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Pyridoxamine dihydrochloride (Pyridorin, NephroGenex) inhibits formation of advanced glycation end products and scavenges reactive oxygen species and toxic carbonyls, but whether these actions translate into renoprotective effects is unknown. In this double-blind, randomized, placebo-controlled trial, we randomly assigned 317 patients with proteinuric type 2 diabetic nephropathy to twice-daily placebo; Pyridorin, 150 mg twice daily; or Pyridorin, 300 mg twice daily, for 52 weeks. At baseline, the mean age ± SD was 63.9±9.5 years, and the mean duration of diabetes was 17.6±8.5 years; the mean serum creatinine level was 2.2±0.6 mg/dl, and the mean protein-to-creatinine ratio was 2973±1932 mg/g. Regarding the primary end point, a statistically significant change in serum creatinine from baseline to 52 weeks was not evident in either Pyridorin group compared with placebo. However, analysis of covariance suggested that the magnitude of the treatment effect differed by baseline renal function. Among patients in the lowest tertile of baseline serum creatinine concentration, treatment with Pyridorin associated with a lower average change in serum creatinine concentration at 52 weeks (0.28, 0.07, and 0.14 mg/dl for placebo, Pyridorin 150 mg, and Pyridorin 300 mg, respectively; P=0.05 for either Pyridorin dose versus placebo); there was no evidence of a significant treatment effect in the middle or upper tertiles. In conclusion, this trial failed to detect an effect of Pyridorin on the progression of serum creatinine at 1 year, although it suggests that patients with less renal impairment might benefit.

Summary Objectives: Clinical decision support (CDS), such as computerized alerts, improves prescribing in the setting of acute kidney injury (AKI), but considerable opportunity remains to improve patient safety. The authors sought to determine whether pharmacy surveillance of AKI patients could detect and prevent medication errors that are not corrected by automated interventions. Methods: The authors conducted a randomized clinical trial among 396 patients admitted to an academic, tertiary care hospital between June 1, 2010 and August 31, 2010 with an acute 0.5 mg/dl change in serum creatinine over 48 hours and a nephrotoxic or renally cleared medication order. Patients randomly assigned to the intervention group received surveillance from a clinical pharmacist using a web-based surveillance tool to monitor drug prescribing and kidney function trends. CDS alerting and standard pharmacy services were active in both study arms. Outcome measures included blinded adjudication of potential adverse drug events (pADEs), adverse drug events (ADEs) and time to provider modification or discontinuation of targeted nephrotoxic or renally cleared medications. Results: Potential ADEs or ADEs occurred for 104 (8.0%) of control and 99 (7.1%) of intervention patient-medication pairs (p=0.4). Additionally, the time to provider modification or discontinuation of targeted nephrotoxic or renally cleared medications did not differ between control and intervention patients (33.4 hrs vs. 30.3hrs, p=0.3). Conclusions: Pharmacy surveillance had no incremental benefit over previously implemented CDS alerts

Background: Sulodexide, a heterogenous group of sulfated glycosaminoglycans, includes low-molecular-weight heparin (similar to 80% +/- 8%), high-molecular-weight heparin (similar to 5% +/- 3%), and dermatan (similar to 20% +/- 8%), with a mean molecular weight of similar to 9 kDa. The drug is absorbed orally and has no anticoagulant effect in the doses used. Small preliminary studies consistently showed sulodexide to be associated with decreased albuminuria in patients with diabetes.Study Design: We conducted a multicenter placebo-controlled double-blinded study to determine the effect of sulodexide on urine albumin excretion in patients with type 2 diabetic nephropathy.Setting & Participants: Patients with type 2 diabetes and urine albumin-creatinine ratios (ACRs) of 35-200 mg/g in men and 45-200 mg/g in women were enrolled. Serum creatinine level wasIntervention: The study drug was sulodexide, 200 mg/d.Outcome & Measurements: The primary end point was normoalbuminuria (ACR 25%) or 50% decrease in baseline ACR.Results: In 1,056 randomly assigned patients with a mean baseline ACR of 107.8 +/- 83.7 mg/g, comparing the sulodexide versus placebo groups, the primary end point was achieved in 16.5% versus 18.4%; normoalbuminuria, in 7.9% versus 6.1%; and a 50% decrease in albuminuria, in 15.4% versus 17.6%. The relative probability of any given change in albuminuria was identical in both groups.Limitations: We were unable to determine whether the administered sulodexide was absorbed from the gastrointestinal tract.Conclusion: Sulodexide failed to decrease urine albumin excretion in patients with type 2 diabetic nephropathy and microalbuminuria. Am J Kidney Dis. 58(5):729-736. (C) 2011 by the National Kidney Foundation, Inc.

Summary Background and objectives Elevated BP contributes to development and progression of proteinuria and decline in renal function in patients with type 2 diabetes. Our post hoc analysis assessed the baseline BP influence on the antiproteinuric effect in the Aliskiren in the Evaluation of Proteinuria in Diabetes (AVOID) study. Design, setting, participants, & measurements In the AVOID study, 599 hypertensive type 2 diabetic patients with nephropathy received 6 months of aliskiren (150 mg force titrated to 300 mg daily after 3 months) or placebo added to losartan (100 mg) daily and optimal antihypertensive therapy. Changes in early morning urinary albumin:creatinine ratio and eGFR at week 24 were assessed by subgroups of baseline BP: Group A (prespecified target), 130/80 mmHg (n 159); Group B, 140/90 mmHg but 130/80 mmHg (n 189); and Group C (insufficient BP control), 140/90 mmHg (n 251). Results Mean baseline BP (mmHg) levels for Groups A, B, and C were 120/71, 133/78, and 145/81, respectively. BP during the trial was nearly identical to baseline levels in all groups. The antiproteinuric effects of aliskiren were consistent across subgroups of baseline BP (19 to 22% reduction versus placebo). In Group C, the decline in eGFR was significantly lower with aliskiren than with placebo (P 0.013). Conclusions Aliskiren (300 mg) added to losartan (100 mg) plus optimal antihypertensive therapy provides antiproteinuric effects independent of BP in patients with type 2 diabetes and nephropathy. Renal function was better preserved with aliskiren in patients with insufficient BP control. Clin J Am Soc Nephrol 6: 1025–1031, 2011. doi: 10.2215/CJN.07590810

Type 2 diabetic nephropathy (type 2 DN) patients traditionally develop significant proteinuria prior to the development of renal impairment. However, this clinical paradigm, based on observations prior to the widespread usage of angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB), has recently been questioned. 2,303 patients enrolled in the Sulodexide Overt Nephropathy Study (OVERT) were analyzed. Prior therapy with ACEi and/or ARB at the time of screening was recorded in 951 patients. 22% of patients had significant renal impairment with a PCR at screening of

Background Antimicrobial regimens evolve with changing recommendations and emerging practice patterns. We sought to explore the diversity of these patterns and to identify which inpatient regimens may be emerging in US Veterans Affairs medical centers (VAMC). Methods We extracted antimicrobial use and admission data from all acute care VA medical centers between 2005 and 2016. A regimen was defined as all unique antimicrobials and their routes given in a day to a single patient. We applied smoothing to account for intended discontinuation and intermittent dosing due to clearance. We described the distribution of regimens among VAMCs using the Gini index (a Gini index of 0 would mean all regimens were equally frequent and 1 would mean that one regimen dominated all others). We calculated the rank percentile of all regimens. We also used the absolute change in rank percentile between years 2005 and 2016 of the regimen used to describe emerging and declining regimens. Results There were 55,767 distinct regimens. Table 1 describes the Gini index and its decomposition among VAMCs. Overlap accounts for most of the inequality present because regimens are shared between VAMCs. Approximately 20% of the inequality present can be accounted for by variation between VAMCs. Table 2 describes the top 10 rising and the top 10 declining regimens. Conclusion While there was a large number of distinct regimens, there was a relative handful of antimicrobial regimens dominated—most of which were commonly present among VAMCs (as manifest by the Gini “overlap” percent). Most regimens in the top 10 were broad-spectrum IV agents, with PO levofloxacin and doxycycline being notable standouts. IV vancomycin, which was the single most common regimen in 2005, decreased markedly. Linezolid and mixed PO metronidazole agents appear to be on the decline. Disclosures V. Stevens, Pfizer, Inc.: Grant Investigator, Research grant.

Background Historically, Zika virus infection presented as a mild disease. However, more severe disease was reported during recent outbreaks in French Polynesia and more recently within southern regions of North America as well as Central and South America. It is still unclear what predicts more severe manifestations. Here we report on potential predictors of severe Zika virus infection within VA, selected for their role in immunological status. Methods We extracted the first positive Zika visit for a patient between February 9, 2016 and April 1, 2017. Each visit was classified by acuity (no ED visit, ED only, observation, ward, ICU [in this order of severity]). Diagnoses were extracted by ICD-9-CM and ICD-10-CM codes. Predictors included history of hepatitis C virus (HCV; a flavivirus) by laboratories, dengue diagnosis, immunocompromising condition diagnosis, gender, age, and history of exposure to dengue endemic region (either through birth, travel, or residency). These predictors were used in a generalized ordered logit model, relaxing the proportional odds assumption, to estimate odds ratios for a higher level of visit acuity over the current or lower levels of acuity. Robust covariance estimates were used. Results There were 748 unique patient visits meeting criteria. Distribution of predictors among the patient sample are shown in Table 1. As expected, most were males with a majority only visiting the ED. Wards and ICU were combined due to the small number of ICU visits. Table 2 shows results of model for predictors of higher acuity visits. Age was generally associated with higher levels of acuity. Odds ratios could not be computed for HCV and immunocompromised predictors. Conclusion There may be an increased risk of Zika disease severity based on age. We could not rule out associations with other predictors due to the size of our study. Further larger studies are needed to investigate these and other predictors. Disclosures All Authors: No reported disclosures.

OBJECTIVE Proteinuric diabetic patients with reduced glomerular filtration rate (GFR) are at high risk of renal and cardiovascular disease progression and treatment-related adverse events. This post hoc analysis assessed the efficacy and safety of aliskiren added to the maximal recommended dose of losartan according to baseline estimated GFR (eGFR) (stage 1–3 chronic kidney disease [CKD]). RESEARCH DESIGN AND METHODS In the Aliskiren in the Evaluation of Proteinuria in Diabetes (AVOID) study, 599 hypertensive patients with type 2 diabetes and nephropathy received 6 months of aliskiren (150 mg daily titrated to 300 mg daily after 3 months) or placebo added to 100 mg losartan and optimal antihypertensive therapy. Exclusion criteria included eGFR 5.1 mmol/l. RESULTS Baseline characteristics were similar between treatment groups in all CKD stages. The antiproteinuric effects of aliskiren were consistent across CKD stages (19, 22, and 18% reduction). In the stage 3 CKD group, baseline serum creatinine levels were equal, but renal dysfunction, prespecified as a postrandomization serum creatinine elevation >176.8 μmol/l (2.0 mg/dl) occurred more frequently in the placebo group (29.2 vs. 13.6%, P = 0.032). Serum potassium elevations >5.5 mmol/l (based on a single measurement) were more frequent with aliskiren (22.5 vs. 13.6%) in stage 3 CKD. Adverse event rates were similar between treatments, irrespective of CKD stage. CONCLUSIONS Aliskiren added to losartan reduced albuminuria and renal dysfunction and was well tolerated, except for hyperkalemia (stage 3), independent of baseline CKD stage in patients with type 2 diabetes, hypertension, and nephropathy.

About 30% of patients with anti-glomerular basement membrane antibody (anti-GBM) disease may also have concomitant antineutrophil cytoplasmic antibody (ANCA) positivity. Both these processes can affect the kidneys and/or lungs. We report a case of a patient with dual positivity for anti-GBM antibodies and ANCAs who underwent both pulmonary and kidney biopsies. There is only 1 previous report in the literature of a patient with dual positivity for anti-GBM antibodies and ANCAs who also underwent both pulmonary and kidney biopsies. Our case is unique in that our patient had dual positivity and also had evidence of unique tissue injury mediated by both antibodies in both the kidneys and lungs. We discuss the significance of dual-antibody positivity based on reported cases.

Kidney disease alters the pharmacokinetic disposition of many medications, requiring dosage adjustment to maintain therapeutic serum concentrations. The Cockcroft-Gault (CG) equation is used for pharmacokinetic studies and drug dosage adjustments, but the Modification of Diet in Renal Disease (MDRD) Study equation is more accurate and more often reported by clinical laboratories than the CG equation.Diagnostic test study.Pooled data set for 5,504 participants from 6 research studies and 4 clinical populations with measured glomerular filtration rate (GFR).Estimated kidney function using the MDRD Study and CG equations incorporating actual (CG) or ideal body weight (CG(IBW)) and standardized serum creatinine concentrations.Measured GFR assessed by using iodine-125-iothalamate urinary clearance.Concordance of assigned kidney function categories designated by the Food and Drug Administration (FDA) Guidance for Industry for pharmacokinetic studies and recommended dosages of 15 medications cleared by the kidneys.Concordance of kidney function estimates with measured GFR for FDA-assigned kidney function categories was 78% for the MDRD Study equation compared with 73% for the CG equation (P0.001) and 66% for the CG(IBW) equation (P0.001). Concordance between the MDRD Study equation and CG and CG(IBW) equations was 78% and 75%, respectively (P0.001). Concordance of kidney function estimates with measured GFR for recommended drug dosages was 88% for MDRD Study equation compared with 85% for the CG equation (P0.001) and 82% for the CG(IBW) equation (P0.001), with lower concordance when dosing recommendations for drugs included narrow GFR ranges. Concordance rates between the CG and CG(IBW) equations and MDRD Study equation were 89% and 88%, respectively (P0.05).Results based on simulation rather than pharmacokinetic studies. Outcome was drug dosage recommendations, rather than observed drug efficacy and safety.The MDRD Study equation can also be used for pharmacokinetic studies and drug dosage adjustments. As more accurate GFR-estimating equations are developed, they should be used for these purposes.

Purpose: We investigated the recently discovered association between gadolinium based magnetic resonance imaging contrast agents and the development of nephrogenic systemic fibrosis in patients with chronic kidney disease or acute kidney injury.Materials and Methods: A systematic review of the PubMed® database and publicly available patient databases was performed to characterize nephrogenic systemic fibrosis and its possible association with exposure to gadolinium based magnetic resonance imaging contrast agents.Results: Data from case series reports, nephrogenic systemic fibrosis patient databases, nephrogenic systemic fibrosis case reporting to the Food and Drug Administration after gadolinium contrast agent exposure and retrospective case control studies suggest a strong association between the use of gadolinium based magnetic resonance imaging contrast agents and the subsequent development of nephrogenic systemic fibrosis in patients with renal disease. These data also suggest that the risk of nephro...

Background. Urinary albumin excretion frequently persists in diabetic patients who are treated with angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB). Sulodexide, a glycosaminoglycan mixture of 80% heparan sulfate and 20% dermatan sulfate, has been hypothesized to reduce persistent albuminuria. We have conducted a multi-center randomized double-blind pilot study in order to determine the effect of 6 months' therapy with sulodexide on urinary albumin excretion and to address logistical issues for a full-scale trial.Methods. A total of 149 patients with type 2 diabetes and an albumin:creatinine ratio (ACR) between 20 and 300 mg/g were randomized with equal allocation to either placebo, 200 mg of sulodexide or 400 mg of sulodexide. The primary endpoint was the achievement, at 6 months, of either 3(1) return to normoalbuminuria (ACR Results. The primary efficacy endpoint was achieved in 25.3% of the patients in the two sulodexide groups combined versus 15.4% of the placebo-treated patients (P = 0.26). The primary endpoint was achieved in 33.3% (P = 0.075 for the comparison to placebo) in the sulodexide 200 mg group and 18.4% (P = 0.781) in the sulodexide 400 mg group. (No consistent patterns of side effects were observed.Conclusion. Based on the experience gained in this pilot study, one full-scale trial is currently being conducted to evaluate the effects of sulodexide on change in ACR in patients with persistent microalbuminuria, and a longer-term trial is underway to evaluate the effects of sulodexide on long-term renal disease progression in patients with overt proteinuria.

Albuminuria is a well-known predictor of poor renal outcomes in patients with type 2 diabetes and in essential hypertension (1–4). Albuminuria has also been shown more recently to be a predictor of cardiovascular outcomes in these populations (5–8). There is emerging data that reduction of albuminuria leads to reduced risk of adverse renal and cardiovascular events (9–12). It has become increasingly clear that albuminuria should not only be measured in all patients with type 2 diabetes and hypertension, but also steps should be taken to suppress albuminuria to prevent future renal and cardiovascular adverse events. This review discusses the measurement of albuminuria and summarizes the current literature on the association between albuminuria and adverse cardiovascular and renal outcomes in type 2 diabetes and hypertension. It also summarizes the evidence that reduction of albuminuria leads to improvement in the risk profiles of these patients. Microalbuminuria is defined as levels of albumin ranging from 30 to 300 mg in a 24-h urine collection (13). Overt albuminuria, macroalbuminuria, or proteinuria is defined as a urinary albumin excretion of ≥300 mg/24 h. Urinary albuminuria comprises 20–70% or urinary total protein excretion. Measuring urinary albumin excretion by dipstick without simultaneously measuring creatinine is subject to false-negative and false-positive results due to variations in urine concentration caused by hydration level (13). Although urinary dipsticks are acceptable for quick screening, other more precise measurements should be done to quantify urinary albumin excretion rates (AERs). Albuminuria can be measured in several ways (Table 1): 1 ) measurement of albumin-to-creatinine ratio (ACR) in a random or first morning spot collection, 2 ) 24-h urine collection with measurement of creatinine to verify adequacy of the collection, and 3 ) timed (4-h or overnight) urine collections (13). Although the 24-h urine collection would overcome issues of diurnal variation …

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 Patients with Type 2 diabetes and albuminuria are at high risk to progress to end-stage renal disease (ESRD). Although angiotensin receptor blockers confer renoprotection, many diabetic patients still develop overt nephropathy and reach ESRD. Glycosaminoglycans belong to the same family as heparin and heparinoids. Pilot studies with sulodexide, a glycosaminoglycan, have shown that sulodexide can reduce urinary albumin excretion rates in diabetic patients. No hard renal end-point data are available. Methods Two multicentre, double-masked, randomized placebo controlled trials were designed to study the renoprotective potential of sulodexide. The Sulodexide Microalbuminuria Trial examined the efficacy of sulodexide given over 26 weeks in 1000 patients with Type 2 diabetes, hypertension and microalbuminuria. The Sulodexide Overt Nephropathy Trial examined the efficacy of sulodexide in 2240 patients with Type 2 diabetes, hypertension and proteinuria >= 900 mg/24 h. Results The primary outcome of The Sulodexide Microalbuminuria Trial was (i) conversion to normoalbuminuria and at least a 25% decrease in the urinary albumin creatinine ratio (UACR), or (ii) at least a 50% reduction in UACR. The primary outcome of The Sulodexide Overt Nephropathy Trial was time to a composite end point of doubling of serum creatinine or ESRD. Conclusions The sulodexide nephropathy programme will document whether therapy with sulodexide confers renal protection in Type 2 diabetes and nephropathy.

This study was designed to assess dialysis subjects’ perceived autonomy support association with phosphate binder medication adherence, race and gender. A multi-site cross-sectional study was conducted among 377 dialysis subjects. The Health Care Climate (HCC) Questionnaire assessed subjects’ perception of their providers’ autonomy support for phosphate binder use, and adherence was assessed by the self-reported Morisky Medication Adherence Scale (MMAS). Serum phosphorus was obtained from the medical record. Regression models were used to examine independent factors of medication adherence, serum phosphorus, and differences by race and gender. Non-white HCC scores were consistently lower compared with white subjects’ scores. No differences were observed by gender. Reported phosphate binder adherence was associated with HCC score, and also with phosphorus control. No significant association was found between HCC score and serum phosphorus. Autonomy support, especially in non-white end stage renal disease subjects, may be an appropriate target for culturally informed strategies to optimize mineral bone health.

Background Patients with end-stage renal disease (ESRD) require phosphate binders for hyperphosphatemia and erythropoiesis-stimulating agents (ESAs) and intravenous (IV) iron for anemia. Ferric citrate (FC) is a novel, iron-based phosphate binder that increases iron stores and decreases IV 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 IV 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 IV 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 IV 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 IV 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 IV 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 ≥6.0mg/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±2.25mg/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±0.95mg/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±392.1pg/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.

The presence of elevated levels of albuminuria is associated with an increased risk of progressive renal function loss over time. This association is found in various pathophysiological conditions, including diabetic nephropathy, hypertensive nephropathy, and various primary renal diseases, but also, the general, otherwise healthy population. Emerging data report that elevated albuminuria causes tubulointerstitial damage through activation of proinflammatory mediators, which ultimately leads to a progressive decline in renal function. Nowadays, various drugs are available that decrease the rate of GFR loss in patients with kidney disease. Well known are renin-angiotensin-aldosterone system inhibitors, but there are also other drugs and interventions, like intensive glucose control, anti-inflammatory agents (pentoxifylline), or a low-protein diet. These interventions have an additional effect beyond their original target, namely lowering albuminuria. Analyses from clinical trials show that the reduction in albuminuria observed during the first months of treatment with these drugs correlates with the degree of long-term renal protection: the larger the initial reduction in albuminuria, the lower the risk of ESRD during treatment. In addition, in treated patients, residual albuminuria is again the strongest risk marker for renal disease progression. These observations combined provide a strong argument that albuminuria is an appropriate therapeutic target in patients with CKD.

Background β-Trace protein (BTP) and β 2 -microglobulin (B2M) are novel glomerular filtration markers that have stronger associations with adverse outcomes than creatinine. Comparisons of BTP and B2M to creatinine and cystatin C are limited by the absence of rigorously developed glomerular filtration rate (GFR) estimating equations for the novel markers. Study Design Study of diagnostic test accuracy. Setting & Participants Pooled database of 3 populations with chronic kidney disease (CKD) with mean measured GFR of 48mL/min/1.73m 2 (N=3,551; MDRD [Modification of Diet in Renal Disease] Study, AASK [African American Study of Kidney Disease and Hypertension], and CRIC [Chronic Renal Insufficiency Cohort] Study). Index Tests GFR estimated using creatinine, cystatin C, BTP, or B2M level. Reference Test GFR measured as the urinary clearance of iothalamate. Results For BTP and B2M, coefficients for age, sex, and race were smaller than for creatinine and were similar or smaller than for cystatin C. For B2M, coefficients for sex, age, and race were smaller than for creatinine and were similar (age and race) or smaller (sex) than for cystatin C. The final equations with BTP (BTP, age, and sex) or B2M (B2M alone) were less accurate than either the CKD-EPI (CKD Epidemiology Collaboration) creatinine or cystatin C equations. The combined BTP-B2M equation (BTP and B2M alone) had similar accuracy to the CKD-EPI creatinine or cystatin C equation. The average of the BTP-B2M equation and the CKD-EPI creatinine–cystatin C equation was not more accurate than the CKD-EPI creatinine–cystatin C equation. Limitations No external validation population, study population was restricted to CKD, few participants older than 65 years, or nonblack nonwhite race. Conclusions BTP and B2M are less influenced by age, sex, and race than creatinine and less influenced by race than cystatin C, but provide less accurate GFR estimates than the CKD-EPI creatinine and cystatin C equations. The CKD-EPI BTP and B2M equation provides a methodological advance for their study as filtration markers and in their associations with risk and adverse outcomes, but further study is required before clinical use.

Background Early preparation for renal replacement therapy (RRT) is recommended for patients with advanced chronic kidney disease (CKD), yet many patients initiate RRT urgently and/or are inadequately prepared. Methods We conducted audio-recorded, qualitative, directed telephone interviews of nephrology health care providers (n = 10, nephrologists, physician assistants, and nurses) and primary care physicians (PCPs, n = 4) to identify modifiable challenges to optimal RRT preparation to inform future interventions. We recruited providers from public safety-net hospital-based and community-based nephrology and primary care practices. We asked providers open-ended questions to assess their perceived challenges and their views on the role of PCPs and nephrologist-PCP collaboration in patients’ RRT preparation. Two independent and trained abstractors coded transcribed audio-recorded interviews and identified major themes. Results Nephrology providers identified several factors contributing to patients’ suboptimal RRT preparation, including health system resources (e.g., limited time for preparation, referral process delays, and poorly integrated nephrology and primary care), provider skills (e.g., their difficulty explaining CKD to patients), and patient attitudes and cultural differences (e.g., their poor understanding and acceptance of their CKD and its treatment options, their low perceived urgency for RRT preparation; their negative perceptions about RRT, lack of trust, or language differences). PCPs desired more involvement in preparation to ensure RRT transitions could be as “smooth as possible”, including providing patients with emotional support, helping patients weigh RRT options, and affirming nephrologist recommendations. Both nephrology providers and PCPs desired improved collaboration, including better information exchange and delineation of roles during the RRT preparation process. Conclusions Nephrology and primary care providers identified health system resources, provider skills, and patient attitudes and cultural differences as challenges to patients’ optimal RRT preparation. Interventions to improve these factors may improve patients’ preparation and initiation of optimal RRTs.

Patients with chronic kidney disease have an increased risk for progression to ESRD. The purpose of this study was to examine factors that predict increased risk for adverse renal outcomes. Cox regression was performed to assess the potential of 38 baseline risk factors to predict the clinical renal composite outcome of 50% or 25-ml/min per 1.73 m(2) GFR decline or ESRD among 1094 black patients with hypertensive nephrosclerosis (GFR 20 to 65 ml/min per 1.73 m(2)). Patients were trial participants who had been randomly assigned to one of two BP goals and to one of three antihypertensive regimens and followed for a range of 3 to 6.4 yr. In unadjusted and adjusted analyses, baseline proteinuria was consistently associated with an increased risk for adverse renal outcomes, even at low levels of proteinuria. The relationship of proteinuria with adverse renal outcomes also was evident in analyses that were stratified by level of GFR, which itself was associated with adverse renal outcomes but only at levels40 ml/min. Other factors that were significantly associated with increased renal events after adjustment for baseline GFR, age, and gender, both with and without adjustment for baseline proteinuria, included serum creatinine, urea nitrogen, and phosphorus. In black patients with hypertensive nephrosclerosis, increased proteinuria, reduced GFR, and elevated levels of serum creatinine, urea nitrogen and phosphorus were directly associated with adverse clinical renal events. These findings identify a subset of this high-risk population that might benefit from even more aggressive treatment.

We described the characteristics in a referred cohort of type II diabetic patients in the Developing Education on Microalbuminuria for Awareness of renal and cardiovascular risk in Diabetes study evaluating the global prevalence and determinants of microalbuminuria (MA). A cross-sectional study evaluating 32,208 type II diabetic patients without known albuminuria from 33 countries was performed. Overall, 8057 patients were excluded, either because of prior known proteinuria or non-diabetic nephropathy (3670), or because of invalid urine collections (4387). One single random urinary albumin/creatinine ratio was obtained in 24,151 patients (75%). The overall global prevalence of normo-, micro-, and macroalbuminuria was 51, 39, and 10%, respectively. The Asian and Hispanic patients had the highest prevalence of a raised urinary albumin/creatinine ratio (55%) and Caucasians the lowest (40.6), P0.0001. HbA1c, systolic blood pressure (BP), ethnicity, retinopathy, duration of diabetes, kidney function, body height, and smoking were all independent risk factors of MA, P0.0001. Estimated glomerular filtration rate was below 60 ml/min/1.73 m(2) in 22% of the 11,573 patients with available data. Systolic BP below 130 mmHg was found in 33 and 43% had an HbA1c below 7%. The frequency of patients receiving aspirin was 32%, statins 29%, and BP-lowering therapy 63%. A high prevalence globally of MA and reduced kidney function, both conditions associated with enhanced renal and cardiovascular risk, was detected in type II diabetic patients without prior known nephropathy. Early detection, monitoring of vascular complications, and more aggressive multifactorial treatment aiming at renal and vascular protection are urgently needed.

Elevated arterial pressure enhances the risk for cardiovascular (CV) events in patients with diabetic nephropathy. The optimal BP and the component of the elevated BP that affect the risk have not been defined. A post hoc analysis was performed to assess the impact of achieved systolic, diastolic, and pulse pressures on CV outcomes in 1590 adults who had overt diabetic nephropathy and were enrolled in the Irbesartan Diabetic Nephropathy Trial (IDNT) and had a baseline serum creatinine above the normal range, up to 266 micromol/L (3.0 mg/dL), 24-h urine protein >900 mg/d, and at least 6 mo of follow-up. Patients were randomized to irbesartan, amlodipine, or placebo, with other antihypertensive agents to a BP goal of < or =135/85 mmHg. Progressively lower achieved systolic BP (SBP) to 120 mmHg predicted a decrease in CV mortality and congestive heart failure (CHF) but not myocardial infarctions (MI). A SBP below this threshold was associated with increased risk for CV deaths and CHF events. Achieved diastolic BP

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 po...

Hyperphosphatemia is common in end-stage renal disease and associates with mortality. Phosphate binders reduce serum phosphorus levels; however, adherence is often poor. This pilot study aims to assess patients' self-motivation to adhere to phosphate binders, its association with phosphorus control, and potential differences by race.Cross sectional design. Subjects were enrolled from one academic medical center dialysis practice from July to November 2012. Self-motivation to adhere to phosphate binders was assessed with the autonomous regulation (AR) scale (range: 1-7) and self-reported medication adherence with the Morisky Medication Adherence Scale. Linear regression models adjusting for age, sex, health literacy, and medication adherence were applied to determine associations with serum phosphorus level, including any evidence of interaction by race.Among 100 participants, mean age was 51 years (±15 years), 53% were male, 72% were non-white, 89% received hemodialysis, and mean serum phosphorus level was 5.7 ± 1.6 mg/dL. More than half (57%) reported the maximum AR score (7). Higher AR scores were noted in those reporting better health overall (P = .001) and those with higher health literacy (P = .01). AR score correlated with better medication adherence (r = 0.22; P = .02), and medication adherence was negatively associated with serum phosphorus (r = -0.40; P.001). In subgroup analysis among non-whites, higher AR scores correlated with lower serum phosphorus (high vs lower AR score: 5.55 [1.5] vs 6.96 [2.2]; P = .01). Associations between AR score (β 95% confidence interval: -0.37 [-0.73 to -0.01]; P = .04), medication adherence (β 95% confidence interval: -0.25 [-0.42 to -0.07]; P = .01), and serum phosphorus persisted in adjusted analyses.Self-motivation was associated with phosphate binder adherence and phosphorus control, and this differed by race. Additional research is needed to determine if personalized, culturally sensitive strategies to understand and overcome motivational barriers may optimize mineral bone health in end-stage renal disease.

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 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.

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

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.

Historically diabetic nephropathy has been a devastating complication of both type I and type II diabetes. The past 2 decades have seen enormous conceptual advances in understanding the pathogenesis of diabetic nephropathy. The genetic determinants of diabetic renal disease have also been elucidated as well as biochemical events and cytokine interactions. Most importantly, key clinical trials have identified therapeutic interventions which can slow or halt the progression of diabetic nephropathy, specifically the therapeutic use of angiotensin-converting enzyme inhibition and intensive blood sugar control. Multiple treatment modalities for patients once they reach end-stage renal disease are also available and great strides have been improving outcomes in these areas as well.

Atrial natriuretic peptide (ANP), an endogenous hormone synthesized by the cardiac atria, has been shown to improve renal function in multiple animal models of acute renal failure. In a recent multicenter clinical trial of 504 patients with acute tubular necrosis (oliguric and nonoliguric), ANP decreased the need for dialysis only in the oliguric patients. In the present study, 222 patients with oliguric acute renal failure were enrolled into a multicenter, randomized, double-blind, placebo-controlled trial designed to assess prospectively the safety and efficacy of ANP compared with placebo. Subjects were randomized to treatment with a 24-hour infusion of ANP (anaritide, 0.2 microgram/kg/min; synthetic form of human ANP) or placebo. Dialysis and mortality status were followed up for 60 days. The primary efficacy end point was dialysis-free survival through day 21. Dialysis-free survival rates were 21% in the ANP group and 15% in the placebo group (P = 0.22). By day 14 of the study, 64% and 77% of the ANP and placebo groups had undergone dialysis, respectively (P = 0.054), and 9 additional patients (7 patients, ANP group; 2 patients, placebo group) needed dialysis but did not receive it. Although a trend was present, there was no statistically significant beneficial effect of ANP in dialysis-free survival or reduction in dialysis in these subjects with oliguric acute renal failure. Mortality rates through day 60 were 60% versus 56% in the ANP and placebo groups, respectively (P = 0.541). One hundred two of 108 (95%) versus 63 of 114 (55%) patients in the ANP and placebo groups had systolic blood pressures less than 90 mm Hg during the study-drug infusion (P < 0.001). The maximal absolute decrease in systolic blood pressure was significantly greater in the anaritide group than placebo group (33.6 versus 23.9 mm Hg; P < 0.001). This well-characterized population with oliguric acute renal failure had an overall high morbidity and mortality.

Diabetic nephropathy is the most common cause of end-stage renal disease in the United States. We undertook a study to assess the impact of assignment to different levels of blood pressure control on the course of type 1 diabetic nephropathy in patients receiving angiotensin-converting enzyme (ACE) inhibitor therapy. We also examined the long-term course of this well-characterized cohort of patients receiving ACE inhibitor therapy. One hundred twenty-nine patients with type 1 diabetes and diabetic nephropathy who had previously participated in the Angiotensin-Converting Enzyme Inhibition in Diabetic Nephropathy Study who had a serum creatinine level less than 4.0 mg/dL were randomly assigned to a mean arterial blood pressure (MAP) goal of 92 mm Hg or less (group I) or 100 to 107 mm Hg (group II). Patients received varying doses of ramipril as the primary therapeutic antihypertensive agent. All patients were followed for a minimum of 2 years. Outcome measures included iothalamate clearance, 24-hour creatinine clearance, creatinine clearance estimated by the Cockcroft and Gault formula, and urinary protein excretion. The average difference in MAP between groups was 6 mm Hg over the 24-month follow-up. The median iothalamate clearance in group I was 62 mL/min/1.73 m(2) at baseline and 54 mL/min/1.73 m(2) at the end of the study compared with a baseline of 64 mL/min/1.73 m(2) and final 58 mL/min/1.73 m(2) in group II. There were no statistically significant differences in the rate of decline in renal function between groups. There was a significant difference in follow-up total urinary protein excretion between group I (535 mg/24 h) and group II (1,723 mg/24 h; P = 0.02). Thirty-two percent of 126 patients achieved a final total protein excretion less than 500 mg/24 h. Patients from groups I and II had equivalent rates of adverse events. In patients with type 1 diabetes mellitus and diabetic nephropathy, the MAP goal should be 92 mm Hg or less for optimal renoprotection, if defined as including decreased proteinuria. With the combination of ACE inhibition and intensive blood pressure control, many patients can achieve regression or apparent remission of clinical evidence of diabetic nephropathy.

An irrefutable body of evidence from multiple well-powered clinical trials and numerous clinical studies in patients with type 1 and type 2 diabetes mellitus (DM) has demonstrated that inhibition of the renin-angiotensin system (RAS) retards the progression of diabetic nephropathy (1–11). The consistency of these clinical trial outcomes has resulted in guidelines from diabetes and renal societies to treat all patients with diabetes and diabetic nephropathy with drugs that inhibit the RAS (angiotensin-converting enzyme inhibitors [ACEI]) and/or angiotensin receptor antagonists (ARB) (12,13). The article by Ficociello et al. in this issue of CJASN documents the challenges and pitfalls of transporting these clinical trial and study results to a general population of patients (14). It is disheartening to read that, even in the most recent time of observation, 33% of patients with diabetic nephropathy did not receive any ACEI therapy despite current guideline recommendations. The transportability of clinical trial results is affected by differences between the study population and the general clinic population. By design, patients in clinical trials are judged to be compliant, do not have diseases other than diabetic nephropathy that could affect their kidney function, have clearly defined and accurately measured kidney function, and must meet many other inclusion and exclusion criteria. Certainly the general population of patients differs from those in a clinical trial, and those differences can affect the perceived efficacy of the intervention. The large number of patients in the observational study by Ficociello et al. with HgAIC levels far above those recommended by guidelines despite attendance in a dedicated diabetes clinic would suggest noncompliance. Interventions cannot benefit patients if they are not compliant or if the interventions are not properly implemented. Patients entering clinical trials are likely more compliant on average than a general clinic population. In addition, important …

had glomerular changes characteristic of the diabetic state including enlarged glomeruli and an increase in Background. The glomerular and retinal vessels are both aVected in patients with type I and type II mesangial matrix without Kimmelstiel‐Wilson nodules (mesangial sclerosis lesion); and two had other primary diabetes mellitus. However, the prevalence of the nodular form of diabetic glomerular sclerosis glomerular diseases (IgA and membranous nephropathy). Patients with Kimmelstiel‐Wilson nodules ( Kimmelstiel‐Wilson lesion) and other forms of glomerular pathology including diVuse mesangial sclerosis had elevated serum creatinines compared to patients with mesangial sclerosis lesions, but there were no and their clinical correlates in type II diabetes are less well known. In addition, although recent studies have other significant diVerences. Patients with Kimmelstiel‐ Wilson nodules had more severe overall retinopathy suggested that non-diabetic glomerular disease was a common cause of proteinuria in type II diabetes, the than those with mesangial sclerosis lesions (P=0.0043): six of seven with proliferative retinopathy had prevalence of other diseases is unknown. The literature on this subject is clouded by clinical bias regarding Kimmelstiel‐Wilson nodules, and seven of the eight patients without retinopathy had mesangial sclerosis patients with diabetes who undergo renal biopsy. Methods. Glomerular and retinal pathology and clin- lesions. Conclusions. The two discrete patterns of glomerular ical correlates were studied in 36 patients enrolled in a prospective clinical trial of patients with type II pathology and the correlation between diabetic retinopathy and the Kimmelstiel‐Wilson lesion but not diabetes mellitus, proteinuria, renal insuYciency, and hypertension. the mesangial sclerosis lesion suggest that the Kimmelstiel‐Wilson and mesangial sclerosis lesions of

VER THE PAST several years, it has become clear that the determination of the presence of small but excessive amounts of albumin in the urine of patients with diabetes or hypertension is a harbinger of serious future renal and/or cardiovascular complications. The accurate determination of microalbuminuria gives the clinician an opportunity to intervene, to slow or to halt the development of these complications. In 1983, Keen and Chlouverakis first developed a radioimmunoassay for albumin that allowed the quantification of previously undetectable levels of urinary albumin excretion (UAE). 1 This radioimmunoassay is performed using 125 Ilabeled crystalline human albumin and antihuman albumin antibodies. With this assay, UAE rates as low as 1 µg/min could be detected and quantified. 2 In healthy normal adults, UAE rates vary but average 4 to 6 µg/min, with less than 10% of normal adults having UAE rates exceeding 12 µg/min. 3 A consensus group has defined microalbuminuria as a UAE of 20 to 200 µg/min or 30 to 300 mg/24 hr. 4 The clinical term ‘‘proteinuria’’ is applied when UAE rates exceed 200 µg/min or 300 mg/24 hr. Many factors can alter UAE transiently, such as water loading, hyperglycemia, urinary tract infections, extreme physical exercise, or uncontrolled hypertension or congestive heart failure. 5,6 Most studies have suggested that microalbuminuria measurements be repeated three times to ensure accuracy. Microalbuminuria as a predictor of progressive renal disease has best been defined in patients with type I diabetes mellitus (DM). The prevalence of microalbuminuria in patients with type I DM is approximately 30%. 7 Numerous studies have demonstrated that 75% to 100% of patients with microalbuminuria progress to proteinuria and declining renal function. 7-9 Indeed, although data from large clinical trials are lacking, the number of overall studies available (both clinical and histologic) would support the view that microalbuminuria in patients with type I DM represents early diabetic nephropathy. Patients with microalbuminuria have been found to have higher elevations in their mean arterial blood pressure and greater degrees of mesangial expansion compared with patients with type I DM and

Hypertension is a common problem among patients with glomerular disease and CKD. Optimal blood pressure targets for these patients have been the source of much debate. Careful review of the available data supports a blood pressure target of less than 140/90 mmHg. Consideration for a lower goal of less than 130/80 mmHg should be given for patients with heavy proteinuria. Renin-angiotensin system inhibitors should be used as the cornerstone of therapy for all patients with glomerular disease and CKD.

Diabetic nephropathy (DN) refers to the structural and functional changes in the kidneys of patients with diabetes mellitus (type 1 or 2). A subset of patients with presumed DN may not have overt proteinuria as a prerequisite to renal failure, contrary to the classical paradigm. No animal model fully recapitulates the human subset. All studies on this subject are observational and most lack biopsy data. Many mechanisms have been postulated, including use of renin-angiotensin system agents, recurrent bouts of acute kidney injury, genetic predisposition, and renal lesions other than DN. A well-designed biopsy study and a series of intervention trials are needed to fully understand this entity.

The typical assumption is that patients with CKD will have progressive nephropathy. Methodological issues, such as measurement error and regression to the mean, have made it difficult to document whether kidney function might improve in some patients. Here, we used data from 12 years of follow-up in the African American Study of Kidney Disease and Hypertension to determine whether some patients with CKD can experience a sustained improvement in GFR. We calculated estimated GFR (eGFR) based on serum creatinine measurements during both the trial and cohort phases. We defined clearly improved patients as those with positive eGFR slopes that we could not explain by random measurement variation under Bayesian mixed-effects models. Of 949 patients with at least three follow-up eGFR measurements, 31 (3.3%) demonstrated clearly positive eGFR slopes. The mean slope among these patients was +1.06 (0.12) ml/min per 1.73 m(2) per yr, compared with -2.45 (0.07) ml/min per 1.73 m(2) per yr among the remaining patients. During the trial phase, 24 (77%) of these 31 patients also had clearly positive slopes of (125)I-iothalamate-measured GFR during the trial phase. Low levels of proteinuria at baseline and randomization to the lower BP goal (mean arterial pressure ≤92 mmHg) associated with improved eGFR. In conclusion, the extended follow-up from this study provides strong evidence that kidney function can improve in some patients with hypertensive CKD.

Introduction : Hyperglycaemia induces development and progression of microvascular complications in diabetes. A direct link between high glucose levels and intrarenal renin–angiotensin activation has been demonstrated. This post-hoc analysis assessed the influence of baseline glycaemic control on the reduction of albuminuria with aliskiren or placebo added to losartan in the Aliskiren in the EValuation of PrOteinuria In Diabetes (AVOID) study. Materials and methods : In AVOID, 599 patients with type 2 diabetes, hypertension and nephropathy received 6 months’ aliskiren or placebo added to losartan 100 mg and optimal antihypertensive therapy. Changes in urinary albumin creatinine ratio at end of study were assessed by tertiles of baseline HbA 1c levels. Results : Patients were divided into tertiles of HbA 1c (

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.

Background The traditional paradigm of glomerular filtration rate (GFR) progression in patients with chronic kidney disease (CKD) is a steady nearly linear decline over time. We describe individual GFR progression trajectories over 12 years of follow-up in participants in the African American Study of Kidney Disease and Hypertension (AASK). Study Design Longitudinal observational study. Setting & Participants 846 AASK patients with at least 3 years of follow-up and 8 GFR estimates. Measurements Longitudinal GFR estimates from creatinine-based equations. Predictors Patient demographic and clinical features. Outcomes Probability of a nonlinear trajectory and probability of a period of nonprogression calculated for each patient from a Bayesian model of individual estimated GFR (eGFR) trajectories. Results 352 (41.6%) patients showed a >0.9 probability of having either a nonlinear trajectory or a prolonged nonprogression period; in 559 (66.1%), the probability was >0.5. Baseline eGFR >40 mL/min/1.73 m2 and urine protein-creatinine ratio Limitations Clinical trial population; absence of direct GFR measurements. Conclusions In contrast to the traditional paradigm of steady GFR progression over time, many patients with CKD have a nonlinear GFR trajectory or a prolonged period of nonprogression. These findings highlight the possibility that stable kidney disease progression can accelerate and, conversely, provide hope that CKD need not be relentlessly progressive. These results should encourage researchers to identify time-dependent factors associated with periods of nonprogression and other desirable trajectories.

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 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 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.

Introduction: Aldosterone blockade reduces albuminuria in diabetic patients with chronic kidney disease (CKD), and improves prognosis in chronic heart failure. This study assessed the effects of direct renin inhibition with aliskiren in combination with losartan and optimal antihypertensive therapy on urinary aldosterone, plasma renin activity (PRA) and plasma renin concentration (PRC). Materials and methods: In the AVOID study, 599 patients with type 2 diabetes, hypertension and nephropathy received 6 months aliskiren (150 mg force titrated to 300 mg once daily after 3 months) or placebo added to losartan 100 mg and optimal antihypertensive therapy. Urinary aldosterone excretion, PRA and PRC were measured at baseline and after 24 weeks in a prespecified subset of 133 patients. Results: Aliskiren added to losartan provided reductions from baseline in urinary aldosterone compared with adding placebo (−24% vs. −4%, p = 0.017) at week 24. There was no significant difference between the aliskiren and placebo groups in the proportion of patients with aldosterone breakthrough (aliskiren 35%, placebo 46%, p = 0.199). Aliskiren treatment reduced PRA by 90% at 24 weeks and increased PRC by 328%. Conclusions: Adding aliskiren to recommended renoprotective treatment with losartan and optimal antihypertensive therapy provided significant reductions in urinary aldosterone excretion which may attenuate decline in kidney function.

Chronic kidney disease (CKD), defined as an eGFR < 60 ml/min/1.73 m², affects up to 25% of the United States population. In addition, it is estimated that approximately 6% of the population have early evidence of CKD and will likely progress to end stage renal disease (ESRD) in the near future. Further, ESRD is more common in many ethnic minorities, with African-Americans having the highest rates of treated ESRD, closely followed by Hispanic Americans, when compared to non- Hispanic White persons. Although African-Americans with CKD are more likely to die than non-Hispanic White persons with CKD, these trends reverse once progression to ESRD is established. The reasons for the disparities in the prevalence and incidence of CKD, ESRD, and mortality are unclear, but likely involve a complex interaction of socioeconomic, environmental and genetic factors. This review highlights current data pertaining to the social and economic impact of ethnic differences in the prevalence and incidence of CKD and ESRD in the United Stated. It is hoped that highlighting the current trend of kidney related health disparities will not only lead to an improved understanding of these issues, but also more informed research agendas, that are ultimately aimed at alleviating ethnic differences in kidney health outcomes.

Background Angiotensin-converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARBs) reduce cardiovascular disease (CVD) events, but a recent meta-analysis of selected studies suggested that ARBs may increase cancer risks.Objective Candesartan, irbesartan, telmisartan, valsartan, and losartan were assessed for incident cancers in 15 large parallel long-term multicenter double-blind clinical trials of these agents involving 138 769 participants.Patients and methods Individuals at high CVD risk were randomized to telmisartan (three trials, n=51 878), irbesartan (three trials, n=14 859), valsartan (four trials, n=44 264), candesartan (four trials, n=18 566), and losartan (one trial, n=9193) and followed for 23-60 months. Incident cancer cases were compared in patients randomized to ARBs versus controls. In five trials (n=42 403), the ARBs were compared to ACEi and in 11 trials (n=63 313) to controls without ACEi. In addition, in seven trials (n=47 020), the effect of ARBs with ACEi was compared to ACEi alone and in two trials ARBs with ACEi versus ARB alone (n=25 712).Results Overall, there was no excess of cancer incidence with ARB therapy compared to controls in the 15 trials [ 4549 (6.16%) cases of 73 808 allocated to ARB versus 3856 (6.31%) of 61 106 assigned to non-ARB controls; odds ratio (OR) 1.00, 95% confidence interval (CI) 0.95-1.04] overall or when individual ARBs were examined. ORs comparing combination therapy with ARB along with ACEi versus ACEi was 1.01 (95% CI 0.94-1.10), combination versus ARB alone 1.02 (95% CI 0.91-1.13), ARB alone versus ACEi alone 1.06 (95% CI 0.97-1.16) and ARB versus placebo/control without ACEi 0.97 (95% CI 0.91-1.04). There was no excess of lung, prostate or breast cancer, or overall cancer deaths associated with ARB treatment.Conclusion There was no significant increase in the overall or site-specific cancer risk from ARBs compared to controls.