes statements regarding causality., Conclusions: BMI is associated independently with urine total protein and albumin excretion in African Americans with hypertensive nephrosclerosis, particularly in younger patients., (Copyright © 2010 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Ambulatory blood pressure (ABP) monitoring provides unique information about day-night patterns of blood pressure (BP). The objectives of this article were to describe ABP patterns in African Americans with hypertensive kidney disease, to examine the joint distribution of clinic BP and ABP, and to determine associations of hypertensive target organ damage with clinic BP and ABP. This study is a cross-sectional analysis of baseline data from the African American Study of Kidney Disease Cohort Study. Masked hypertension was defined by elevated daytime (>or= 135/85 mm Hg) or elevated nighttime (>or= 120/70 mm Hg) ABP in those with controlled clinic BP (<140/90 mm Hg); nondipping was defined by a

The African American Study of Kidney Disease and Hypertension (AASK) was conducted over a 7-year period at 21 clinical centers across the United States to investigate whether one of two levels of blood pressure control and/or one of three classes of antihypertensive medications was more effective at slowing the rate of renal disease in African Americans with renal insufficiency presumed secondary to hypertension. Analysis at the end of the study revealed an overall participant retention rate of 90% (still alive and not on dialysis); defined as having had at least one 125I-iothalamate GFR, the primary data collection element, measured in the final year of the study. Adherence, defined as not missing 3 consecutive protocol visits (6 months) during the study, was 77%. Adherence to protocol visits showed that participants assigned to a low blood pressure goal (mean arterial pressure [MAP] of 92 mm/Hg or lower) had a 30% (95% CI, 9%-45%) lower risk of nonadherence as compared to those assigned to the usual goal [MAP of 102-107] (p = 0.006). No statistically significant difference was observed between randomized drug assignments. Higher baseline systolic (p = 0.0001) and diastolic (p = 0.007) blood pressures were associated with a higher risk of nonadherence. Declining to provide an annual income is associated with a higher risk of nonadherence compared to those with incomes of $15,000 or higher (p = 0.04). In discussing the identifying factors that may predict nonadherence and the strategies that assisted in improving adherence and retention, this article offers insights for researchers in achieving high levels of participation in long-term clinical studies.

Background: Preclinical data suggest that cyclooxygenase 2 inhibitors decrease proteinuria and preserve glomerular structure in animal models of diabetic nephropathy. The objective of this study is to compare the efficacy and safety of celecoxib with placebo for decreasing proteinuria in patients with diabetic nephropathy., Study Design: Placebo-controlled double-blinded crossover design., Setting & Participants: 24 patients with type 1 or 2 diabetes mellitus, proteinuria with protein of 500 mg/d or greater, and serum creatinine level of 3.0 mg/dL or less., Intervention: Patients were randomly assigned to: (1) 6 weeks of celecoxib followed by a 3-week washout period, followed by 6 weeks of placebo followed by another 3-week washout; or (2) 6 weeks of placebo followed by a 3-week washout, followed by 6 weeks of celecoxib followed by another 3-week washout period. All patients were administered quinapril, 20 to 40 mg/d, or irbesartan, 150 to 300 mg/d. All patients were administered aspirin, 81 mg/d., Outcomes & Measurements: Proteinuria was assessed by means of protein-creatinine ratio. Data were analyzed using the mixed-effect statistical model., Results: There was no significant difference in urinary proteinuria after 6 weeks of treatment with placebo or celecoxib (proteinuria ratio, celecoxib versus placebo, 1.041; 95% confidence interval, 0.846 to 1.282). Celecoxib had no significant effect on potassium or estimated glomerular filtration rate. Frequencies of adverse events were similar between the placebo and celecoxib treatments., Limitations: This pilot study was not designed to evaluate the safety or long-term clinical effects of celecoxib., Conclusions: Celecoxib, 200 mg/d, for 6 weeks did not alter proteinuria. Few adverse events were noted in this high-risk population.

Background: African Americans are at increased risk of kidney failure caused by hypertension. The primary objective of the African American Study of Kidney Disease and Hypertension (AASK) Cohort Study is to identify risk factors for progressive kidney disease in African Americans with hypertensive chronic kidney disease in the setting of recommended antihypertensive therapy., Study Design, Setting, & Participants: On completion of the AASK Trial, a randomized, double-blind, 3 x 2 factorial trial, participants who had not yet begun dialysis treatment or undergone kidney transplantation were invited to enroll in a prospective Cohort Study. Cohort Study participants received recommended antihypertensive drug therapy, including high rates of angiotensin-converting enzyme-inhibitor (73%) and angiotensin receptor blocker (10%) use with a blood pressure goal of less than 130/80 mm Hg., Predictor, Outcomes, & Measurements: Baseline clinical and demographic characteristics are described separately at the baseline of the AASK Trial and Cohort Study., Results: Of 1,094 persons enrolled in the AASK Trial (June 1995 to September 2001; mean age, 55 years; 61% men), 691 enrolled in the AASK Cohort Study (April 2002 to present), 299 died or reached dialysis therapy or transplantation, and 104 declined to participate in the AASK Cohort Study. Mean baseline systolic/diastolic blood pressures were 150/96 mm Hg in the Trial and 136/81 mm Hg in the Cohort Study. Cohort Study participants had greater serum creatinine levels at the start of the Cohort Study (2.3 versus 1.8 mg/dL [203 versus 159 micromol/L]), corresponding to an estimated glomerular filtration rate of 43.8 versus 50.3 mL/min/1.73 m2 (0.73 versus 0.84 mL/s/1.73 m2), than Trial participants and greater urine protein-creatinine ratios (0.38 versus 0.19 mg/mg, respectively). Individuals who were eligible, but declined to participate in the Cohort Study, had greater systolic blood pressure, but similar kidney function., Limitations: Some parameters, such as iothalamate glomerular filtration rate, urinary albumin level, echocardiogram, and ambulatory blood pressure, were not performed in both the Trial and the Cohort Study, limiting the ability to evaluate changes in these parameters over time., Conclusion: Despite well-controlled blood pressure in the AASK Trial, Cohort Study participants still had evidence of progressive chronic kidney disease. Thus, the AASK Cohort Study is well positioned to address its primary objective.

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.

Background: The African American Study of Kidney Disease and Hypertension was a multicenter trial comparing the effects of 2 levels of blood pressure control (usual or low goal) and initial therapy with metoprolol, ramipril, or amlodipine. We examined effects of treatment-group assignment on health-related quality of life (HRQOL) measures and reported symptoms during 4 years of follow-up., Methods: HRQOL was assessed at baseline and annually by using the Medical Outcomes Study 36-Item Short Form (SF-36) and a symptom checklist. Using a 2-slope model, treatment effects were evaluated for change from baseline to year 1 and for average change during the first 4 years of follow-up., Results: A total of 1,094 participants were randomly assigned. Average age was 55 years, 61% were men, and the mean of the first glomerular filtration rate in the study was 46 mL/min/1.73 m2 (0.76 mL/s). No significant differences in HRQOL were seen between the low- and usual-blood-pressure groups. Reported side effects also were similar between blood-pressure groups. Mean Physical Health Component (PHC) and Mental Health Component (MHC) scores had a significantly smaller decrease in the ramipril than metoprolol group in both the initial period from baseline to year 1 (PHC, 2.08 +/- 0.56; MHC, 1.89 +/- 0.62) and during the first 4 years of follow-up (PHC, 1.60 +/- 0.44; MHC, 1.48 +/- 0.48). The MHC also had a slightly smaller decrease during the first 4 years in the ramipril group than amlodipine group (1.20 +/- 0.61)., Conclusion: Aggressive blood pressure control is well tolerated in African Americans with hypertensive kidney disease, measured by using the SF-36 and reported symptoms. The clinical significance of smaller decreases in PHC and MHC scores in the ramipril compared with metoprolol group is not clear.

WAGR syndrome is a rare genetic disorder characterized by a de novo deletion of 11p13 and is clinically associated with Wilms' tumor, aniridia, genitourinary anomalies, and mental retardation (W-A-G-R). Although the genotypic defects in WAGR syndrome have been well established, the large variety of phenotypic manifestations of the syndrome has never been reported. We report on 54 cases of WAGR syndrome to demonstrate both the classical clinical signs and nonclassical manifestations found in a large population of individuals with this disorder. An understanding of WAGR syndrome and its clinical findings can provide important insight regarding the functions of the involved genetic region. Recommendations for diagnosis, evaluation, and surveillance of patients with WAGR syndrome are also presented.

The African American Study of Kidney Disease and Hypertension examined the effect on renal function decline of 2 blood pressure (BP) goals (low mean arterial pressure [MAP] < or =92 versus usual MAP 102 to 107 mm Hg) and 3 antihypertensives (ramipril versus amlodipine versus metoprolol). We previously reported that in all drug groups combined the BP intervention had similar effects on the primary outcome of glomerular filtration rate (GFR) slope or the main secondary clinical composite outcome of end-stage renal disease (ESRD), death, or GFR decline by 50% or 25 mL/min per 1.73 m2. This report examines the effect of the BP intervention separately in the 3 drug groups. The BP effect was similar among the drug groups for either GFR slope or the main clinical composite. However, the BP effect differed significantly among the drug groups for the composite of ESRD or death (P=0.035) and ESRD alone (P=0.021). Higher event rates for amlodipine patients assigned to the usual BP goal (0.087 per patient-year for ESRD or death and 0.064 per patient-year for ESRD) were seen compared with the remaining groups of the factorial design (range, 0.041 to 0.050 for ESRD or death; and range, 0.027 to 0.036 for ESRD). The low BP goal was associated with reduced risk of ESRD or death (risk reduction 51%; 95% confidence interval, 13% to 73%) and ESRD (54%; 8% to 77%) for amlodipine patients, but not for patients assigned to the other drug groups. These secondary analyses suggest a benefit of the low BP goal among patients assigned to amlodipine, but they must be interpreted cautiously.

Renal function measurements were obtained in 1,703 African Americans with presumed hypertensive nephrosclerosis who were screened for entry into the African-American Study of Hypertension and Kidney Disease (AASK). We examined the effect of race on relationships involving renal variables by comparing African Americans enrolled into the AASK with non-African Americans enrolled into the Modification of Diet in Renal Disease (MDRD) study. We examined the effect of gender on renal variables by comparing African American men and women. We compared various methods for estimating glomerular filtration rate (GFR) with iodine 125-labeled ((125)I)-iothalamate GFR. AASK data were also used to derive a new formula for estimating GFR in African Americans. After adjusting for age, sex, and baseline GFR, African American patients on the AASK study were heavier and had larger body surface areas and body mass indices than either MDRD African Americans or non-African Americans. African Americans had greater serum creatinine levels and urinary creatinine excretions for any given level of GFR. Mean GFR was greater in African American men than African American women (59.7 versus 51.7 mL/min/1.73 m(2)), although serum creatinine levels were also greater in men (1.91 versus 1.73 mg/dL). Seventy-eight percent of women with serum creatinine levels between 1.2 and 1.5 mg/dL had GFRs less than 65 mL/min/1.73 m(2). For African Americans in the AASK, GFR was overestimated by the 24-hour creatinine clearance and underestimated by the Cockcroft-Gault formula. A prediction formula developed in the MDRD study more accurately predicted GFR in AASK patients than these measurements. AASK data were also used to derive a new five-term formula for estimating GFR that was slightly more accurate in the African Americans in the AASK than the MDRD formula (median percentage of error, 12.4% for the MDRD formula versus 12.1% for the AASK formula). Important differences exist in renal variables between African Americans and non-African Americans and between African American men and African American women. Formulas using demographic data and readily measured serum values estimate (125)I-iothalamate GFR.

We have previously shown that immediately after liver transplantation (LT) the porcine recipient exhibits elevated plasma glucagon, increased fractional synthetic rate (FSR) of fibrinogen, and decreased FSR of fixed or structural liver proteins. The purpose of this study was to evaluate the effect of nutritional and hormonal supplementation on these observations 24 h after LT. Two groups of nine pigs were studied 1 day after LT using radioisotopic and arteriovenous difference techniques. A control group underwent LT with saline infusion and a supplemented group underwent LT with infusion of glucose, amino acids (6 and 1.06 mg/kg. min, respectively), and intraportal insulin (0.6 mU/kg. min) and glucagon (1.3 ng/kg. min). Primed constant infusions of [3H]leucine were used to determine leucine flux, an estimate of whole body protein breakdown, and fractional synthetic rates (FSR). The following changes were noted with supplementation: elevated plasma insulin (6 +/- 1 versus 29 +/- 4 microU/ml, control versus supplemented, respectively, P < 0.05), decreased glucagon to normal levels (323 +/- 65 versus 102 +/- 12 pg/ml, P < 0.05), decreased fibrinogen FSR (108 +/- 15 versus 70 +/- 6%/day, P < 0.025), and increased fixed liver protein FSR (8 +/- 1 versus 13 +/- 2%/day, P < 0.05, respectively). Albumin FSR was unaltered by supplementation (8 +/- 2 versus 6 +/- 1%/day, respectively). Nutritional and hormonal supplementation immediately after LT restored the measured protein synthesis in the allograft to near normal levels 1 day after transplantation., (Copyright 1999 Academic Press.)

The liver plays a central role in carbohydrate metabolism and glucose homeostasis; therefore, the rapid recovery of glucose homeostasis after liver transplantation (LT) is important. The purpose of this study was to evaluate hepatic and whole-body glucose production (WBGP) on postoperative day 1 after LT using a combination of arteriovenous differences and radioisotope techniques. Two groups of female commercially bred pigs with an average body weight of 31.9 +/- 1.4 kg were studied. A control group (n = 6) underwent laparotomy. A transplanted group (n = 6) was submitted to LT. All pigs were instrumented with catheters placed in the carotid artery and the hepatic, portal, and jugular vein, and flow probes were placed around the hepatic artery and portal vein. WBGP was measured by a primed constant infusion of 3-[3H]glucose 1 day postoperatively. Plasma glucose was 89 +/- 6 versus 98 +/- 7 mg/dL in the control and transplanted groups, respectively. WBGP was increased by 42 per cent in the transplanted group (2.54 +/- 0.17 vs 3.62 +/- 0.39 mg/kg.min), but the net hepatic glucose output was not different between the control and the transplanted groups (1.53 +/- 0.28 vs 1.68 +/- 0.31 mg/kg.min). These results demonstrate that net hepatic glucose output was not different between the control and transplanted pigs, suggesting that LT does not compromise the ability of the liver to produce glucose. However, the WBGP was increased by 42 per cent in the transplanted group, suggesting either a significant contribution from another organ or a significant intrahepatic utilization of glucose.

Background: The liver is one of the principal organs responsible for the uptake and release of amino acids in the body. The ability of the transplanted liver to clear plasma amino acids is associated with a functioning allograft. However, clinical assessment is limited by the inability to access the portal vein postoperatively. Therefore, using a porcine liver transplant model, we examined (1) the plasma levels of amino acids presented to the new hepatic allograft and (2) the capacity of the new allograft to clear these amino acids from the circulation., Materials and Methods: Two groups of commercially bred pigs were studied: a control group (n = 8) underwent laparotomy and a transplanted group (n = 6) underwent orthotopic liver transplantation (LT) using veno-venous bypass. All pigs had catheters placed in the carotid artery and portal and hepatic veins and ultrasonic transit time flow probes placed around the hepatic artery and portal vein. Plasma profiles of 23 amino acids were analyzed by high-pressure liquid chromatography. Hepatic balances of amino acids, using arteriovenous difference techniques coupled with hepatic blood flows, were also analyzed on postoperative day 1., Results: Neither portal vein blood flow (703 +/- 74 ml/min vs 666 +/- 82 ml/min) nor hepatic artery blood flow (322 +/- 43 ml/min vs 209 +/- 59 ml/min) was significantly different between the control and the transplanted groups, respectively. The transplanted group had significantly increased plasma levels of alanine (135 +/- 13 mumol/l vs 382 +/- 72 mumol/l), hydroxyproline (30 +/- 5 mumol/l vs 60 +/- 9 mumol/l), methionine (25 +/- 2 mumol/l vs 55 +/- 10 mumol/l), ornithine (36 +/- 5 mumol/l vs 141 +/- 33 mumol/l), phenylalanine (84 +/- 5 mumol/l vs 120 +/- 12 mumol/l), threonine (75 +/- 9 mumol/l vs 159 +/- 27 mumol/l), and tryptophan (17 +/- 2 mumol/l vs 31 +/- 4 mumol/l). The transplanted group also had significantly decreased plasma levels of isoleucine (122 +/- 12 mumol/l vs 85 +/- 8 mumol/l) and taurine (71 +/- 7 mumol/l vs 35 +/- 7 mumol/l). These individual amino acid changes were not accompanied by impairment in the net hepatic amino acid balance or the hepatic fractional extraction of amino acids between the two groups., Conclusion: These results suggest that the circumstances associated with liver transplantation alter the fasting amino acid profile immediately postoperatively. However, liver transplantation does not impair the normal hepatic allograft uptake of most plasma amino acids. Thus, the changes observed in the circulating levels of amino acids may represent alterations in nonhepatic production and/or utilization. Furthermore, altered plasma amino acid profiles following liver transplantation are not necessarily indicative of impaired hepatic allograft amino acid metabolism.

These studies were undertaken to evaluate the mechanisms for changes in plasma insulin and glucagon levels observed post-liver transplantation. Two groups of pigs were studied: a control group (n = 8) underwent laparotomy and catheter placement in the carotid artery and portal and hepatic veins. Hepatic blood flow was measured by ultrasonic flow probes placed around the hepatic artery and portal vein. An experimental group (n = 8) underwent orthotopic liver transplantation and similar instrumentation. On Day 1 after surgery, an estimate of insulin and glucagon secretion and hepatic extraction was determined using arteriovenous difference techniques. Serum assays were performed for markers of hepatic and renal function. Plasma insulin levels of the transplanted pigs were higher in the carotid artery (4 +/- 1 microU/ml vs 7 +/- 1 microU/ml), but not in the hepatic vein (5 +/- 1 microU/ml vs 7 +/- 1 microU/ml) and in the portal vein (10 +/- 2 microU/ml vs 12 +/- 2 microU/ml). Arterial plasma C-peptide was significantly greater in the transplanted group (0.23 +/- 0.02 ng/ml vs 0.42 +/- 0.03 ng/ml); however, the molar ratio of C-peptide and insulin was not different between the two groups (3.6 +/- 0.9 vs 3.4 +/- 0.4). Plasma glucagon levels of the transplanted pigs were significantly elevated in the carotid artery (111 +/- 11 pg/ml vs 323 +/- 65 pg/ml), portal vein (221 +/- 27 pg/ml vs 495 +/- 69 pg/ml), and hepatic vein (142 +/- 15 pg/ml vs 395 +/- 58 pg/ml). The estimate of pancreatic secretion of insulin (115 +/- 28 microU/kg.min) vs 71 +/- 21 microU/kg.min) and glucagon (2.0 +/- 0.4 ng/kg.min vs 2.7 +/- 0.7 ng/kg.min) and the fractional hepatic extraction rate of insulin (35 +/- 8% vs 32 +/- 5%) were not different between the two groups. However, the hepatic fractional extraction rate of glucagon was significantly decreased in the transplanted group (25 +/- 5% vs 11 +/- 3%). Therefore, the hyperglucagonemia observed 24 hr following liver transplantation is partly due to reduced hepatic fractional extraction of glucagon while the hyperinsulinemia is mainly due to the nonhepatic clearance of insulin. We speculate that decreased renal function may contribute to the hyperinsulinemia, elevated C-peptide concentrations, and hyperglucagonemia.

To our knowledge postoperative hepatic hemodynamics and hepatic metabolism have not been fully studied on a long-term basis. Our goal was to develop a large animal model that would permit the measurement of hepatic blood flow (BF), perihepatic pressures (P), and hepatic metabolism in a long-term setting. Catheters were inserted into the jugular vein, carotid artery, pulmonary artery, hepatic vein, and portal vein (PV) of 27 commercially bred pigs; ultrasonic transit time flowmeter probes were placed around the hepatic artery and PV. Daily postoperative measurements of jugular vein P, carotid artery P, pulmonary artery P, hepatic vein P, and PVP, as well as hepatic artery BF and PVBF, were recorded for 20 days. Hepatic carbohydrate metabolism was assessed by arteriovenous difference techniques. Jugular vein P, pulmonary artery P, hepatic vein P, PVP, and heart rate reached steady-state values during the first week, with a mean +/- SEM of 1.0 +/- 0.3 mm Hg for jugular vein P, 21.4 +/- 2.1 mm Hg for pulmonary artery P, 4.3 +/- 0.4 mm Hg for HVP, 7.8 +/- 0.5 mm Hg for PVP, and 116 +/- 4 beats per minute for heart rate. Mean carotid artery P increased from 65 +/- 3 mm Hg during surgery to 94 +/- 2 mm Hg on postoperative day 1 (P < 0.001) and to a mean 101 +/- 2 mm Hg thereafter. Total hepatic BF reached a steady-state value of 1,132 +/- 187 ml/min by postoperative day 7 (P = 0.19). Over week 1 hepatic artery BF measured as a percentage of total hepatic BF decreased from 35.0 +/- 3.0% to 15.5 +/- 2.7%, and PVBF increased from 65.0 +/- 3.0% to 84.5 +/- 2.7% (P < 0.005); both variables were steady thereafter. In the hemodynamic steady state the net hepatic balances of glucose, lactate, glycerol, and alanine in 5 pigs were 9.9 +/- 4.0, -4.2 +/- 0.4, -2.3 +/- 1.1, and -0.68 +/- 0.22 micromol/kg per min respectively. The net gut (portal-drained viscera) balances of glucose, lactate, alanine, and glycerol were -2.0 +/- 2.5, 1.1 +/- 0.5, 0.73 +/- 0.18, and -0.69 +/- 0.19 micromol/kg per min respectively. Thus, a reliable large animal model was developed to study acute and chronic hepatic hemodynamics and metabolism.

Efficacy of supplementing total protein or a limiting amino acid to maintain muscle development during food restriction was examined in growing rats. Male rats weighing 108 +/- 8 g were assigned to one of five diet groups plus an initial group. Animals were fed either a wheat gluten-based diet or the wheat gluten-based diet supplemented with adequate levels of lysine. These diets were fed ad libitum or at a 75% restricted level. One restricted group was fed a high gluten diet designed to meet lysine requirements but at the restricted energy level. Rats were fed these diets for 6 weeks. Lysine supplementation resulted in higher levels of protein, RNA, and DNA in skeletal muscle and liver of animals fed ad libitum. Food restriction resulted in loss of protein and RNA from liver and skeletal muscle and lower ratios of protein/DNA. Initial DNA contents of plantaris and soleus muscles were not affected by food restriction; however, hepatic DNA was reduced. Supplementation of lysine to animals restricted in food intake failed to improve growth of skeletal muscle or liver, and resulted in lower protein contents in liver (11%), plantaris (6%), and soleus (38%). Increasing total protein intake for the animals with the restricted intake resulted in a higher RNA/DNA ratio without a parallel increase in protein in liver or muscle. This study demonstrates that during severe food restriction skeletal muscle DNA is preserved which maintains high potential for growth recovery. This study also indicates that during severe, prolonged food restriction supplementation of protein or limiting amino acids results in lower tissue protein contents.