Kidney Outcomes and Preservation of Kidney Function With Obinutuzumab in Patients With Lupus Nephritis: A Post Hoc Analysis of the NOBILITY Trial.

OBJECTIVE: To determine whether adding obinutuzumab to standard-of-care lupus nephritis (LN) therapy could improve the likelihood of long-term preservation of kidney function and do so with less glucocorticoids. METHODS: Post hoc analyses of the phase II NOBILITY trial were performed. Time to unfavorable kidney outcome (a composite of treatment failure, doubling of serum creatinine, or death), LN flare, first 30% and 40% declines in estimated glomerular filtration rate (eGFR) from baseline, and chronic eGFR slope during the trial were compared between patients with active LN who were randomized to take obinutuzumab (n = 63) or placebo (n = 62) in combination with mycophenolate mofetil and glucocorticoids. The number of patients who achieved complete renal response (CRR) on 7.5 mg or less per day of prednisone was also determined. RESULTS: Obinutuzumab reduced the risk of developing the composite kidney outcome by 60%, LN flare by 57%, and first eGFR decline of 30% or 40% by 80% and 91%, respectively. Patients receiving obinutuzumab had a significantly slower decline in eGFR than patients receiving placebo, with an annualized eGFR slope advantage of 4.1 ml/min/1.73 m2 /year (95% confidence interval 0.14-8.08). Overall, 38% of patients receiving obinutuzumab compared with 16% of patients receiving placebo achieved CRR at week 76 while receiving 7.5 mg or less per day of prednisone (P < 0.01); at week 104, the difference did not achieve significance (38% vs 22%; P = 0.06). CONCLUSION: Post hoc analyses of NOBILITY demonstrated that compared with standard-of-care therapy, obinutuzumab treatment resulted in superior preservation of kidney function and prevention of LN flares. More patients achieved CRR at week 76 with less glucocorticoid use in the obinutuzumab group.

Designing a public access naloxone program for public transportation stations.

The opioid overdose epidemic has caused over 600,000 deaths in the U.S. since 1999. Public access naloxone programs show great potential as a strategy for reducing opioid overdose-related deaths. However, their implementation within public transit stations, often characterized as opioid overdose hotspots, has been limited, partly because of a lack of understanding in how to structure such programs. Here, we propose a comprehensive framework for implementing public access naloxone programs at public transit stations to curb opioid overdose-related deaths. The framework, tailored to local contexts, relies on coordination between local public health organizations to provide naloxone at public access points and bystander training, local academic institutions to oversee program evaluation, and public transit organizations to manage naloxone maintenance. We use the city of Cambridge, Massachusetts as a case study to demonstrate how it and other municipalities may implement such an initiative.

Obinutuzumab Effectively Depletes Key B-cell Subsets in Blood and Tissue in End-stage Renal Disease Patients.

The THEORY study evaluated the effects of single and multiple doses of obinutuzumab, a type 2 anti-CD20 antibody that induces antibody-dependent cell-mediated cytotoxicity and direct cell death, in combination with standard of care in patients with end-stage renal disease. Methods: We measured B-cell subsets and protein biomarkers of B-cell activity in peripheral blood before and after obinutuzumab administration in THEORY patients, and B-cell subsets in lymph nodes in THEORY patients and an untreated comparator cohort. Results: Obinutuzumab treatment resulted in a rapid loss of B-cell subsets (including naive B, memory B, double-negative, immunoglobulin D+ transitional cells, and plasmablasts/plasma cells) in peripheral blood and tissue. This loss of B cells was associated with increased B cell-activating factor and decreased CXCL13 levels in circulation. Conclusions: Our data further characterize the mechanistic profile of obinutuzumab and suggest that it may elicit greater efficacy in indications such as lupus where B-cell targeting therapeutics are limited by the resistance of pathogenic tissue B cells to depletion.

B-cell depletion with obinutuzumab for the treatment of proliferative lupus nephritis: a randomised, double-blind, placebo-controlled trial.

OBJECTIVE: Randomised trials of type I anti-CD20 antibodies rituximab and ocrelizumab failed to show benefit in proliferative lupus nephritis (LN). We compared obinutuzumab, a humanised type II anti-CD20 monoclonal antibody that induces potent B-cell depletion, with placebo for the treatment of LN in combination with standard therapies. METHODS: Patients with LN receiving mycophenolate and corticosteroids were randomised to obinutuzumab 1000 mg or placebo on day 1 and weeks 2, 24 and 26, and followed through week 104. The primary endpoint was complete renal response (CRR) at week 52. Exploratory analyses through week 104 were conducted. The prespecified alpha level was 0.2. RESULTS: A total of 125 patients were randomised and received blinded infusions. Achievement of CRR was greater with obinutuzumab at week 52 (primary endpoint, 22 (35%) vs 14 (23%) with placebo; percentage difference, 12% (95% CI -3.4% to 28%), p=0.115) and at week 104 (26 (41%) vs 14 (23%); percentage difference, 19% (95% CI 2.7% to 35%), p=0.026). Improvements in other renal response measures, serologies, estimated glomerular filtration rate and proteinuria were greater with obinutuzumab. Obinutuzumab was not associated with increases in serious adverse events, serious infections or deaths. Non-serious infusion-related reactions occurred more frequently with obinutuzumab. CONCLUSIONS: Improved renal responses through week 104 were observed in patients with LN who received obinutuzumab plus standard therapies compared with standard therapies alone. Obinutuzumab was well tolerated and no new safety signals were identified. TRIAL REGISTRATION NUMBER: NCT02550652.

Two-Year Safety and Effectiveness of Peficitinib in Moderate-To-Severe Rheumatoid Arthritis: A Phase IIb, Open-Label Extension Study.

INTRODUCTION: Peficitinib is a novel orally bioavailable, once-daily Janus kinase (JAK) inhibitor approved in Japan for the treatment of rheumatoid arthritis (RA). This 2-year extension study of two global phase IIb trials investigated the long-term safety and effectiveness of peficitinib. METHODS: All eligible patients with moderate-to-severe RA including patients in the placebo group who participated in one of two global phase IIb trials ('with methotrexate' or 'without methotrexate') were included in this 2-year open-label extension study and were converted to peficitinib 100 mg once daily. The primary objective was to evaluate an additional 2 years of safety by assessing treatment-emergent adverse events (AEs) and clinical laboratory evaluations for 105 weeks. Evaluation of an additional 2 years of effectiveness using American College of Rheumatology (ACR) 20/50/70 responses was the exploratory objective. RESULTS: Overall, 611 patients were enrolled in the extension study: 319 (52.2%) patients completed the study and 292 (48%) discontinued treatment, including for withdrawal of patient consent (n = 96), failure to achieve low disease activity (n = 62), and AE not including death (n = 41). AEs were reported in 463 (76%) patients. The most common AEs (per 100 patient-years) were upper respiratory tract infections (9.9) and urinary tract infections (7.2). Serious AEs were reported in 80 (13%) patients, with incidences per 100 patient-years of serious infections 2.7, herpes zoster 1.5 (including one herpes zoster ophthalmic), and malignancies 0.6 (most frequently basal cell carcinoma). At week 105, 269 (44%) patients demonstrated an ACR20 response relative to their respective phase IIb trial baselines. CONCLUSION: Among 319 patients who completed this 2-year extension of two global phase IIb studies, peficitinib 100 mg once daily demonstrated a stable safety profile and sustained effectiveness in patients with moderate-to-severe RA. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT01711814. Registered 19 October 2012. FUNDING: Astellas Pharma Global Development, Inc.

Outcome of participants with nephrotic syndrome in combined clinical trials of lupus nephritis.

OBJECTIVE: The outcome of participants with nephrotic syndrome in clinical trials of lupus nephritis has not been studied in detail. METHODS: Collated data from two randomised controlled trials in lupus nephritis, Lupus Nephritis Assessment of Rituximab (LUNAR) and A Study to Evaluate Ocrelizumab in Patients With Nephritis due to Systemic Lupus Erythematosus (BELONG) were analysed. Nephrotic syndrome was defined as albumin <3 g/dL and urine protein/creatinine ratio ≥3.5 g/g at start of trial. Renal response was defined as a first morning urine protein/creatinine ratio ≤0.5 g/g in addition to ≤25% increase in creatinine from trial entry assessed at week 48. Logistic regression was used to evaluate the association of nephrotic syndrome with renal response while adjusting for treatment received and ACE inhibitor or angiotensin receptor blocker use. RESULTS: 28 (26%) participants with nephrotic syndrome achieved renal response as compared with 130 (52.5%) of those without (p<0.001). Having nephrotic syndrome at baseline significantly lowered the likelihood of achieving renal response (OR 0.32, 95 % CI 0.19 to 0.54, p<0.001). 125 (80%) participants achieved resolution of their nephrotic syndrome in a median time of 16 weeks. CONCLUSIONS: Nephrotic syndrome at baseline decreases the likelihood of renal response at 1 year. Longer clinical trials or better short-term predictors of long-term outcomes may better assess the effect of novel therapeutic approaches on subjects with nephrotic syndrome.

Peripheral Blood B Cell Depletion after Rituximab and Complete Response in Lupus Nephritis.

BACKGROUND AND OBJECTIVES: Incomplete peripheral blood B cell depletion after rituximab in lupus nephritis might correlate with inability to reduce tubulointerstitial lymphoid aggregates in the kidney, which together could be responsible for inadequate response to treatment. We utilized data from the Lupus Nephritis Assessment with Rituximab (LUNAR) study to characterize the variability of peripheral blood B cell depletion after rituximab and assess its association with complete response in patients with lupus nephritis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We analyzed 68 participants treated with rituximab. Peripheral blood B cell depletion was defined as 0 cells/µl, termed "complete peripheral depletion," assessed over 78 weeks. Logistic regression was used to estimate the association between characteristics of complete peripheral depletion and complete response (defined as urine protein-to-creatinine ratio <0.5 mg/mg, and normal serum creatinine or an increase in creatinine <15%, if normal at baseline), assessed at week 78. RESULTS: A total of 53 (78%) participants achieved complete peripheral depletion (0 cells/µl) in a median time of 182 days (interquartile range, 80-339).The median duration of complete peripheral depletion was 71 days (interquartile range, 14-158). Twenty-five (47%) participants with complete peripheral depletion achieved complete response, compared with two (13%) without. Complete peripheral depletion was associated with complete response (unadjusted odds ratio [OR], 5.8; 95% confidence interval [95% CI], 1.2 to 28; P=0.03). Longer time to achieving complete peripheral depletion was associated with a lower likelihood of complete response (unadjusted OR, 0.89; 95% CI, 0.81 to 0.98; P=0.02). Complete peripheral depletion lasting >71 days (the median) was associated with complete response (unadjusted OR, 4.1; 95% CI, 1.5 to 11; P=0.008). CONCLUSIONS: There was substantial variability in peripheral blood B cell depletion in patients with lupus nephritis treated with rituximab from the LUNAR trial. Achievement of complete peripheral depletion, as well as the rapidity and duration of complete peripheral depletion, were associated with complete response at week 78. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2018_09_06_CJASNPodcast_18_10_.mp3.

The Effect of Verapamil, a P-Glycoprotein Inhibitor, on the Pharmacokinetics of Peficitinib, an Orally Administered, Once-Daily JAK Inhibitor.

Peficitinib is an orally administered, once-daily Janus kinase inhibitor currently in development for the treatment of rheumatoid arthritis. It has been shown to be a P-glycoprotein (P-gp) substrate in vitro. The effects of verapamil, an inhibitor of the efflux pump P-gp, on the pharmacokinetic profile of peficitinib were assessed in this open-label, single-center, single-sequence, crossover drug-interaction study. Twenty-four healthy volunteers received a single 150-mg dose of peficitinib on days 1 and 12 of a 14-day treatment period and received verapamil 80 mg 3 times daily on days 5-14. Repeated-dose administration of verapamil increased mean peficitinib AUCinf , AUClast , and Cmax by 27%, 27%, and 39%, respectively, and also increased the mean AUC and Cmax of peficitinib metabolites H1, H2, and H4. Coadministration of verapamil with peficitinib 150 mg was generally well tolerated. Overall, the most commonly reported adverse event was headache, which occurred in 5 subjects (21%); all reported adverse events were grade 1 severity, with the exception of 1 grade 2 incident of vomiting.

Peficitinib, a JAK Inhibitor, in Combination With Limited Conventional Synthetic Disease-Modifying Antirheumatic Drugs in the Treatment of Moderate-to-Severe Rheumatoid Arthritis.

OBJECTIVE: To evaluate the efficacy and safety of orally administered once-daily peficitinib in combination with limited conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) in patients with moderate-to-severe rheumatoid arthritis (RA). METHODS: In this randomized, double-blind, phase IIb trial, patients with RA (n = 289) were treated with peficitinib 25 mg, 50 mg, 100 mg, or 150 mg or matching placebo once daily for 12 weeks. The primary end point was the percentage of patients who met the American College of Rheumatology 20% improvement criteria (achieved an ACR20 response) at week 12. RESULTS: ACR20 response rates at week 12 were 22.0%, 36.8%, 48.3% (P < 0.05), 56.3% (P < 0.01), and 29.4% in the peficitinib 25 mg, 50 mg, 100 mg, 150 mg, and placebo groups, respectively. Patients in the peficitinib 100 mg and 150 mg groups achieved a rapid and statistically significant ACR20 response compared with those in the placebo group (P < 0.05), reaching statistical significance by week 2. Overall, the incidence of adverse events (AEs) was similar between patients receiving peficitinib and those receiving placebo. The most common AEs were upper respiratory tract infection (5% [n = 15]), nausea (4% [n = 12]), and urinary tract infection (4% [n = 10]). There was 1 case of herpes zoster in the placebo group, and 1 serious infection (limb abscess) in the peficitinib 25 mg group. There were no incidences of grade 2 or higher neutropenia or lymphopenia. CONCLUSION: In patients with moderate-to-severe RA, orally administered once-daily peficitinib in combination with limited csDMARDs resulted in a dose-dependent ACR20 response rate over 12 weeks with satisfactory tolerability.

Drug Interactions Between Peficitinib, an Orally Administered, Once-Daily Janus Kinase Inhibitor, and Rosuvastatin in Healthy Subjects.

BACKGROUND AND OBJECTIVE: Peficitinib is an orally administered, once-daily Janus kinase inhibitor in development for the treatment of rheumatoid arthritis. Peficitinib and its major metabolite H2 inhibit the hepatic uptake transporter organic anion transporting polypeptide 1B1 (OATP1B1) in vitro. This article reports a clinical study evaluating the effects of peficitinib on the pharmacokinetics of rosuvastatin, a substrate for the OATP1B1 transporter, and vice versa. METHODS: In an open-label, single-sequence clinical study, 24 healthy adults of East Asian and non-East Asian origin received a single dose of rosuvastatin 10 mg on days 1 and 10. On days 5-13, subjects received a daily dose of 150 mg peficitinib. Serial blood samples for pharmacokinetic assessment of rosuvastatin were collected up to 96 h post-dose on days 1 and 10, and for peficitinib were collected up to 24 h post-dose on days 9 and 10. RESULTS: Co-administration of peficitinib with rosuvastatin increased rosuvastatin area under the concentration-time curve (AUC) and maximum plasma concentration (C max) by 18 and 15%, respectively and increased peficitinib AUC and C max by 16 and 28%, respectively. In East Asian (n = 6) vs. non-East Asian subjects (n = 18), peficitinib mean AUC for a dosing interval was 45 and 21% higher, and mean C max was 67 and 34% higher, when administered alone or with rosuvastatin. Peficitinib was well tolerated with few adverse events overall. CONCLUSION: In this study, once-daily oral administration of peficitinib had no clinically significant effect on the pharmacokinetics of rosuvastatin, a probe substrate for OATP1B1. Therefore, it is unlikely that peficitinib will have a clinically significant effect on the exposure of other substrates for OATP1B1. CLINICALTRIALS. GOV NUMBER: NCT01959399.

Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of ASP2408, a Potent Selective T-Cell Costimulation Modulator After Single and Multiple Ascending Doses in Healthy Volunteers and RA Patients.

ASP2408 is a next-generation anti-cytotoxic T lymphocyte antigen-4 fusion protein engineered for improved CD86 binding affinity as a treatment for rheumatoid arthritis (RA). In 72 healthy subjects (n = 6/treatment), ASP2408 was administered as single ascending doses intravenously at 0.003 to 10.0 mg/kg or subcutaneously at 0.3 to 3.0 mg/kg. It showed decreased clearance and prolonged half-life with increasing doses, consistent with target-mediated disposition. The apparent bioavailability was 36.3%-56.7% across single subcutaneous doses. Sixteen RA patients (n = 8/treatment) on stable methotrexate received 3 × 3.0 mg/kg subcutaneously every 4 weeks or every 2 weeks. Similar to single-dose treatment, ASP2408 concentrations peaked 2 to 3 days postdose, with a median t1/2 of approximately 8 days. Using CD86 receptor occupancy (RO) as a mechanistic biomarker, ASP2408 demonstrated dose-dependent binding to its target. ASP2408 3.0 mg/kg subcutaneously every 4 weeks and every 2 weeks led to a mean %CD86 RO ≥ 74.7% and ≥ 81.5%, respectively, within each dosing interval. ASP2408 was well tolerated across studies with no evidence of dose-limiting toxicity or clinically significant changes in clinical laboratory test results, vital signs, or 12-lead electrocardiograms. ASP2408 elicited antidrug antibodies in the majority of patients, but with no clinical sequelae.

A Phase 1 Dose-Escalation Study of ASP2409, a Selective T-Cell Costimulation Inhibitor, in Stable Rheumatoid Arthritis Patients on Methotrexate Therapy.

ASP2409 represents a new class of CTLA4-Ig molecules with higher binding avidity and selectivity to CD86. This first-in-human study was to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of ASP2409 in stable rheumatoid arthritis patients on methotrexate therapy with a randomized, double-blind, placebo-controlled dose-escalation study design. Patients were enrolled and randomized in each of 8 dose-escalation cohorts ranging from 0.001 to 3.0 mg/kg to receive either ASP2409 or placebo in a sequential manner. Escalation to higher dose levels occurred in the absence of dose-limiting toxicity. A total of 57 patients completed the study. ASP2409 showed nonlinear PK over the dose range of 0.01 to 3.0 mg/kg following a single intravenous administration, indicating target-mediated drug disposition. Area under the concentration-time curve (AUC) and maximum concentration (Cmax ) increased at a greater than dose-proportional rate. The half-life of ASP2409 increased dose dependently and ranged from 1.57 to 6.68 days. ASP2409 showed a dose-dependent increase in the extent and duration of CD86 receptor occupancy. There were no clinically relevant safety issues up to a single dose of 3.0 mg/kg. No maximum tolerated dose was reached. The incidence and duration of antidrug antibodies did not correlate with adverse events. ClinicalTrials.gov identifier: NCT02171143.

Targeting Cell Death Pathways for Therapeutic Intervention in Kidney Diseases.

Precise regulation of cell death and survival is essential for proper maintenance of organismal homeostasis, development, and the immune system. Deregulated cell death can lead to developmental defects, neuropathies, infections, and cancer. Kidney diseases, especially acute pathologies linked to ischemia-reperfusion injury, are among illnesses that profoundly are affected by improper regulation or execution of cell death pathways. Attempts to develop medicines for kidney diseases have been impacted by the complexity of these pathologies given the heterogeneous patient population and diverse etiologies. By analyzing cell death pathways activated in kidney diseases, we attempt to differentiate their importance for these pathologies with a goal of identifying those that have more profound impact and the best therapeutic potential. Although classic apoptosis still might be important, regulated necrosis pathways including necroptosis, ferroptosis, parthanatos, and mitochondrial permeability transition-associated cell death play a significantly role in kidney diseases, especially in acute kidney pathologies. Although targeting receptor-interacting protein 1 kinase appears to be the best therapeutic strategy, combination with inhibitors of other cell death pathways is likely to bring superior benefit and possible cure to patients suffering from kidney diseases.

Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: the Lupus Nephritis Assessment with Rituximab study.

OBJECTIVE: To evaluate the efficacy and safety of rituximab in a randomized, double-blind, placebo-controlled phase III trial in patients with lupus nephritis treated concomitantly with mycophenolate mofetil (MMF) and corticosteroids. METHODS: Patients (n = 144) with class III or class IV lupus nephritis were randomized 1:1 to receive rituximab (1,000 mg) or placebo on days 1, 15, 168, and 182. The primary end point was renal response status at week 52. RESULTS: Rituximab depleted peripheral CD19+ B cells in 71 of 72 patients. The overall (complete and partial) renal response rates were 45.8% among the 72 patients receiving placebo and 56.9% among the 72 patients receiving rituximab (P = 0.18); partial responses accounted for most of the difference. The primary end point (superior response rate with rituximab) was not achieved. Eight placebo-treated patients and no rituximab-treated patients required cyclophosphamide rescue therapy through week 52. Statistically significant improvements in serum complement C3, C4, and anti-double-stranded DNA (anti-dsDNA) levels were observed among patients treated with rituximab. In both treatment groups, a reduction in anti-dsDNA levels greater than the median reduction was associated with reduced proteinuria. The rates of serious adverse events, including infections, were similar in both groups. Neutropenia, leukopenia, and hypotension occurred more frequently in the rituximab group. CONCLUSION: Although rituximab therapy led to more responders and greater reductions in anti-dsDNA and C3/C4 levels, it did not improve clinical outcomes after 1 year of treatment. The combination of rituximab with MMF and corticosteroids did not result in any new or unexpected safety signals.

Economic outcomes in patients diagnosed with systemic lupus erythematosus with versus without nephritis: results from an analysis of data from a US claims database.

BACKGROUND: Based on a literature search, there are limited data on the economic burden of systemic lupus erythematosus (SLE), particularly in patients with lupus nephritis. OBJECTIVE: The objective of this study was to compare health care resource utilization and direct medical care costs over a period of 12 months in patients with a history of SLE with or without nephritis. METHODS: Patients aged >or=18 years with >or=1 claim for an immunosuppressive/disease-modifying antirheumatic drug, antimalarial agent, NSAID/cyclooxygenase-2 inhibitor, or other SLE-related treatment (eg, opioid and combination analgesic, antianxiety agent, antihyperlipidemic agent, antihypertensive agent, bisphosphonate, vitamin D) dated between January 1, 2007, and December 31, 2007, were identified using a nationally representative, US commercial insurance claims database. The date of the first dispensation of the treatment represented the index date. Patients were required to have >or=2 claims containing a diagnosis of SLE during a 6-month preindex period through 3 months postindex and to have continuous health plan enrollment for 6 months before and 12 months after the index date. Patients with >or=1 claim containing a diagnosis of nephritis during the preindex period were identified. Health care resource utilization and direct medical care cost data were assessed over a period of 12 months; paid amounts were used as a proxy for costs and were expressed in year-2008 US dollars. RESULTS: A total of 15,590 patients with SLE were identified (13,828 women, 1762 men; mean age, 48 years); 1068 (6.9%) had a history of nephritis. The mean age of patients with SLE without nephritis was significantly greater compared with the group with nephritis (47.9 vs 46.5 years, respectively; P < 0.001), and a greater proportion of this group were women (89.0% vs 84.7%; P < 0.001). Over a period of 12 months, 30.3% of patients with nephritis were hospitalized compared with 13.6% of those without nephritis (P < 0.001); the mean lengths of hospital stays were 16.52 and 9.69 days (P < 0.001) in patients with and without nephritis, respectively. Patients with nephritis also underwent more outpatient laboratory tests (mean, 64.42 vs 30.96; P < 0.001) and had a significantly higher mean number of intravenous infusions (mean, 1.7 vs 1.1; P < 0.001), and total 12-month follow-up costs were significantly greater in patients with nephritis compared with those without nephritis (mean, $30,652 vs $12,029; P < 0.001). Costs associated with inpatient and outpatient care were 252% and 146% higher in patients with SLE with nephritis, respectively. Outpatient costs were associated with approximately half of the total costs in patients with or without nephritis; pharmacy costs accounted for 20% of the total costs in patients with SLE and nephritis and 27% of total costs among those without nephritis. Significantly higher costs also were found in patients with nephritis when only SLE-related costs were assessed and after differences in patient characteristics and comorbidities were adjusted through multivariate analyses (all, P < 0.05). CONCLUSIONS: The present data analysis found that patients with SLE with nephritis consumed significantly more health care resources, with >2.5-fold the costs, compared with those without nephritis. The majority (84%) of added costs were attributable to inpatient hospitalizations and outpatient services, and 16% were attributable to pharmacy services.

Thiazide diuretics, potassium, and the development of diabetes: a quantitative review.

National guidelines and a recent clinical trial have supported the use of thiazide diuretics as the preferred initial pharmacological treatment for hypertension. However, evidence from this and other clinical trials have also found an increased incidence of new onset diabetes among those patients receiving thiazide diuretics. The mechanisms responsible for the increased incidence of diabetes with thiazide diuretics have not been fully elucidated. This article provides a review of intervention studies that included data on the relation between thiazide-induced hypokalemia and glucose intolerance. We conducted a literature search from 1966 to June 2004 to identify clinical trials using thiazide diuretics where the metabolic effects on potassium and glucose are reported. A total of 59 clinical trials constituting 83 thiazide diuretic study arms were identified. Trial size, length, type of thiazide diuretic, and dose varied substantially among the studies. The association between average changes in potassium and glucose in the study arms is considered jointly in a weighted statistical model. The Pearson's correlation coefficient, weighted by study sample size, for the relationship between glucose and potassium was -0.54 (95% CI, -0.67 to -0.36; P < 0.01). A sensitivity analysis, which considered subset analyses and effect of covariates, as well as inverse-variance weighting, supported this finding. These data suggest that thiazide-induced hypokalemia is associated with increased blood glucose. Treatment of thiazide-induced hypokalemia may reverse glucose intolerance and possibly prevent the future development of diabetes.

Angiotensin receptor blockade and arterial compliance in chronic kidney disease: a pilot study.

BACKGROUND: Almost 20 million people in the US have chronic kidney disease (CKD). Cardiovascular disease and arterial wall abnormalities are common in this population. Because angiotensin II may have adverse effects on the arterial wall, we hypothesized that an angiotensin receptor blocker (ARB) would improve arterial compliance as compared with placebo in subjects with CKD. METHODS: We performed a double-blinded, placebo-controlled pilot study in which 25 subjects with stages 2 or 3 CKD and proteinuria <1 g were randomized to either the ARB, eprosartan, or placebo and titrated to achieve a goal blood pressure (BP) <130/85 mm Hg. Arterial compliance was measured at baseline and at 8 weeks. RESULTS: Baseline characteristics were similar between the groups and included mean estimated glomerular filtration rate 63 +/- 14 ml/min/1.73 m(2), heart rate 76 +/- 10 beats/min, BP 142 +/- 12/81 +/- 8 mm Hg, 64% diabetic, 44% male, and 40% white, though subjects in the eprosartan group were younger (60 +/- 12 vs. 70 +/- 6 years, p = 0.01). There were no significant differences between the groups in large or small artery compliance measurements either at baseline or at 8 weeks, but there was a statistically significant improvement from baseline in small artery compliance in the eprosartan group (from median 2.5 ml/mm Hg x 100 [90% CI (1.1, 4.7)] to 4.0 ml/mm Hg x 100 [90% CI (1.9, 6.7)] (p = 0.01)) not seen in the placebo group. CONCLUSION: Use of an ARB to achieve recommended BP is associated with improved small artery compliance in people with CKD, though larger studies are needed to confirm these findings.

Resistant hypertension revisited: a comparison of two university-based cohorts.

BACKGROUND: More than a decade ago, we found that a suboptimal medication regimen was the leading cause of resistant hypertension (RH) among patients referred to a tertiary care clinic. Since then, lower blood pressure (BP) goals have been recommended, suggesting that more patients may have RH. To assess whether the reasons for and treatment of RH have changed, we determined the frequency of various causes of resistance, the proportion of patients achieving goal BP, and the changes made in antihypertensive regimens. METHODS: The charts of all new patients seen at the RUSH University Hypertension Center between January 1, 1993, and November 1, 2001, were reviewed for strict criteria for RH: 1) physician referral for uncontrolled hypertension; 2) BP > or =140/90 mmHg despite use of three antihypertensive drugs; and 3) at least one follow-up visit. Patients were followed-up until goal BP was achieved on two consecutive visits or their last visit or until March 2002. RESULTS: Of 1281 patients, 141 met criteria for RH. A cause of resistance was found in 94% of cases, including the following: drug-related causes (58%); nonadherence (16%); psychological causes (9%); office resistance (ie, in-clinic BP readings that were higher than goal despite treatment with antihypertensive medications and despite normotensive BP outside of the clinic as demonstrated by 24-h ambulatory BP monitoring) (6%); and secondary hypertension (5%). Overall, 53% of patients had their BP controlled to <140/90 mmHg, largely from regimen optimization and intensification, proper use of diuretics, and on average 4.1 +/- 1 antihypertensive medications (3.7 +/- 0.9 on referral). CONCLUSIONS: These data are strikingly similar to those from our previous study of RH, in which a suboptimal medication regimen was the most common reason for resistance. Goal BP was most commonly achieved after optimizing the diuretic regimen and increasing the number of medications, suggesting that physicians should use these measures to attain the recommended lower BP goals If goal BP is not reached, referral to a clinical hypertension specialist may be appropriate.

Effects of sevelamer and calcium-based phosphate binders on uric acid concentrations in patients undergoing hemodialysis: a randomized clinical trial.

OBJECTIVE: Gout affects a large fraction of persons with advanced chronic kidney disease, and hyperuricemia may increase the risk of cardiovascular disease. Several hypouricemic agents are contraindicated in patients with end-stage renal disease. Sevelamer is a nonabsorbed hydrogel that binds phosphorus and bile acids in the intestinal tract. Results of short-term and open-label studies suggest that sevelamer might lower the concentration of uric acid, another organic anion. We undertook this study to test our hypothesis that the reduction in serum uric acid concentration induced by sevelamer would be confirmed in a long-term, randomized, clinical trial comparing sevelamer with calcium-based phosphate binders. METHODS: Two hundred subjects undergoing maintenance hemodialysis were randomly assigned to receive either sevelamer or calcium-based phosphorus binders in an international, multicenter, clinical trial. Data on baseline and end-of-study uric acid concentrations were available in 169 subjects (85%); the change in uric acid concentration from baseline to the end of the study was the outcome of interest. RESULTS: Baseline clinical characteristics, including mean uric acid concentrations, were similar in subjects randomly assigned to receive sevelamer and calcium-based phosphate binders. The mean change in uric acid concentration (from baseline to the end of the study) was significantly larger in sevelamer-treated subjects (-0.64 mg/dl versus -0.26 mg/dl; P = 0.03). The adjusted mean change in uric acid concentration was more pronounced when the effects of age, sex, diabetes, vintage (time since initiation of dialysis), dialysis dose, and changes in blood urea nitrogen and bicarbonate concentrations were considered (-0.72 mg/dl versus -0.15 mg/dl; P = 0.001). Twenty-three percent of sevelamer-treated subjects experienced a study-related reduction in the concentration of uric acid equal to -1.5 mg/dl or more, compared with 10% of calcium-treated subjects (P = 0.02). CONCLUSION: In a randomized clinical trial comparing sevelamer and calcium-based phosphate binders, treatment with sevelamer was associated with a significant reduction in serum uric acid concentrations.